H.S. Reinhold

Human tumour pH and its variation

The variation in human tumour pH values is large. The aim of this study was to analyse the reasons for these large variations and to determine whether tumour pH can be predicted on the basis of any easily measured parameter. One hundred and five determinations of tumour pH were performed in various human tumours, using the Philips C 902S tissue pH electrode. No correlations were found between the tumour pH and the tumour histology, degree of differentiation, tumour size, patient age or treatment history, and whether or not the tumour was ulcerated. However, tumour pH was significantly lower in primary tumours than in lymph node metastases. Tumours at their primary site (primary, recurrent or residual) were also more acid than distant metastases. The vascular disruption caused by the measuring technique was found to be acceptable.

Quantitative studies of microcirculatory function in malignant tissue: Influence of temperature on microvascular hemodynamics during the early growth of the BA 1112 rat SARCOMA

Abstract Red blood cell (RBC) velocity, vessel diameter and blood flow were determined in the microcirculation of the BA 1112 sarcoma at different levels of ambient temperature. These studies were carried out in modified Algire chamber preparations utilizing television techniques in situ during a period of 7 days. At an environment temperature of 25°C, arteriolar inflow through single vessels was of the order of 10.2±4.7 × 10 −5 ml/min. As a result of increased RBC-velocity, arteriolar volume inflow through individual vessels was significantly higher at an environment temperature of 35°C (24.4±16.2 × 10−5 ml/min). In both groups, the arteriolar inflow was distributed in a similar manner. Acute hyperthermic conditions of 41.3°C decreased arteriolar inflow (3.5 ± 1.5 × 10−5 ml /min) and the number of perfused capillaries. Our findings indicate that blood supply to mesenchymal tumors can be enhanced by elevating the environmental and local temperature to 35°C. However, in comparison to room temperature conditions, the arteriolar volume inflow does not appear to perfuse an increased number of capillaries. Acute hyperthermic temperatures reduced vascularization and transparency only in the tumor portion of the chamber suggesting that microscopic blood vessels in the BA 1112 rat sarcoma can be irreversibly damaged during early growth through local application of heat.

Tumour pH in human mammary carcinoma

Human tumour pH was investigated using the new Philips C902S tissue pH electrode. In 22 mammary carcinomas a pH of 7.29 +/- 0.050 (S.E.M.) was observed, whereas in the human subcutis this value was 7.63 +/- 0.034. Tumour pH in some experimental rat tumours was slightly lower than in humans, 7.15 +/- 0.029 in rhabdomyosarcoma BA1112 and 7.07 +/- 0.024 in a small group of other miscellaneous rat tumours. Rat skeletal muscle was found to have a pH of 7.59 +/- 0.070. It is concluded that a small but highly significant (P less than 0.0001) pH difference exists between human mammary carcinoma and human subcutis. This difference is smaller than expected on the basis of animal studies.

Whole-body hyperthermia in cancer therapy: a report of a phase I–II study☆

Twenty-seven patients were treated with whole-body hyperthermia alone or in combination with either chemotherapy or radiotherapy. Whole-body hyperthermia was performed in the Pomp-Siemens cabin with hot air and a warm water mattress, the patient being covered with plastic film to avoid cooling by perspiration. The heat treatment lasted for 2 hr at 41.8-42.0 degrees C. Toxicity, such as liver damage and respiratory problems, was considerable. There were two fatalities. Hyperthermia gave an improved therapeutic effect in 6 of the patients. Considerable pain relief was observed in 8 of 10 patients. Whole-body hyperthermia at 42 degrees C can be effective but the potential toxicity limits its use to those patients with severe complaints for whom no other palliative treatment is available.

Enhancement of thermal damage to the microcirculation of ‘sandwich’ tumours by additional treatment

The effects of hyperthermia on tumour microcirculation were investigated. For this purpose, transparent tumours were grown in the ‘sandwich’ system in the dorsal skin flap of the rat (Rhabdomyosarcoma BA1112 in WAG/Rij rats). Heating was performed with air; the temperature of the cover slip overlying the tumour was kept at either 42.5° or 42°C by means of an electronic controller. Evaluation of the effect was based on microscopic observation and photographic recordings and was expressed as the proportion of tumours with intact microcirculation, i.e., the proportion of tumours not showing heat damage. The results indicate that, at 42.5°C after a latent period of about 1 hr, the microcirculation of the tumours begins to slow down. At the end of a treatment time of 180 min, about 70% of the tumours show microcirculatory damage. It appears that some time is required before the majority of the tumours show heat damage. The effect is still essentially the same at 42°C, but the damage is to a much lesser extent. When the animals received additional treatment, i.e. misonidazole, glucose or 5-thio- d-glucose, the damaging effect of the hyperthermic treatment at 42°C appeared to be increased. The effects of all combined treatments approximated the degree of inactivation obtained with 42.5°C treatment.

Cardiovascular changes during whole body hyperthermia treatment of advanced malignancy

SummaryCardiovascular studies were carried out on patients subjected to whole body hyperthermia treatment for advanced malignancy in order to assess the magnitude of the changes occurring and the degree of strain imposed on the system. The subjects, who were anaesthetised with a nitrous oxide/oxygen and relaxant sequence, were heated in a modified Siemens hyperthermia cabin and maintained at a body temperature of 41.8‡ C for 2 h. The results of 30 treatments are presented. Large increases in cardiac output and heart rate were accompanied by large decreases in peripheral resistance in both the systemic and pulmonary vascular beds. The pulmonary arterial pressure rose whereas that in the systemic circulation fell. This caused right ventricular work to increase proportionately more than left ventricular work. Care should be exercised when subjecting patients with limited right ventricular function to this treatment.

Radiofrequency capacitive heating of deep-seated tumours using pre-cooling of the subcutaneous tissues: Results on thermometry in Dutch patients

The capacity of a radiofrequency, 13.56 MHz, capacitive hyperthermia system using extensive pre-cooling of the subcutaneous tissue to induce locoregional deep heating has been investigated in 11 patients. Tumour location was presacral in nine--and eccentric towards the lateral side of the pelvis in two patients. For thermometry multiple catheters (mean 2.7) were inserted into the treatment volume. The mean numbers of temperature measuring points per treatment were 9.4 in tumour, 5.5 in muscle and 7.2 in subcutaneous fat. RF energy was applied after 30 min of cooling through two flexible boli perfused with saline water at 5-10 degrees C. Patient tolerance to pre-cooling was very good and after some initial discomfort the patient became rapidly accustomed to the cold water boli. For some patients better temperatures were achieved when the conventional anterior-posterior applicator set-up was replaced by a set-up with an applicator on each lateral side of the patient. As patients can tolerate temperatures within the fat tissue as high as 45.5 degrees C without complaining it appears important to monitor the temperature at the transition of fat to muscle tissue to prevent subcutaneous burns. The study shows that pre-cooling cannot avoid preferential heating at the interface from fat to muscle tissue. In this patient group the quality of the hyperthermia treatment appeared to be rather poor: 60% of the measured tumour temperatures were below 40 degrees D.

The use of implanted closed-tip catheters for the introduction of thermometry probes during local hyperthermia treatment series

In the past two and a half years custom-made closed-tip catheters have been used to allow extensive temperature monitoring with multi-junction thermocouple probes during local hyperthermia. Data from animal experiments indicate that the use of thermometry probes within such a catheter provides reliable temperature measurements. In order to reduce stress to the patient the catheters were fixed so that they could stay in place during the total treatment series. The catheters, outer diameter 1.22 mm, were introduced through hollow needles under sterile conditions before the first hyperthermia session, and fixed using Histo-acryl (tissue adhesive) and Tegaderm (transparent adhesive). Recently, the data concerning the first 180 catheters placed in 74 treatment areas were evaluated. In one patient, an abscess developed 10 days after removal of the (3) catheters, which required surgical intervention, but it was not clear whether these problems had developed as a result of catheter placement. There were no problems with 139 of the remaining 177 catheters (79 per cent) and in 50 treatment fields (68 per cent), respectively, for a duration of 9-55 (mean 23) days. Ten catheters (6 per cent) were lost during the treatment series after 1-22 (mean 10) days. With 28 catheters (16 per cent) infection was observed, 14-27 (mean 19) days after insertion, which necessitated catheter removal before the last treatment session in 11 cases (6 per cent). The complication rate decreased with increasing experience; from 29 per cent (25/85) in the early period to 14 per cent (13/92) in the later period. We conclude that the use of closed-tip catheters under proper control generally causes few, if any, problems. This results in the acquisition of a substantial amount of reliable temperature data at reproducible sites, and it is well tolerated by the patient.

A ring capacitor applicator in hyperthermia: energy distributions in a fat-muscle layered model for different ring electrode configurations

The energy deposition pattern within a radially layered fat-muscle phantom, diameter 135 mm, heated by a novel ring capacitor applicator has been determined experimentally as well as theoretically. Good to excellent agreement is found between measured and predicted energy distributions. For the specific absorption rate in the muscle tissue the differences are in general smaller than 6%. When the ring electrodes are placed directly on the phantom surface both measured and predicted energy distributions show the presence of superficial hot spots located within the fat layer at the site of the ring electrodes. The theoretical distributions showed that the radial component of the E-field contributes for more than 90% to the energy absorption at the hot spot in the fatty tissue in front of the ring electrodes. Introducing a small air gap (10 mm) between the phantom surface and the ring electrode results in a decrease of the energy absorption within the fatty tissue at the hot spot location by 30%. Further theoretical analysis of the energy distribution within the inhomogeneous model showed that the intensity of the hot spots at the ring electrodes can be controlled by adjustment of the applicator configuration. Independent of the size of the electrode to phantom gap the specific absorption rate values predicted in the fat-muscle model show a more favorable distribution at a frequency of 27.12 MHz than at 13.56 MHz. For a similar electrode to phantom gap the specific absorption rate within the fatty tissue is approximately two times lower at 27.12 than at 13.56 MHz. For the model calculations performed the best ratio of fat to muscle SAR (0.2) is obtained with distilled water as bolus medium in the gap.

Evaluation of calculated temperature distributions for a 27 MHz ridged waveguide used in localized deep hyperthermia.

The computational model developed by van den Berg has been used to perform two-dimensional simulations of tissue-equivalent phantoms heated by a 27 MHz ridged waveguide. The program is able to calculate temperature distributions for realistic inhomogenous tissue configurations (as derived from CT scans) in about 20 min on a PDP 11-44. Results for tissue-equivalent phantoms are evaluated with respect to their accuracy in predicting actual temperature distributions by comparing them with measured temperature distributions. In general the computer simulation tends to overestimate the depth of penetration; this can be ascribed to the two dimensional approach followed which does not take into account the divergence of the electric field in the third dimension. This effect can to a certain degree be compensated by assigning a higher value for the electrical conductivity of the medium. For homogenous phantoms this results in a satisfactory agreement between measured and calculated temperature distributions. Furthermore, a correct approximation for the electric field distribution over the aperture appears to be of importance, since it significantly influences the calculation results, especially for waveguide loads whose size exceeds the width of the ridge area. For inhomogeneous media the simulation results, using realistic (literature) values for the electrical conductivity, can be used with these limitations in mind, as a best-case estimate of the absorbed power distribution at depth. For more accurate simulations a three-dimensional computer model is ultimately needed.