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H S Reinhold

Publications and source records attributed to H S Reinhold.

At least 19 recordsLinked to original sources
PubMed2001

A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model. I. Relative contributions of glucose and heating to tumor acidification.

PURPOSE: To establish dose-effect relationships for tumor acidification induced by heat and glucose as a basis for testing the value of adding glucose administration to combined heat and x-ray treatment at clinically achievable glucose and temperature levels. METHODS AND MATERIALS: Rhabdomyosarcoma BA1112 was grown s.c. in the upper leg of 16-20-week-old Wag/Rij rats. Animals were given 2 consecutive 100-min periods of saline (S) or glucose (G) infusion, while keeping tumor temperature at 37 degrees, 42 degrees, or 43 degrees C for 1 or 2 periods, in various combinations, each involving 6 animals. Glucose was infused i.v. as a 20% solution at 2.4-3 g/kg/h. Tumors were heated using 2,450-MHz electromagnetic radiation, and tumor pH was measured using a 0.7 mm fiberoptic probe. RESULTS: Mean overall baseline pH was 7.00 (SD 0.10). The change induced by G37G43 (i.e., glucose infusion for a full 200 min, first 100 min at 37 degrees C, final 100 min at 43 degrees C) was -0.48 +/- 0.03 (SEM) pH units, and -0.17 +/- 0.03 for S37S43. The effect of G37G42 was -0.37 +/- 0.03 pH units, compared with -0.08 +/- 0.02 for S37S42 and -0.28 +/- 0.04 for glucose alone (G37G37). Glucose was less effective when given after or fully parallel to heating: -0.21 +/- 0.02 pH units for S43G37 and -0.37 +/- 0.02 for G43G43. CONCLUSION: The glucose-induced tumor pH drop is much more pronounced than that induced by heat, both of which are dose dependent. The effects of glucose and heat seem additive if heating is started when glucose-induced acidification has reached its plateau level, but the overall effect is diminished if administration is fully simultaneous or in reversed order. Schedule G37G43 is optimal with respect to tumor acidification. Its predicted superiority in thermoradiotherapy as compared with S37S42, S37S43, and G37G42 treatment regimens was confirmed in a subsequent experimental tumor control study.

Animals↗
PubMed2001

A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model II. Improved tumor control at clinically achievable temperatures.

PURPOSE: To assess the therapeutic gain (at the TCD(50) level) that can be obtained by boosting thermoradiotherapy with intravenous glucose infusion at different temperatures. This completes our series of studies to determine the optimal conditions and the effectiveness of glucose administration at clinically achievable glucose levels and treatment temperatures. METHODS AND MATERIALS: Subcutaneous rat rhabdomyosarcoma BA1112 was irradiated with graded single doses of 300-kV X-rays (dose range 0-60 Gy). Fifteen minutes after irradiation, a 100-min intravenous infusion was started, consisting of either glucose (20% solution, 2.4-3 g/kg/h) or saline as a control. Then heat was applied to the tumors at 42 degrees C or 43 degrees C (water bath) during a subsequent 100-min period of infusion. Tumor control was scored as the absence of palpable growth at 100 days after treatment. RESULTS: Glucose infusion enhanced tumor control independent of temperature in the range 42-43 degrees C. At 42 degrees C, the TCD(50) for X-irradiation decreased by 5.9 Gy (SEM 1.8 Gy), from 41.6 (1.6) to 35.7 (1.5) Gy, and at 43 degrees C from 33.3 (1.6) to 27.3 (1.5) Gy, representing a glucose enhancement ratio of approximately 1.2. At doses corresponding to the TCD(50) at either 42 or 43 degrees C, the addition of glucose increased tumor control from 50% to 70%. An enhancement ratio of 2.1 was found for the combination of irradiation, glucose infusion, and heating at 43 degrees C, with respect to irradiation alone (TCD(50) 56.3 Gy, reanalyzed earlier data). The contribution of combined heat and glucose to tumor control represented an additive effect, probably on the hypoxic cell population. CONCLUSION: Moderate glucose administration (blood concentration 300 mg/100 mL) sizably improves experimental tumor control after combined X-irradiation and hyperthermia under clinically feasible conditions. Clinical treatment should benefit from this additional modality, in particular if unsatisfactory local control rates are due to insufficient heating. The therapeutic gain has to be evaluated further in clinical studies.

Animals↗
PubMed1991

Dose-effect relationships for glucose-induced tumour acidification and its erythrocyte flux.

Preclinical investigations were performed with glucose administration in WAG/Rij rats carrying the rhabdomyosarcoma BA1112 in two sites per animal: one in the subcutis of the flank (for pH measurements in the tumour tissue) and one in the transparent "sandwich" chamber for measuring the erythrocyte flux in the tumour tissue as an indication for changes in tumour blood flow. A glucose solution (20%) was slowly infused intravenously in a range of dose levels, similar to those reported for inducing long-term hyperglycaemia in man. The eventual aim of such investigations is to sensitise tumours for hyperthermic treatment. This approach is not new, but the present experiments were performed with the aim to explore the level of the minimal amount of glucose which would nonetheless yield a likely therapeutic effect. Endpoints in this study were the blood glucose level and pH and the relative erythrocyte flux in the tumour tissue. Obviously, as one would expect, many significant changes in the various parameters were found as a response to administration of glucose. However, the changes in the blood glucose level, the induced decrease in tumour pH and the influence of the tumour volume did not show a well-defined relationship which was reliable enough to predict the exact influence of the various parameters on the magnitude of the desired changes in individual animals and/or tumours. This was probably caused by interfering differences in physiological feedback mechanisms. Nonetheless, the data indicate that the optimal effect was not obtained with the highest treatment level, but with moderate doses of glucose, i.e. 2.4-3 g.kg/h which induced a satisfactory tumour acidification of 0.25 pH units. This may turn out to a clinically useful pH drop for enhancing the cytotoxic effect of hyperthermia. The erythrocyte flux through the tumour tissue does not appear to be influenced to a sizeable extent by such a treatment.

Animals↗
PubMed1990

Development of blood vessel-related radiation damage in the fimbria of the central nervous system.

The identification problem of the dose-limiting tissue component was investigated in the CNS of rats. Moderate single doses of radiation, ranging from 20 to 25 Gy were applied to the brain of adult female rats. The sequence of events was analyzed by scoring a series of morphological changes in one of the white matter structures that appears to represent a sensitive location, that is the fimbria hippocampi. The previously defined "Tissue Injury Unit", characterized by a dilation of the blood vessel lumen, a thickening of the blood vessel wall, an enlargement of endothelial cell nuclei, and a hypertrophy of the adjacent astrocytes which represents a combined score of four different, but related histological changes, proved to be slightly more sensitive and responsive than the earliest recognizable changes in the neurological structures, that is demyelination. In addition, the incidence of demyelination could be expressed as a function of the intensity of the "Tissue Injury Unit". These findings can be interpreted as an additional indication that blood vessel changes and the hypertrophy of the perivascular astrocytes precede degenerative changes in the white matter of the CNS after moderate doses of X rays.

Animals↗
PubMed1990

Measurement of tumor pH during microwave induced experimental and clinical hyperthermia with a fiber optic pH measurement system.

The influence of hyperthermia on tissue pH was investigated using a modified version of the fiber optic monitoring system. This newly developed system was tested for use in tissues and found to be suitable for pH measurement during microwave induced hyperthermia. The fiber optic pH probe (0.7 mm diameter) could be easily used in the electromagnetic fields produced by the microwave applicators, whereas only the display unit required some shielding. Tissue pH of experimental and clinical tumors was measured concurrently with local microwave hyperthermia treatment. The mean initial intratumor pH of a rat rhabdomyosarcoma was 7.03 (SD 0.13, n = 19) and the pH of human subcutis was 7.45 (SD 0.02, n = 8). In rat tumor a primary pH decrease was observed during heating which was fully reversed during cooling. The coefficient of temperature dependence was -0.016 pH unit/degree C (SD 0.004, n = 12). After approximately 1 hr of heating at 43 degrees C a further pH decrease of 0.1-0.3 unit occurred which was not reversed directly after treatment. Measurements during clinical local microwave hyperthermia treatments after radiotherapy revealed similar changes in pH values, primary as well as secondary. The estimated coefficient of temperature dependence for the reversible pH change, which occurred in subcutis as well as in tumor tissue, was -0.016 pH unit/degree C (SD 0.004, n = 12). The fiber optic pH measurement system is expected to be a valuable tool in the thorough investigation of temperature and time related pH changes in tumor during experimental as well as clinical hyperthermia treatment.

Acid-Base Equilibrium↗
PubMed1990

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.

Absorption↗
PubMed1989

The relationship between the unmodified initial tissue pH of human tumours and the response to combined radiotherapy and local hyperthermia treatment.

The relationship between unmodified tumour pH before treatment and tumour response was investigated in patients receiving combined radiotherapy and local hyperthermia treatment. Tumour pH showed a statistically significant positive correlation with the response rate (Spearman correlation coefficient 0.31, n = 50, 2P less than 0.05). The mean pH of tumours showing a complete response (CR) was significantly higher than that of tumours showing a partial response (PR) as well as those showing no change (NC). As the means of the PR and NC groups were not significantly different from each other, these groups were combined for further analysis. The pH of the CR group was also significantly different from that of the NC + PR group (CR: 7.36 +/- 0.05, median 7.36, n = 18, NC + PR: 7.16 +/- 0.06, median 7.21, n = 32); Mann-Whitney test: 2P less than 0.05). Stratification of the data with respect to radiotherapy dose, hyperthermia dose or tumour volume showed that these factors were not associated with tumour pH to such a degree that they might have seriously biased the results. The results suggest that enhancement of the cytotoxic effects of hyperthermia by low pH known from experiments with cell cultures is not observed in tumours which are treated with radiotherapy and hyperthermia, and that even the converse may occur. The reasons for this are discussed at length and it is suggested that sudden modification of the tumour pH directly prior to or during treatment is imperative to obtain any sensitizing effect.

Combined Modality Therapy↗
PubMed1989

Differences in the response of the microcirculation to hyperthermia in five different tumours.

The response of the microcirculation in five different tumours, growing in 'sandwich' observation chambers in the back of the rat, to hyperthermia was investigated. The tumours investigated encompassed three human xenografted tumours, of which two were carcinomata of the colon and one of the lung, and two isologous rat tumours, the Rhabdomyosarcoma BA1112 and a rat mammary carcinoma. It was concluded (1) that the various tumours required significantly different exposure times for inducing 50% stoppage of the tumour microcirculation (ST50). This seems to indicate that differences in the characteristics of the tumour cells are more important for causing microcirculatory stoppage than is the sensitivity of the cells of the blood vessels. (2) An increase in surface (i.e. volume) was observed in all four tumours examined for this phenomenon. The rate of increase (usually 1-2% per hour at 42.5 degrees C) was, however, significantly different between the various tumours. This rate was higher exposure temperatures (43 and 43.5 degrees C), but this was only investigated for the Rhabdomyosarcoma BA1112. Extensive statistical analysis of this phenomenon of volume increase could not demonstrate a correlation with any of the circulation parameters. (3) The relative velocity of the erythrocytes in selected capillaries in the tumours decreases as a result of the hyperthermic treatment, and is probably related to the tumour-specific ST50. (4) A human colon carcinoma xenograft, one of the tumours investigated, showed strong fluctuations in the parameter 'erythrocyte velocity'. The appearance of such fluctuations did not seem to influence the heat-induced stoppage of the circulation. Probably the phenomenon of fluctuations in the velocities of the erythrocytes in the tumour capillaries is a tumour-specific phenomenon.

Adenocarcinoma↗
PubMed1988

Time- and dose-related changes in the white matter of the rat brain after single doses of X rays.

Following the local irradiation of the rat brain with single doses of 17.5-25 Gy of X rays, necrosis of the white matter was seen after a latent interval of greater than 26 weeks. At 39 weeks and 52 weeks after irradiation the incidence of necrosis was dose-related. The doses associated with a 50% incidence of necrosis in the white matter (ED50) at these times were 23.45 +/- 0.49 and 20.98 +/- 0.91 Gy, respectively. At both these times the incidence of necrosis was higher in the fimbria than in the capsula interna and the corpus callosum. This reflects a variation in the latency time for the appearance of necrosis. Necrosis occurs earlier in the fimbria. In the corpus callosum and the capsula interna the latency times for the appearance of necrosis were also dose-dependent. In the latent period prior to the onset of necrosis of the fimbria, a number of dose-related changes were seen in the vasculature and the associated astroglial cells. These changes, which included blood vessel dilation, blood vessel wall thickening, endothelial cell nuclear enlargement and the hypertrophy of perivascular astrocytes, were highly correlated and when combined appeared to represent a "unit of tissue injury". The incidence and severity of this "unit of tissue injury" apparently increased with time after irradiation until necrosis ensued. These dose-related vascular/glial changes were preceded by a reduction in the endothelial cell and vascular density. No early changes were seen in the number of glial parenchymal cells.

Animals↗
PubMed1987

Experimental hyperthermic treatment of a human colon carcinoma xenograft. The thermal sensitivity of the tumour microcirculation.

The effect of hyperthermia on the microcirculation of a human colon tumour growing in a 'sandwich' observation chamber in immune-suppressed rats was investigated. Evaluation of the effect was based on microscopic observation, measurement of the relative flow rate of the blood in the capillaries of the tumour and photographic recording. The results indicated that moderate hyperthermia (3 h at 42.5 degrees C) has a destructive effect on the microcirculation of the tumour, followed the next day by severe necrosis. These results indicate that this human colon carcinoma xenograft has--for the endpoints that were investigated--a heat sensitivity that is comparable with rodent tumours.

Animals↗
PubMed1987

Dose-dependent and time-dependent changes in the choroid plexus of the irradiated rat brain.

A histological assessment has been made of both time- and dose-related changes in the choroid plexus after the local irradiation of the rat brain with single doses of 17.5-25 Gy of X rays. These investigations involved the serial killing of animals 1-52 weeks after irradiation and the quantitative and semiquantitative evaluation of histological sections. Counts of the relative number of cells in the choroid plexus of the lateral ventricles showed an atrophy of the epithelial layer after 13 weeks. However, this was not as marked as the reduction in the number of endothelial cells in the wall of blood vessels. Moreover, the epithelium had recovered by 39 weeks after irradiation, while the dose-related depletion in endothelial cells tended to be progressive. A highly correlated group of changes in the vascular-connective tissue was used to produce a numerical "factor". This represented a combined score of radiation damage which was both time- and dose-related. These data suggest that, as an expression of late radiation damage to the choroid plexus, the effect on the endothelium was more important than that to the epithelial cells.

Animals↗