Development of a rapidly computable descriptor of prostate tissue temperature during transurethral conductive heat therapy for benign prostate hyperplasia.

Benign prostate hyperplasia (BPH) is a condition in older men in which the mass of tissue in the prostate gland gradually increases over the course of many years, ultimately leading to urinary outflow obstruction. Current treatment of this condition is to surgically remove the obstructing tissue. One novel alternative therapy being studied is transurethral thermocoagulation of excessive prostatic mass. In this approach, a heat-emitting catheter is placed in the prostatic urethra, and the intraprostatic segment of the catheter is heated to temperatures above 60 degrees C for one hour. Two-dimensional cylindrical-co-ordinate computer simulations of this treatment modality were run to model resultant temperature distributions within the prostate gland and surrounding tissues. The simulations revealed that resultant tissue temperature changes were related directly to the power delivered to the catheter and inversely to the rate of blood perfusion. Further analysis of the temperature profiles produced a rapidly computable predictor of tissue temperature in the radial dimension. Using the predictor, a 'kill radius' around the prostatic urethra can be easily computed on-line, during treatment, from clinically available data, catheter power and catheter temperature. The computed kill radius may serve as a useful predictor of the extent of thermal devitalization of unwanted obstructing tissue and the long-term success of the treatment in relieving urinary outflow obstruction without surgery.

Droop: a rapidly computable descriptor of local minimum tissue temperature during conductive interstitial hyperthermia.

Although the goal of local hyperthermia therapy for cancer is to elevate the temperature of a tumour to cytotoxic levels, without the presence of 'cold spots', varying blood flow has made the achievement of consistent, therapeutic temperature distributions extraordinarily difficult. The paper presents a novel approach to estimating local minimum tumour temperatures during conductive interstitial hyperthermia which facilitates identification and elimination of cold spots. Conductive interstitial hyperthermia is modelled mathematically for a parallel array of implanted, electrically heated catheters which warms the treated tissue by thermal conduction and blood perfusion. Computer simulations employing the bioheat transfer equation reveal a predictive relationship between implanted catheter temperature, catheter power, implantation geometry and local minimum tumour temperature. Formulation of this relationship in terms of a parameter named 'droop' allows estimation of local minimum intratumoural temperatures from individual catheter temperature and power. Computer simulations are also performed to determine the sensitivity of the droop-based estimator to variations in properties of the tissue and catheters. Generally, variations in geometry or thermal properties of about 10 per cent cause estimation errors of less than 1 degree C in magnitude. These results suggest that online estimates of thermal 'droop' may provide a practical route to more consistent control of intratumoural minimum temperature during conductive interstitial heat therapy.

Oxygen radicals in ulcerative colitis.

This article reviews the pathophysiologic concept that superoxide and hydrogen peroxide, generated by activated leukocytes, together with low-molecular-weight chelate iron derived from fecal sources and from denatured hemoglobin, amplify the inflammatory response and subsequent mucosal damage in patients with active episodes of ulcerative colitis. The putative pathogenic mechanisms reviewed are as follows: (1) Dietary iron is concentrated in fecal material owing to normally limited iron absorption. (2) Mucosal bleeding, characteristic of ulcerative colitis, as well as supplemental oral iron therapy for chronic anemia, further conspire to maintain or elevate mucosal iron concentration in colitis. (3) Fenton chemistry, driven especially by leukocyte-generated superoxide and hydrogen peroxide, leads to formation of hydroxyl radicals. (4) The resultant oxidative stress leads to the extension and propagation of crypt abscesses, either through direct membrane disruption by lipid peroxidation or through generation of secondary toxic oxidants such as chloramines. (5) Chemotactic products of lipid peroxidation, including 4-hydroxynonenal, provide positive feedback to accelerate this inflammatory/oxidative process, leading to acute exacerbations of the disease. (6) Other oxidized products, such as oxidized tryptophan metabolites, created by free radical mechanisms in or near the mucosa, may act as carcinogens or tumor promotors that contribute to the exceedingly high incidence of colon carcinoma in patients suffering from chronic ulcerative colitis. In this way, self-sustaining cycles of oxidant formation may amplify flare-ups of inflammation and mucosal injury in ulcerative colitis. This concept, if proved correct by subsequent research, would provide a rationale for several novel clinical approaches to the management of ulcerative colitis, including use of SOD mimetics, iron chelators, and chain-breaking antioxidants.

Effective estimation and computer control of minimum tumour temperature during conductive interstitial hyperthermia.

The goal of heat therapy in the treatment of malignant disease is to raise the temperature of all neoplastic tissue to a cytotoxic temperature for a predetermined period of time. This seemingly simple task has proved difficult in vivo in part because of non-uniform power absorption and in part because of non-homogeneous and time-varying tumour blood flow. We have addressed this difficulty first by utilizing the conceptually simple technique of conductive interstitial hyperthermia, in which the tumour is warmed by multiple, electrically heated catheters, and second by implementing on-line control of minimum tumour temperatures near each catheter, estimated on the basis of the steady-state ratio of catheter power to catheter temperature rise. This report presents an analysis of the accuracy, precision, and stability of the on-line minimum temperature estimation/control technique for 22 patients who received 31 separate courses of conductive interstitial hyperthermia for the treatment of malignant brain tumours, and in whom temperature was monitored independently by 12-16 independent sensors per patient. In all patients the technique was found to accurately and precisely estimate and control the local minimum temperatures. Comparison of measured and estimated temperatures revealed a mean difference of 0.0 +/- 0.4 degrees C for those sensors within 1.0 mm of the expected location for minimum temperatures. This technique therefore offers an attractive method for controlling hyperthermia therapy-even in the presence of time varying local blood flow.

Design and evaluation of closed-loop feedback control of minimum temperatures in human intracranial tumours treated with interstitial hyperthermia.

The dynamic nature of blood flow during hyperthermia therapy has made the control of minimum tumour temperature a difficult task. The paper presents initial studies of a novel approach to closed-loop control of local minimum tissue temperatures utilising a newly developed estimation algorithm for use with conductive interstitial heating systems. The local minimum tumour temperature is explicitly estimated from the power required to maintain each member of an array of electrically heated catheters at a known temperature, in conjunction with a new bioheat equation-based algorithm to predict the 'droop' or fractional decline in tissue temperature between heated catheters. A closed loop controller utilises the estimated minimum temperature near each catheter as a feedback parameter, which reflects variations in local blood flow. In response the controller alters delivered power to each catheter to compensate for changes in blood flow. The validity and stability of this estimation/control scheme were tested in computer simulations and in closed-loop control of nine patient treatments. The average estimation error from patient data analysis of 21 sites at which temperature was independently measured (three per patient) was 0.0 degree C, with a standard deviation of 0.8 degree C. These results suggest that estimation of local minimum temperature and feedback control of power delivery can be employed effectively during conductive interstitial heat therapy of intracranial tumours in man.

Computer-aided design and evaluation of novel catheters for conductive interstitial hyperthermia.

Conductive interstitial heating is a modality in which heating elements are implanted directly into the treated tissue. One implementation of such therapy employs electrically heated catheters that are implanted in staggered, parallel rows. To explore strategies for maximising the uniformity of tissue temperature distributions achieved with heated catheters, a two-dimensional computer model with cylindrical co-ordinates was used to evaluate radially and longitudinally the temperature distributions produced by a typical interior catheter surrounded by other similar catheters. Insights from the computer model led to new designs for catheters containing multiple heating elements that produced more uniform thermal distributions, eliminating previous 'cold spots' within the treatment volume located near the ends of the catheter. The new catheter designs also include compartments for the optional placement of radioactive seeds for simultaneous thermoradiotherapy.

Theoretical basis for controlling minimal tumor temperature during interstitial conductive heat therapy.

This paper describes simulation of steady-state intratumoral temperatures achieved by a simple modality of local heat therapy: interstitial treatment with parallel arrays of warmed, conductive heating elements. During "conductive heating" power is directly deposited only in the interstitial probes. Adjacent tissue is warmed by heat conduction. Simulations of interstitial conductive heating involved solution of the bioheat transfer equation on a digital computer using a finite difference model of the treated tissue. The simulations suggest that when the complete temperature distributions for conductive interstitial hyperthermia are examined in detail, substantial uniformity of the temperature distributions is evident. Except for a thin sleeve of tissue surrounding each heating element, a broad, flat central valley of temperature elevation is achieved, with a well defined minimum temperature, very close to modal and median tissue temperatures. Because probes are inserted directly in tumor tissue, the thin sleeve of overheated tissue would not be expected to cause normal tissue complications. The temperature of the heated probes must be continuously controlled and increased in the face of increased blood flow in order to maintain minimum tumor temperature. However, correction for changes in blood flow is possible by adjusting probe temperature according to a feedback control scheme, in which power dissipation from each probe is the sensed input variable. Conductive interstitial heating with continually controlled probe temperature deserves investigation as a technique for local hyperthermia therapy.

Hyperthermia catheter implantation and therapy in the brain. Technical note.

For the treatment of malignant gliomas, a technique for implanting hyperthermia catheters was developed that utilized a stereotactic template and head-stabilization frame mounted on a computerized tomography (CT) scanner. Computerized tomography scans were used to measure tumor dimensions and to determine the number, implantation depths, and active heating lengths of the catheters, which were implanted through twist-drill holes while the patient was in the CT room. Heat was subsequently delivered via implanted catheters using a computer-controlled hyperthermia system, which partially compensates for heterogeneous and time-varying tumor blood flow.

Association of magnesium deficiency with the blood pressure-lowering effects of calcium.

The role of dietary calcium and magnesium in the development of hypertension was studied in nine groups, each consisting of nine spontaneously hypertensive rats aged 8-31 weeks. The animals were fed AIN 76A semi-purified diets varying in calcium (0.075, 0.5 and 2.5%) and magnesium (0.01, 0.05 and 0.75%) concentrations according to a 3 x 3 factorial design. Dietary calcium and systolic blood pressure were inversely related, significantly (P less than 0.05) after 12 weeks. Total and ultrafilterable serum calcium concentrations were also significantly negatively correlated with blood pressure (r = -0.46; P = 0.001 and r = -0.57; P = 0.001, respectively). Repeated measures analysis of variance indicated that dietary magnesium had no effect on systolic blood pressure, and no calcium x magnesium interaction on blood pressure was observed. Signs of magnesium deficiency, calcium deposits in the kidneys, and histological lesions were observed in groups on a high-calcium diet receiving normal and low levels of magnesium. Thus a lowering of blood pressure by calcium supplementation, without concomitant magnesium supplementation, was accompanied by biochemical and histological abnormalities in this animal model.

A rapid, widely applicable screen for drugs that suppress free radical formation in ischemia/reperfusion.

Substantial injury can occur during reoxygenation of previously ischemic tissue in many experimental models, as the result of the generation of oxygen-derived free radicals. To test the antiradical activity of potentially protective compounds in this setting, we developed a simple screening system, applicable to fresh biopsy specimens, in which warm ischemia and reoxygenation of excised tissue are performed in vitro. Tissue production of malondialdehyde (MDA) equivalents is used as a nonspecific-but-sensitive marker of oxygen radical damage. Test compounds with putative antiradical activity are added prior to the reoxygenation phase, and their ability to suppress MDA production is an index of activity in preventing reoxygenation injury. Comparison with ischemic but not reoxygenated controls confirms the oxygen-dependent nature of the effect. Standard positive controls of known effective agents, such as butylated hydroxytoluene or deferoxamine, provide a reference for the activity of the test compound. The method is applicable to surgical biopsy specimens in veterinary and human medicine.

Results of a preliminary study of the potential of vasodilators for improving thermotherapy of deep-seated tumours [printed with original paging at end of 2(2); omitted from Int J Hyperthermia 1986 Jan-Mar;2(1)].

Administration of the vasodilator hydralazine to a single mongrel dog with a transplanted, superficial transmissible venereal tumour in the abdomen permitted tumour-adjacent normal tissue temperature differences produced in local hyperthermia to be enhanced by nearly 2 degrees C. A preliminary study of tumour and normal tissue perfusion rate in the dog, employing the 15O-labelled water-positron emission tomography technique, suggested that administration of the vasodilator led to a significant reduction in the tumour perfusion rate, consistent with the observed tumour temperature enhancement. Computational studies with a multi-layer, one-dimensional cylindrical model of deep-tumour heating suggest that vasodilator-induced reductions of tumour perfusion rates could significantly increase deep tumour-superficial normal tissue temperature differences produced in deep-tumour thermotherapy.

Hyperthermia-induced vascular injury in normal and neoplastic tissue.

The sequential morphologic alterations in normal skeletal muscle in rats, Walker 256 tumors in rats, and transmissible venereal tumors (TVT) in dogs following microwave-induced hyperthermia (43 degrees C and 45 degrees C for 20 minutes), were studied by histologic and ultrastructural examination. Normal muscle and Walker 256 tumors showed edema, congestion, and hemorrhage at 5 minutes post-heating (PH), followed by suppuration, macrophage infiltration, and thrombosis at 6 and 48 hours PH, and finally by regeneration and repair by 7 days PH. Vascular endothelial damage and parenchymal degeneration were present 5 minutes PH. Progressive injury occurred for at least 48 hours PH. Two hyperthermia treatments separated by a 30- or 60-min cooling interval, were applied to Walker 256 tumors in a subsequent study. Increased selective heating of tumor tissue versus surrounding normal tissue, and increased intratumoral steady state temperatures were found during the second hyperthermia treatment. Canine TVTs were resistant to hyperthermia damage. These results suggest that vascular damage contributes to the immediate and latent cytotoxic effects of hyperthermia in normal tissue and some types of neoplastic tissue, and that selective heating of neoplastic tissue occurs in tumor tissue with disrupted microvasculature.

Irradiation-hyperthermia in canine hemangiopericytomas: large-animal model for therapeutic response.

Results of irradiation-hyperthermia treatment in 11 dogs with naturally occurring hemangiopericytoma were reported. Similarities of canine and human hemangiopericytomas were described. Orthovoltage X-irradiation followed by microwave-induced hyperthermia resulted in a 91% objective response rate. A statistical procedure was given to evaluate quantitatively the clinical behavior of locally invasive, nonmetastatic tumors in dogs that were undergoing therapy for control of local disease. The procedure used a small sample size and demonstrated distribution of the data on a scaled response as well as transformation of the data through classical parametric and nonparametric statistical methods. These statistical methods set confidence limits on the population mean and placed tolerance limits on a population percentage. Application of the statistical methods to human and animal clinical trials was apparent.

Improved preferential tumor hyperthermia with regional heating and systemic blood cooling: a balanced heat transfer method.

Absorption of power in large body volumes can occur with some approaches used for hyperthermia treatment of cancer. A systemic heat absorption rate exceeding the heat dissipation rate can lead to systemic temperature elevation that limits the magnitude and duration of application of power and hence the degree of preferential tumor temperature rise. We describe a hyperthermia approach consisting of regional electromagnetic power absorption and extracorporeal blood cooling with regulation of both systemic heat absorption and dissipation rates ("balanced heat transfer"). A test of this approach in five dogs with nonperfused tumor models demonstrated intratumoral temperatures greater than 42 degrees C, while systemic temperature remained at 33 degrees C and visceral temperatures within the heated region equilibrated between 33 and 42 degrees C. Solutions of the bioheat transfer equation were obtained for a simplified model with a tumor perfusion rate lower than surrounding normal tissue perfusion rate. In this model, the use of arterial blood temperatures less than 37 degrees C allowed higher power densities to be used, for given normal tissue temperatures, than when arterial temperature was greater than or equal to 37 degrees C. As a result, higher intratumoral temperatures were predicted. Control of arterial blood temperature using extracorporeal cooling may thus (1) limit systemic temperature rise produced by regional heating devices and (2) offer a means of improving intratumoral temperature elevations.

Abnormal response of tumor vasculature to vasoactive drugs.

The effects of the vasoconstrictor phenylephrine and the vasodilator hydralazine on blood flow to tumor were studied and compared to those on blood flow to normal tissues in vivo. Regional blood flow and cardiac output were measured with the use of radioactive microspheres in 150- to 250-g inbred Harlan F344 rats bearing subcutaneous nodules of two types of transplantable carcinoma ("hard" and "soft") with microscopically different vascular patterns. Three groups of rats were treated with hydralazine, saline, or phenylephrine, and regional blood flow was determined at the time of maximum blood pressure response. Results were correlated with quantitative morphometric analysis of arteriolar and capillary wall thickness in tumor and normal tissue. Phenylephrine decreased and hydralazine increased normal tissue perfusion as indicated by cardiac output. Tumor blood flow remained low and was not significantly influenced by drug treatment, except for the phenylephrine effect on hard tumors. Histologic study of tumor vessel walls revealed an absence of smooth muscle capable of responding to the vasoactive drugs by constriction or dilation. Evidently, by their selective action on normal vessels, vasoactive drugs can change the ratio of tumor:normal tissue perfusion. In particular, the increase of normal tissue: tumor blood flow by vasodilator drugs may enhance the selectivity of local heat therapy.

Hydralazine-enhanced selective heating of transmissible venereal tumor implants in dogs.

This study was designed to test the hypothesis that vasodilator drugs can enhance selective heating of solid tumors by producing a favorable redistribution of blood flow between tumor and normal tissues. Subcutaneous transmissible venereal tumor implants were heated by inductive diathermy using Helmholtz coils in 8 dogs. The temperature rise in tumor and adjacent muscle was measured before and after giving hydralazine (0.5 mg/kg i.v.). Blood flow to the tumors and underlying muscle was measured with radioactive tracer microspheres. Before hydralazine treatment mean muscle blood flow was about one-third tumor blood flow (0.11 +/- 0.02 vs 0.28 +/- 0.09 ml/min/g), and tumor and normal muscle temperatures were not significantly different (40.0 +/- 0.6 vs 39.7 +/- 0.1 degrees C). After hydralazine tumor blood flow decreased and muscle blood flow increased in every dog, and selective heating of the tumors became possible. Muscle blood flow averaged 0.67 +/- 0.13 ml/min/g, 17 times greater than tumor blood flow, which decreased to 0.04 +/- 0.02 ml/min/g. Core tumor temperature was 48.0 +/- 0.9 vs 38.5 +/- 0.5 degrees C for underlying muscle. Blood pressure was maintained at 80 +/- 5.7 mmHg. These results demonstrate that adjuvant treatment with vasodilators is a promising technique to increase the temperature difference between tumors and surrounding normal tissues during local heat therapy.

Equipment for local hyperthermia therapy of cancer.

Technology for local heat therapy of cancer is evolving rapidly at a number of technologically diverse and geographically scattered institutions and companies. No single technology is superior to others in all applications, and no single company, laboratory, or research group has all the answers. An ideal system would provide focused heating at depth in a predictable fashion, with little probability of generating undesired hot spots in normal tissues and little interference with monitoring equipment. Existing systems approximate this ideal to different degrees, depending on the anatomy and geometry of the tumor and its surrounding tissues. In the foregoing discussion the important problem of measuring temperatures in tumors and normal tissues has been slighted. At the present time, all thermometry is necessarily invasive, and there are limitations to the number of points at which temperatures can be measured utilizing percutaneously placed catheters as conduits for thermometers. However, further advances in the art, the science, and the technology of local heat therapy are likely to be forthcoming in the next few years from a diverse community of investigators and young companies who are following an interesting variety of approaches. Continued research and development in the spirit of constructive, rather than destructive, competition will certainly advance the field substantially--much to the benefit of patients. At present, however, clinical engineers should realize that hyperthermia therapy for cancer is still experimental. Despite the flurry of commercial activity, considerable caution should be exercised in the purchase and use of hyperthermia equipment.

Biology of local heat therapy for cancer.

Successful cancer therapy must selectively destroy tumor tissue while sparing the host's normal tissues. Local heat treatment can have such a selective effect because abnormalities in tumor blood vessels supply less oxygen to heat-stressed tumor cells and are less efficient in cooling tumor tissue by blood perfusion.

Physical principles of local heat therapy for cancer.

Local hyperthermia therapy for cancer can produce selective heating of solid tumors on the basis of known physical laws. If energy is deposited in the general region of the tumor, temperature tends to develop in the tumor higher than that in surrounding normal tissues. The goal of therapy is to achieve cytotoxic temperature elevations in the tumor for an adequate period of time, without damaging nearby normal tissues. Several modalities exist for local heat treatment, of which radiofrequency and ultrasound offer the most promise for controlled, localized heating at depth. A paucity of blood flow in the tumor compared to that in adjacent normal tissues can enhance selective tumor heating considerably. The tumor types that have reduced flow in their central regions are especially vulnerable to heat therapy, both because they can be heated more efficiently and because hypoxic and acidotic tumor tissues are more susceptible to damage by heat. This effect is more pronounced in larger tumors, which have smaller surface-to-volume ratios and so lose heat less rapidly by thermal diffusion. Selective heat treatment of larger tumor masses with low blood perfusion, therefore, is physically practical and rational therapy. Vigorous research efforts are now underway at many centers to optimize this approach.