Vortex configurations, matching, and domain structure in large arrays of artificial pinning centers.

High-resolution scanning Hall probe microscopy has been used to image vortex configurations in very large periodic arrays of artificial pinning sites. Strong matching effects are seen at fields where either one or two vortices can sit at a site; with three vortices per site, however, no clear matching is observed. Matching effects have also been observed at several fractional multiples of the matching field, including 1/5, 1/4, 1/3, 1/2, and 3/4. These fractional values are characterized by striking domain structure and grain boundaries.

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.

PURPOSE: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Effect of vasoactive drugs on tumour blood flow as determined by 2H nuclear magnetic resonance spectroscopy.

A selective reduction in tumour blood flow (TBF) could enhance the effects of hyperthermia treatment and of drugs toxic to hypoxic cells. Vasodilator-induced changes in TBF were monitored in transplanted rat fibrosarcomas by non-invasively measuring the uptake of D2O using 2H nuclear magnetic resonance spectroscopy. Hydralazine (1 or 5 mg kg-1) caused a large (45%) reduction in mean arterial blood pressure (MABP) and a 40-60% reduction in TBF. Low-dose hydralazine (0.1 mg kg-1) caused a 20% reduction in MABP but no significant change in TBF. The doses of prazosin (1 mg kg-1) and calcitonin-gene related peptide (CGRP, 1 nmol kg-1) which caused a 20% reduction in MABP led to a 50-60% reduction in TBF. These results demonstrate the advantage of prazosin and CGRP over hydralazine for the reduction of TBF despite a small hypotensive effect. CGRP may be the most suitable of these agents for clinical use because of its short physiological half-life.

From hydralazine to CGRP to man?

Attempts to selectively reduce tumour blood flow have, in the past, concentrated on the use of hydralazine. However, although this vasodilator can be highly effective in experimental animals, it is only at such high concentration as to result in a severe and clinically unacceptable reduction in systemic blood pressure. At clinically acceptable levels, the drug appears to produce a small increase in tumour blood flow. We have used the techniques of magnetic resonance spectroscopy as indicators of metabolism and blood flow in a search for vasoactive drugs that would produce an effective reduction in tumour blood flow without causing severe hypotension or other serious side effects. Single injections of either prazosin or CGRP are shown to be substantially more effective than hydralazine in causing a reduction in tumour blood flow without massive reduction in blood pressure. Even more effective was CGRP given by continuous infusion. In this case a three-fold reduction in tumour blood flow could be obtained with a reduction of only 15-20% in systemic blood pressure. All these studies, however, have been made with transplanted animal tumours. Using high-dose hydralazine and primary tumours that were either radiation or chemically induced, we obtained a success rate of only about a 35% in causing selective reduction in blood flow. In contrast, in a transplanted tumour line derived from one of the non-responding radiation-induced primary lesions, the success rate was about 95%, consistent with the majority of animal studies using transplanted tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours.

Using 31P NMR spectroscopy, changes in tumour metabolic status were studied in a transplanted rat fibrosarcoma following the administration of vasodilators. Mean Arterial Blood Pressure (MABP) was monitored simultaneously. Two vasodilators were studied, prazosin and CGRP, which altered the NMR parameters Pi/sigma P, beta NTP,Pi, PCr/Pi and PME/Pi in a dose dependent manner. There was a good correlation between the various NMR parameters; for analysis, Pi/sigma P was used for convenience. With increasing doses of vasodilator, Pi/sigma P increased and the MABP decreased. Reduction in pHNMR showed a correlation with decreasing MABP following the administration of prazosin but not after CGRP. Both prazosin and CGRP produced changes in 31P NMR spectra consistent with a reduction in tumour blood flow. The results for prazosin and CGRP were comparable and showed a 15-20% increase in Pi/sigma P for a 20% reduction in MABP. These results were compared with those from hydralazine. With hydralazine an acceptable reduction in blood pressure (up to approximately 25%) has little effect and may even alter NMR parameters consistent with an increase in blood flow, a reduction of approximately 40% is required for a significant decrease in flow. Both prazosin and CGRP are shown to be far more effective than hydralazine in causing tumour hypoxia at a clinically acceptable reduction in blood pressure. CGRP may be the more suitable for clinical use because of its short half life, its capability to achieve controlled hypotension and the relatively few side effects associated with its use.

Differences in vascular response between primary and transplanted tumours.

The vast majority of studies on tumour vasculature are performed on transplanted tumours in rodents. However, it is known that there may be differences between primary and transplanted lesions. The purpose of this study is to test whether a specific vascular response is similar in primary tumours and in transplanted tumours derived from them. The technique used was to give an intraperitoneal injection of 5 mg kg-1 hydralazine, which is known to result in hypoxia in transplanted tumours. Changes in perfusion were indicated by changes in metabolism, monitored using 31P Magnetic Resonance Spectroscopy. The primary tumours were induced by local irradiation many months previously and only 4/11 (36%) of these responded to hydralazine. One of the non responders was subsequently transplanted into isogeneic mice to produce a tumour line which was histologically very similar to the primary. Of these 16/17 (94%) responded. The difference is statistically significant (P = 0.001). The reasons for this difference are not known. A number of possibilities are discussed and in the authors' opinion, the most likely cause is that it results from an artefact of transplantation.

Treatment of menorrhagia by radiofrequency heating.

A new technique is described for the treatment of menorrhagia by heating the whole of the endometrial cavity of the uterus. A capacitively coupled probe at 27.12 MHz is inserted into the uterine cavity, which causes the basilis layer to be raised to approximately 50-55 degrees C whilst the rest of the pelvic contents remain at approximately normal (body) temperature. A major advantage of the method is that no special hysteroscopic skills are required, unlike the two other techniques currently used for endometrial ablation: the Nd-Yag laser or the hysteroresectoscopic loop. Also no toxic flushing/distension fluids are necessary, as are required for all hysteroscopic surgery. The method, however, does require the application of a large amount of RF power to the probe and so care must be taken to position the probe correctly in order to prevent any serious complications. Of 32 patients given a single treatment at a power level of 550 W for 20 min, the 'success rate' was 84% with 31% becoming amenhorrhoiec and 53% showing significant reduction in menstrual bleeding. However, retreatment is possible and by this means, combined with improved treatment techniques, an even higher success rate could be achieved. In two of the earlier patients treated at 550 W a fistula was produced at the anterior vaginal wall which had to be surgically repaired. The probe was subsequently modified, since when this problem has not recurred. This new treatment approach offers an alternative to hysterectomy in the treatment of menorrhagia and may offer a number of significant advantages over methods currently used for endometrial ablation.

The energy metabolism of RIF-1 tumours following hydralazine.

Phosphorus-31 Magnetic Resonance Spectroscopy (MRS) was used to observe the effect of two doses of the vasodilator hydralazine on the energy status of RIF-1 tumours. An intravenous dose of 5 mg/kg hydralazine reduced the high energy phosphate metabolites PCr and ATP, lowered pHMRS and raised the levels of inorganic phosphate of tumours within 20 min of administering the drug. The levels of high energy metabolites continued to decrease for at least 24 h. Normal muscle spectra obtained up to 1 h after drug administration remained unchanged. An intravenous dose of 0.5 mg/kg hydralazine also reduced NTP/Pi and PCr/Pi levels of tumours up to at least 5 h after drug administration, but the effect was smaller than for the higher dose. Blood flow measurements and measurements of systemic blood pressure demonstrated that 5 mg/kg of hydralazine produced a reduction in both systemic blood pressure and tumour blood flow relative to most normal tissues investigated. It is concluded that the changes in the P-31 MRS spectra of tumours were due to a reduction in tumour vascular perfusion following administration of hydralazine.

The combined measurement of blood flow and metabolism in RIF-1 tumours in vivo. A study using H2 flow and 31P NMR spectroscopy.

Blood flow and phosphorus metabolites have been measured simultaneously in the murine RIF-1 tumour in vivo. Blood flow was measured using the H2 washout technique and 31P NMR spectroscopy was used to measure high energy phosphates, inorganic phosphate and intracellular pH within the tumour. Following NMR and flow measurements, hydralazine was administered and the measurements repeated. There was always a decrease in blood flow, and a fall in nucleoside triphosphate detected by NMR, after administration of hydralazine. At blood flows in excess of 15 mL 100 g-1 min-1, the nucleoside triphosphate/inorganic phosphate ratio was 1.0 or greater, whereas at flows in the range of 5-12 mL 100 g-1 min-1 the ratio fell to below 0.5, and at flows below 5 mL 100 g-1 min-1 there was no detectable resonance from nucleoside triphosphate.

Treatment of functional menorrhagia by radiofrequency-induced thermal endometrial ablation.

42 patients were enrolled in a trial of radiofrequency-induced thermal endometrial ablation for the treatment of functional menorrhagia. The radiofrequency electromagnetic energy was delivered via a probe placed within the endometrial cavity. 10 patients received 330 kJ of energy, 10 received 445 kJ, and the other 22 received 660 kJ. 19 (87%) of those receiving the highest dose became amenorrheic or had a considerable reduction in menstrual flow. The procedure is simple and the heat induced in the endometrium does not penetrate much beyond the inner layers of the myometrium. There is no need for distension of the uterine cavity with flushing media.

Expression of dose in neutron therapy.

A pragmatic approach in neutron dosimetry is to consider the energy spectrum to consist of a neutron and a gamma component. The relationship between the two components of dose in neutron radiotherapy has been investigated for energies currently in clinical use. Changes in the neutron component itself are not dealt with. Because the two components are given simultaneously there is some interaction between them so that the gamma fraction is more effective than if the neutron and gamma doses were separated in time. This interaction has been accounted for using a well-proven extension of the linear-quadratic (LQ) equation. Using values of the LQ parameters alpha and beta measured recently in vivo, we have modelled the total effect from the neutron and gamma dose-contributions in terms of an equivalent neutron dose. This allows a comparison of different methods of expressing the measured physical dose with the biologically effective dose. The current practice in neutron therapy is to give the total (neutron plus gamma) dose, quoting also the gamma contamination. In all cases within the range of energies used for therapy, the total dose will give an overestimate of the biologically effective dose by approximately 4% for each 5% of gamma contamination. Expression of the neutron dose only (ignoring the gamma component) will give an underestimate of the biologically effective dose by approximately 1.5% for each 5% of gamma contamination, i.e. the error is approximately three times less for neutron dose than for total dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The response of mouse skin to irradiation with neutrons from the 62 MV cyclotron at Clatterbridge, U.K.

Acute skin reactions on mouse feet were used to measure the effect of 62 MeV p-Be neutrons from the cyclotron at Clatterbridge, U.K. The results were compared with the response to 16 MeV d-Be neutrons from the cyclotron at Hammersmith, 4 MeV d-Be neutrons from the van de Graaff accelerator at the Gray Laboratory, and 250 kVp X-rays. Up to 16 equal radiation fractions were given alone, or 16 fractions followed by "top-up" doses of 4 MeV d-Be neutrons to study the effect of neutron doses less than 1 Gy per fraction. For equivalent skin reactions, 9-16% more dose (total neutron + gamma) was needed with p(62)-Be neutrons compared with d(16)-Be neutrons. This did not vary significantly between 1 and 16 fractions. The top-up studies indicated that this figure might rise to approximately 14-32% at very low doses of neutrons, the value depending on the method of analysis of the data. The data indicate that the "standard" clinical protocol of 1.47 Gy per fraction (N + gamma dose) in 12 fractions given at Hammersmith with d(16)-Be neutrons would correspond to a dose of 1.64 Gy per fraction (N + gamma) at Clatterbridge using a similar regime of p(62)-Be neutrons. d(4)-Be neutrons were more effective than d(16)-Be neutrons by a factor of 1.6 over the whole range of dose per fraction studied (0.05-14.5 Gy per fraction of d(4)-Be neutrons). Relative to X-rays, the RBE for p(62)-Be neutrons was 1.6 +/- 0.02 for a single X-ray dose of 30 Gy, rising to 2.9 +/- 0.04 for an X-ray dose per fraction of 4.6 Gy given 16 times. The full-course fractionation data and the top-up data together indicate an extrapolated limiting RBE at vanishingly small doses per fraction of 4.2-4.8 depending on the method of analysis. The X-ray data were well-fitted by a linear-quadratic (LQ) model of dose-fractionation, with alpha/beta = 8.6 +/- 1.5 Gy. The LQ model also provides a fairly good description of the neutron responses, alpha/beta being large (greater than 24) reflecting predominantly linear underlying dose-responses for all the neutron beams. This in turn reflects the small variation observed in the relative effectiveness between the 3 neutron beams with changes in dose per fraction.

The concept of thermal dose.

1. In the ideal but theoretical situation, where hyperthermia is defined to be at a specific, constant temperature, duration of heating is a perfectly acceptable and satisfactory method of describing thermal dose. 2. In the real situation, the dose is far from constant. Time will be required to reach the desired temperature and to cool afterwards. During hyperthermia the temperature is variable. We are thus obliged to use a biologically equivalent thermal dose to account for these variations. 3. Various attempts have been made to solve this problem, but at present, the most feasible approach appears to be the integration of the biological isoeffect relationship (Dewey formula) over the whole treatment. 4. This method provides a practical and reasonable method of comparing hyperthermal treatments under conditions likely to be met in practice, i.e. moderate variation about a fairly steady temperature. However, the formula would certainly be inaccurate if there were a sudden reduction in temperature resulting in a significant effect of step-down sensitisation or a long treatment resulting in the development of thermotolerance. Also, it must be emphasised that the formula does not account for absolute differences in sensitivity among tissues. Nor does it address the problem of varying sensitivity throughout a course of fractionated heat treatments. 5. Less is known about the applicability of such a formula to the combination of heat and ionizing radiation when the two treatment modalities interact. The parameters are fairly similar to those for heat alone, although the transition appears to be lowered to 41.5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies relevant to a means of quantifying the effects of hyperthermia.

There is as yet no fully satisfactory method of defining 'thermal dose'. However, in order to relate different hyperthermal treatments it has been suggested that the relationship between heating time and temperature be used to derive an isoeffect parameter which might be useful in this context. The equation t2/t1 = RT1-T2, where t is the treatment time, T the temperature, R = 2 for T greater than 42.5 degrees C and R = approximately 6 for T less than 42.5 degrees C, has been shown to fit the isoeffect data from many studies both in vivo and in vitro. Whether or not this relationship is applicable when the temperature is varying has been tested using an animal model system, i.e. the response of the baby rat tail. It has shown that the relationship between time and temperature is indeed characterized by the above equation, and the phenomena of thermotolerance and step-down sensitization were clearly demonstrated. Tails were then alternated between waterbaths at different temperatures in order to simulate varying temperature. The measured effects were, in general, in good agreement with those derived from the formula. The maximum difference between the observed and predicted effect, obtained under rather extreme conditions unlikely to be experienced clinically, amounted to an under-estimate of the effective temperature by approximately 0.3 degrees C, i.e. a net small effect of thermotolerance. It is therefore suggested that the above formula for 'heat dose' provides a reasonable interim method for comparing clinical hyperthermic treatments. The formula does not, however, account for differing absolute sensitivities between tissues nor for effects of fractionating heat treatments.

1985 Douglas Lea memorial lecture. Hyperthermia in the treatment of cancer.

There are sound biological reasons for using hyperthermia in the treatment of malignant disease. This review includes a discussion of this rationale and describes effects of hyperthermia either given alone or in combination with ionising radiation to cells in vitro, tumours or normal tissues. Topics discussed include thermotolerance, step-down sensitisation, fractionation, re-treatment of previously irradiated sites, thermal enhancement ratio and thermal dose. Problems of heat delivery and temperature measurement are considered and the current status of clinical studies is stated briefly.