Chemical nature of chain breaks produced in DNA by x-irradiation in vitro.
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Aldehydes↗
Biomedical subjects
D S Kapp
Publications and source records attributed to D S Kapp.
Lack of in vitro repair of x-ray-induced chain breaks in DNA by the polynucleotide-joining enzyme.
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Carbon Isotopes↗
Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole.
In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m2. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.
Adolescent↗
Site and disease selection for hyperthermia clinical trials.
Significant progress has been made in the past 20 years in understanding the biological basis of hyperthermia-induced cytotoxicity, thermoenhancement of radiation therapy and chemotherapy, and in the development of clinically applicable microwave, radiofrequency, ultrasound and thermometry equipment. Numerous uncontrolled trials have suggested strongly that hyperthermia in conjunction with radiation therapy or chemotherapy may contribute to improved local control rates for recurrent or metastatic cancer without excessive morbidity. Carefully designed and well-controlled site and disease-specific prospective randomized trials with standardized hyperthermia and radiation therapy techniques, adequate thermometry, precise end points for tumour control and normal tissue toxicity are now essential to establish the role of hyperthermia in cancer management. Criteria for tumour site selection will be explored for trials employing radiation therapy and local-regional hyperthermia. Examples of sites selected will be presented which represent areas that can, with current technology, usually be adequately heated, and in which significant patient benefit may result from improved local-regional control.
Clinical Trials as Topic↗
N3 (TNM-UICC) metastatic neck nodes managed by combined radiation therapy and hyperthermia: clinical results and analysis of treatment parameters.
In an attempt to improve the control of N3 (TNM-UICC) fixed and inoperable metastatic nodes, local microwave hyperthermia (HT) was combined with radiation therapy (RT). From February 1981 to January 1985, 34 patients, with N3 metastatic nodes from primary tumours in the head and neck, were treated according to two different prospective, non-randomized protocols: 23 patients received HT combined with the first course of conventionally fractionated radical RT (40 Gy + HT--2 week interval--20-30 Gy), and 11 patients received HT combined with palliative RT (20-50 Gy + HT). All the patients were treated with the same microwave applicator (MA-150) on the BSD-1000 unit, at a frequency of 280-300 MHz. Temperatures were measured by means of 2-3 Bowman probes placed within the tumour (core and periphery) and 5-6 probes on the skin surface. HT sessions were delivered after RT (less than 20 min), 2 or 3 times weekly, for a duration of 30 min after steady-state temperatures were obtained. Twenty-seven patients out of 34 were evaluable, with a follow-up of at least 3 months (range 3-39 months; median 10 months). Clinical results at 3 months revealed 59 per cent complete responses, 30 per cent partial responses, and 11 per cent with progressive disease. Analyses of response rates showed: a marginally significant difference (P = 0.095) between RT alone (historical control) and the entire group of patients treated with RT plus HT; a significant difference (P = 0.034) if RT alone is compared with Protocol A (RT greater than or equal to 60 Gy + HT); no significant difference between the two protocols employing HT, despite the different RT doses utilized; no significant differences in response rates, as a function of minimal intratumoural temperatures achieved, number of weekly HT sessions or total number of HT sessions; and a significantly lower response rate for nodes with maximum diameter greater than 6 cm (P = 0.043). No important differences in acute side effects between irradiated and heated regions in the same patient were noted. Late side effects in patients treated with RT plus HT included three cases (9 per cent) of severe fibrosis, possibly as a consequence of excessive maximum tumour temperature (greater than 46 degrees C).
Adult↗
Stanford University institutional report. Phase I evaluation of equipment for hyperthermia treatment of cancer.
From September 16, 1981, through April 4, 1986, a total of 21 radiative electromagnetic (microwave and radiofrequency), ultrasound and interstitial radio-frequency hyperthermia applicators and three types of thermometry systems underwent extensive phantom and clinical testing at Stanford University. A total of 996 treatment sessions involving 268 separate treatment fields in 131 patients was performed. Thermal profiles were obtained in 847 of these treatment sessions by multipoint and/or mapping techniques involving mechanical translation. The ability of these devices to heat superficial, eccentrically located and deep-seated tumours at the major anatomical locations is evaluated and the temperature distributions, acute and subacute toxicities, and chronic complications compared. Average measured tumour temperatures between 42 degrees C and 43 degrees C were obtained with many of the devices used for superficial heating; average tumour temperatures of 39.6 degrees C to 42.1 degrees C were achieved with the three deep-heating devices. When compared to the goal of obtaining minimum tumour temperatures of 43.0 degrees C, all devices performed poorly. Only 14 per cent (118/847) of treatments with measured thermal profiles achieved minimum intratumoural temperatures of 41 degrees C. Fifty-six per cent of all treatments had associated acute toxicity; 14 per cent of all treatments necessitated power reduction resulting in maximum steady-state temperatures of less than 42.5 degrees C. Direct comparisons between two or more devices utilized to treat the same field were made in 67 instances, including 19 treatment fields in which two or more devices were compared at the same treatment session. The analyses from direct comparisons consistently showed that the static spiral and larger area scanning spiral applicators resulted in more favourable temperature distributions. Three fibreoptic thermometry systems (Luxtron single channel, four channel and eight channel multiple [four] probe array), the BSD Bowman thermistor system and a thermocouple system were evaluated with respect to accuracy, stability and artifacts. The clinical reliability, durability, and patient tolerance of the thermometry systems were investigated. The BSD Bowman and third generation Luxtron systems were found clinically useful, with the former meeting all of our established criteria.
Adult↗
Noninvasive microwave phased arrays for local hyperthermia: a review.
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Biomedical Engineering↗
Correlation of thermal parameters with outcome in combined radiation therapy-hyperthermia trials.
Many studies utilizing combined hyperthermia (HT) and radiation therapy (XRT) in the treatment of advanced or recurrent malignancies have reported a correlation between some measure of the minimum temperature achieved and outcome. Previous reported studies at Stanford have demonstrated a statistically significant correlation between the duration of local control and Tmin, the mean over treatments of the minima of (a) measured intratumoral temperatures in fields which contained diffuse or nodular tumours, or (b) measured interstitial temperatures in fields treated for microscopic residual disease. Recently, T90, the mean of the temperatures above which 90% of all measured intratumoral temperatures fall, has been proposed as an alternative characterization of the efficacy of the HT treatment that reportedly has a superior correlation with outcome. To test this hypothesis, T90 was computed by two different methods for three groups of patients treated at Stanford with XRT-HT for superficially located tumor recurrences. Tmin was found to be strongly correlated with T90 calculated by both methods. All three thermal parameters correlated with complete response at 3 weeks and with local control, although Tmin usually demonstrated the strongest correlation.
Adenocarcinoma↗
Persistent and/or late complications of combined radiation therapy and hyperthermia.
Persistent and/or late complications were analysed in 64 patients (183 fields) that were treated with combined hyperthermia and radiation therapy for advanced, recurrent or metastatic cancer. The incidence and type of complications were evaluated over a minimum follow-up period of 2 years from the onset of treatment (mean 38.7 months; range 24-82.5 months). The primary malignancies included: breast (39), melanomas (6), adenoid cystic carcinomas of salivary glands (4), prostate (4), soft tissue sarcomas (3), squamous cell carcinoma of head and neck (3), lymphomas (3), transitional cell carcinoma of bladder (1) and basal cell carcinoma of the skin (1). The persistent complications noted included induration and fibrosis (39 hyperthermia fields, 22 patients), ulceration at the site of prior tumour (three patients, three fields), and ulceration in normal tissue (one patient, one field). Brachial plexopathy developed in one patient treated for recurrent breast cancer, but she had active disease at that time. A squamous cell carcinoma of the skin developed within the treatment field in a breast cancer patient. Radionecrosis of the mandible was seen in one patient treated for a floor of the mouth cancer, and osteomyelitis with septic arthritis developed in one patient treated for a soft tissue sarcoma of the thigh. Univariate logistic regression analyses of pretreatment and radiation-hyperthermia treatment parameters revealed that maximal tumour temperature had a borderline significant correlation with the development of complications (p = 0.07). Multivariate analyses of the pretreatment and treatment parameters revealed the best-two-covariate model to predict complications included mean maximal tumour temperature and tumour type (macroscopic tumours had greater incidence of complications than for microscopic residual disease). The rate and type of persistent and/or late complications seen following combined radiation and hyperthermia did not appear to dramatically differ from those that would be anticipated from irradiation alone in this patient population, with the exception of an increased incidence of areas of induration and tumour necrosis.
Adult↗
Potential hazards of radiative electromagnetic hyperthermia in the presence of multiple metallic surgical clips.
Three-dimensional computer simulations of a patient under consideration for heating by the BSD Sigma 60 phased array applicator showed marked specific absorption rate (SAR) enhancement in the region where there was a concentration of metallic surgical clips. Subsequent tests in tissue-equivalent phantom material confirmed that metallic objects much shorter than the wavelength in tissue of the radiative electromagnetic field can cause significant changes in the power deposition near the implanted metal. The placement of extensive numbers of surgical clips may therefore hinder the ability to subsequently utilize radiative electromagnetic heating modalities.
Adult↗
Peripheral neuropathy and myonecrosis following hyperthermia and radiation therapy for recurrent prostatic cancer: correlation of damage with predicted SAR pattern.
During the past 10 years, numerous phase I-II studies were conducted and provided clinical experience with combined radiation therapy and hyperthermia treatments. Among the rare complications reported in these combined radiation therapy-hyperthermia trials were myonecrosis and peripheral neuropathy which were felt, mainly on a clinical basis, to be caused by local heat damage. Recently, such complications were noted in two patients with recurrent prostatic cancer treated in our department with radiation therapy combined with deep regional hyperthermia delivered by the Sigma-60 applicator of the BSD 2000 hyperthermia system (Salt Lake City, UT, USA). Analysis of the results of three-dimensional modelling of the SAR (specific absorption rate, W/kg) pattern in these patients indicated high SAR at the sites of the complications. Pretreatment three-dimensional modelling or other methods of predicting potential areas of high power deposition may have a role for future hyperthermia treatment planning aiding in the prevention of possible local heat damage and providing improved delivery of heat to the target volume.
Aged↗
Automated mechanical thermometry probe mapping systems for hyperthermia.
In order to better assess temperature distribution patterns in patients, tissue equivalent phantoms, and experimental animals, mechanical devices and automated control systems for positioning temperature probes in implanted catheters and catheters laid on the skin surface have been developed. They employ stepper motor actuated roller and idler wheel drives to move the probes. Two devices incorporate positive positioners in addition to the drive rollers in order to obtain higher positioning accuracy where significant probe to catheter friction is present. Automated systems have been constructed which can simultaneously position, record and display data from up to 10 temperature sensors in a colour-coded position versus temperature format to produce a real time two-dimensional colour-coded pseudo isotherm display. These thermal mapping devices have been used for characterizing the power deposition patterns of several large area microwave applicators (on the surface and at depth within tissue equivalent phantoms), for intraorgan temperature mapping in experimental animals, and for surface and subcutaneous temperature mapping during clinical treatments.
Animals↗
Stanford 3D hyperthermia treatment planning system. Technical review and clinical summary.
In the field of deep regional hyperthermia cancer therapy the Sigma 60 applicator of the BSD-2000 Hyperthermia System is one of the most widely used devices. This device employs four independent sources of radiofrequency electromagnetic energy to heat tumour sites deep within the body. The difficulty in determining the input parameters for the four sources has motivated the development of a computer-based three-dimensional (3D) treatment planning system. The Stanford 3D Hyperthermia Treatment Planning System has been in clinical use at Stanford Medical Center for the past 2 years. It utilizes a patient-specific, three-dimensional computer simulation to determine safe and effective power deposition plans. An optimization programme for the selection of the amplitudes, phases and frequency for the sources has been developed and used in the clinic. Examples of the application of the treatment planning for hyperthermia treatment of pulmonary, pelvic, and mediastinal tumours are presented. Methods for quantifying the relative effectiveness of various treatment plans are reviewed.
Adult↗
Prognostic factors in metastatic malignant melanoma treated with combined radiation therapy and hyperthermia.
From May 1981 to September 1991, 38 patients with metastatic malignant melanoma were treated with combined radiation therapy and hyperthermia to a total of 97 hyperthermia treatment fields. Prior treatments to these sites included surgery (31 patients, 76 fields), chemotherapy (18 patients, 54 fields), immunotherapy (14 patients, 42 fields) and radiation therapy (7 patients, 13 hyperthermia fields). Hyperthermia was given to fields located in the head and neck region, trunk and extremities in 30, 45 and 22 cases, respectively. Nodular-diffuse tumours were present in 86 fields while 11 fields were treated for microscopic residual tumour deposits. Concurrent radiation therapy was given in 180-400 cGy per fraction, 2-5 times per week for a mean total dose of 4098 cGy per field. Hyperthermia treatments were delivered using either microwave or ultrasound devices (286 and 48 treatments, respectively) with a mean (range) of 3.4 (1-14) hyperthermia treatments per field for a mean (range) of 43 (10-70) min per field. Patients (n = 34; 84 fields) were available for follow-up for a mean (range) of 14.6 (0.4-82.5) months. At 3 weeks post-treatment, 34 fields had complete, ongoing, or partial responses; 39 fields had no response; and there were no recurrences in the 11 fields treated for microscopic residual disease. Local control was maintained in 31% (26/84) fields with a mean follow-up of 14.6 months. At 36 months, five patients remained alive with complete control of their treated local disease. Statistical analyses revealed that patients with soft tissue metastases only, who were older at the time of hyperthermia, had a longer time between initial diagnosis and hyperthermia treatment, received a higher dose of radiation, had no previous chemotherapy, and had small tumour volumes, had a higher initial response. Multivariate analyses revealed that the three-covariate model including time interval between initial diagnosis and hyperthermia treatment, previous chemotherapy, and metastases to soft tissue only, best predicted response. The results of the investigation support the continued study of combined radiation therapy and hyperthermia treatments for selected patients with metastatic melanoma, and indicate that long-term survival can occasionally be obtained with this approach.
Adult↗
Influence of water bolus temperature on measured skin surface and intradermal temperatures.
Temperature measurements utilizing thermometry probes placed on the skin surface are often used clinically to assess temperatures for the purposes of power control and evaluating treatment efficacy. There is a question, however, as to what extent applicator temperature-controlled liquid coupling boluses can create temperature gradients which can cause significant differences between measurements taken by sensors placed on the skin surface and the actual temperature of the tissue beneath. To address this question, experiments were conducted with human subjects instrumented with surface and shallowly implanted temperature sensors. Microwave applicators with circulating bolus water set at 21 and 41 degrees C were used to induce a temperature gradient in depth in the superficial tissue by thermal conduction. No microwave energy was applied. The average measurement offset at 41 degrees C was 15% of the difference in temperature between the interstitially measured skin temperature and the coupling bolus temperature, towards the temperature of the coupling bolus. The corresponding offset with coupling boluses set near 21 degrees C was 32%. Different water bolus types and volumes were observed to induce different percentage offset errors.
Connective Tissue↗
From laboratory studies to clinical trials: past benefits and future directions in hyperthermia.
Three examples of clinical research trials that were direct outgrowths of hyperthermia laboratory investigations performed at Stanford University, as well as elsewhere, are reviewed and directions for future studies presented. The first series of laboratory-clinical studies investigated the influence of the number of hyperthermia treatments on tumour response in combined radiotherapy-hyperthermia regimens. A prospective randomized clinical trial was performed and showed no difference in response rate or duration of local control in combined radiation therapy-hyperthermia regimens comparing two versus six hyperthermia treatments. The results were in agreement with the laboratory studies in RIF murine tumours which suggested that persistent thermotolerance limited the effectiveness of multiple heat treatments in fractionated hyperthermia treatment regimens. The second prospective clinical trial was undertaken to investigate the influence of pretreatment tumour temperatures on subsequent response to radiotherapy and hyperthermia. In agreement with the laboratory studies, low (< 37 degrees C) pretreatment temperatures sensitized superficially located tumours to subsequent hyperthermia treatment. Lower pretreatment temperatures and larger differentials between minimum treatment temperatures and pretreatment maximum or mean temperatures were correlated with the duration of local control. The final studies investigated thermosensitizing agents, agents which were non-toxic at 37 degrees C but became cytotoxic at elevated temperatures. Thermosensitizers such as sulphydryl compounds have demonstrated up to 10,000-fold enhancement of cell killing at exposure to 43 degrees C for 1 h and may be considered for tumour sensitization. However, normal tissue may also be sensitized as was noted for topical anaesthetics such as lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Direct clinical comparison of ultrasound and radiative electromagnetic hyperthermia applicators in the same tumours.
Hyperthermia in conjunction with radiation therapy is a promising method for the treatment of superficially or eccentrically located recurrent or advanced primary malignant tumours. The external hyperthermia applicators most commonly used are radiative electromagnetic (including microwave) or ultrasound devices. Each type of device has its own limitations. The aim was to evaluate the temperature distributions obtained as well as the acute and subacute toxicities in patients that were treated with both radiative radiative electromagnetic and ultrasound applicators to the same tumours. Thirty-nine patients treated to 41 hyperthermia fields for a total of 197 hyperthermia treatments were analysed. Thermal parameter include mean, Tmax, mean Tave, mean Tmin, T50, T90, %T > 43.5 degrees C and %T < 41 degrees C. Acute toxicities including pain in field, referred pain, blister/ulceration, positional discomfort and subacute toxicities (occurring with 24 h of treatment) were determined for each type of hyperthermia applicator. Although there were increased acute toxicities (in-field or referred pain) associated with the ultrasound treatments no significant differences between the two methods of heating were observed in temperature distributions or subacute toxicities. We conclude that there is no generally preferred method of heating superficially or eccentrically located tumours and the type of applicator should be selected on a tumour-size and site-specific basis.
Adult↗
A phase III study on hyperthermia in head and neck canine tumours: not hot enough.
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Animals↗