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Biomedical subjects

P Sminia

Publications and source records attributed to P Sminia.

At least 19 recordsLinked to original sources
PubMed1999

Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 isoforms and TGF-beta type I and type II receptors in multiple sclerosis lesions and human adult astrocyte cultures.

It is known that the pleiotropic cytokine transforming growth factor beta (TGF-beta) has a regulatory role in the process of tissue repair and remodelling following injury. As reports on these molecules in multiple sclerosis (MS) lesion with different lesional activity are rare, we studied the cellular localization of TGF-beta1, -beta2, and -beta3 isoforms, and TGF-beta receptor type I (TGF-betaR-I) and TGF-betaR-II expression by immunohistochemistry on postmortem brain tissue from MS and normal control cases. To validate the TGF-beta staining results we demonstrated that cultured human adult astrocytes that produce biological active TGF-beta2, and to a lesser extent TGF-beta1, were immunoreactive for all 3 TGF-beta isoforms. Moreover, at mRNA level TGF-beta1 was detected in MS and normal control brain tissue. In normal control brain tissue, TGF-beta isoforms were expressed in ramified microglia and TGF-beta2, and -beta3 on neuronal cells in the gray matter TGF-betaR-I and TGF-betaR-II expression was found on endothelial cells, astrocytes, microglia, and neurons. In active demyelinating MS lesions a strong to intense immunoreactivity was detected for all 3 TGF-beta isoforms in perivascular and parenchymal (foamy) macrophages and in hypertrophic astrocytes. Strong immunoreactivity for TGF-betaR-I and TGF-betaR-II was found on macrophages in both parenchymal and perivascular areas and on hypertrophic astrocytes and endothelial cells in active demyelinating MS lesions. In chronic active and inactive MS lesions, all 3 TGF-beta isoforms and their receptors were strongly expressed in hypertrophic astrocytes. Our findings strongly suggest that the expression of the various TGF-beta isoforms and their receptor types found in MS lesions with different cellular activity participate in reactive processes leading to the formation of chronic MS lesions.

Activin Receptors, Type I↗
PubMed1998

Pulse frequency in pulsed brachytherapy based on tissue repair kinetics.

PURPOSE: Investigation of normal tissue sparing in pulsed brachytherapy (PB) relative to continuous low-dose rate irradiation (CLDR) by adjusting pulse frequency based on tissue repair characteristics. METHOD: Using the linear quadratic model, the relative effectiveness (RE) of a 20 Gy boost was calculated for tissue with an alpha/beta ratio ranging from 2 to 10 Gy and a half-time of sublethal damage repair between 0.1 and 3 h. The boost dose was considered to be delivered either in a number of pulses varying from 2 to 25, or continuously at a dose rate of 0.50, 0.80, or 1.20 Gy/h. RESULTS: The RE of 20 Gy was found to be identical for PB in 25 pulses of 0.80 Gy each h and CLDR delivered at 0.80 Gy/h for any alpha/beta value and for a repair half-time > 0.75 h. When normal tissue repair half-times are assumed to be longer than tumor repair half-times, normal tissue sparing can be obtained, within the restriction of a fixed overall treatment time, with higher dose per pulse and longer period time (time elapsed between start of pulse n and start of pulse n + 1). An optimum relative normal tissue sparing larger than 10% was found with 4 pulses of 5 Gy every 8 h. Hence, a therapeutic gain might be obtained when changing from CLDR to PB by adjusting the physical dose in such a way that the biological dose on the tumor is maintained. The normal tissue-sparing phenomenon can be explained by an increase in RE with longer period time for tissue with high alpha/beta ratio and fast or intermediate repair half-time, and the RE for tissue with low alpha/beta ratio and long repair half-time remains almost constant. CONCLUSION: Within the benchmark of the LQ model, advantage in normal tissue-sparing is expected when matching the pulse frequency to the repair kinetics of the normal tissue exposed. A period time longer than 1 h may lead to a reduction of late normal tissue complications. This theoretical advantage emphasizes the need for better knowledge of human tissue-repair kinetics.

Animals↗
PubMed1998

Enhancement of radiosensitivity of rat rhabdomyosarcoma R1H with normobaric carbogen and hyperbaric oxygen (HBO) using conventionally fractionated irradiation.

Hypoxic clonogenic cells are an important contributory factor in tumour radioresistance. The objective of the present study was to evaluate whether hyperbaric oxygen enhances tumour radiosensitivity, using a conventionally fractionated irradiation schedule, and whether the radiosensitizing potential is different from carbogen. Experiments were performed using the rhabdomyosarcoma R1H model transplanted subcutaneously in the flank of WAG/Rij rats. A total of 30 X-ray fractions of 2 Gy were given either in air, normobaric carbogen or high pressure oxygen (HPO) (240 kPa, 2.37 atm) without anaesthesia. The time taken to achieve complete remission was 38.7 +/- 3.6 days, 36.7 +/- 2.7 days and 32.4 +/- 4.1 days for air, normobaric carbogen and HBO, respectively. The differences between air and HBO (p = 0.002) and carbogen and HBO (p = 0.015) were significant. Use of carbogen and HBO produced the same local control probability at 150 days and this was significantly higher than local control under ambient conditions (p < 0.0001). It was concluded that the time to achieve complete remission of the rat rhabdomyosarcoma R1H can be shortened by HBO. Furthermore, both HBO and carbogen give higher local control probabilities than treatment under ambient conditions when used with a conventionally fractionated radiation schedule.

Animals↗
PubMed1997

Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas.

The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastoma patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas.

Cell Division↗
PubMed1996

Hyperthermia, radiation carcinogenesis and the protective potential of vitamin A and N-acetylcysteine.

The in vivo carcinogenic risk of hyperthermia, alone or in combination with irradiation, and the anti-carcinogenic potential of vitamin A and N-acetylcysteine (AcCys) were investigated. Starting 1 month before treatment, 160 rats were divided into four diet groups: no additives, vitamin A-enriched diet, AcCys and the combination vitamin A + AcCys. In 10 animals per diet group, the hind leg was treated with either X-irradiation alone (16 Gy), hyperthermia alone (60 min at 43 degrees C), hyperthermia 5 h prior to irradiation or hyperthermia 5 h after irradiation. Animals were observed for 2 years after treatment with regard to the development of tumours either inside or outside the treated volume. After 16 Gy alone 12 +/- 5% of the animals developed a tumour. Tumour incidence increased to 37 +/- 9% (borderline significance P = 0.07 versus treatment with X-rays alone) when hyperthermia was applied prior to X-rays, and to 24 +/- 8% (NS) with hyperthermia after irradiation. The relative risk ratio (RRR) for tumour induction was increased to 2.4 by hyperthermia if combined with X-irradiation. Pathological characterization of induced tumours showed that these were of the fibrosarcoma, osteosarcoma and carcinoma type. Vitamin A alone or in combination with AcCys slightly protected against the induction of tumours by X-rays without or with hyperthermia (RRR of 0.4). However, morphological changes such as lipid accumulation in hepatocytes and damage to the parenchyma were noticed in livers from all animals that were given a vitamin-A-enriched diet (P < 0.0001). Data from the present and past reports show that hyperthermia alone is not carcinogenic, but that it may increase radiation carcinogenesis. Treatment temperature and time of exposure to heat in addition to the radiation dose applied are important factors in the carcinogenic process. The enhancement of radiation carcinogenesis seems to occur independently of the sequence and time interval between irradiation and hyperthermia. However, not all data are consistent with this interpretation.

Acetylcysteine↗
PubMed1995

Neurological observations after local irradiation and hyperthermia of rat lumbosacral spinal cord.

PURPOSE: Investigation of the effects of hyperthermia on the radiation response of rat lumbosacral spinal cord with respect to: (a) incidence of paralysis, (b) latency, (c) histopathology, and (d) tumor induction. METHODS AND MATERIALS: Rat lumbosacral spinal cord with the cauda equina was single-dose irradiated with 15 to 32 Gy of x-rays. Hyperthermia for 30 min at a spinal cord temperature of 41.1, 42.3, and 42.6 +/- 0.4 degrees C was applied 5 to 10 min after irradiation by means of a 434 MHz microwave applicator. Animals were observed for 21 months while recording myelopathy and development of tumors. RESULTS: The latent period for hind leg paralysis decreased with increasing radiation dose from 359 +/- 31 days (n = 9) after 20 Gy to 200 +/- 4 days (n = 5) after 32 Gy. Hyperthermia enhanced the radiation response of the lumbosacral spinal cord as evidenced by shortening of the latent period for paralysis and a decrease in the biological effective dose. After 20 Gy followed by 30 min 41.1 degrees C, latency was diminished to 214 +/- 16 days (n = 7, p < 0.001 vs. 20 Gy alone). The ED50 was 21.1 Gy, which was diminished to values between 16 and 17 Gy if radiation was followed by hyperthermia, giving a thermal enhancement ratio between 1.24 and 1.32. Histopathological examination of the spinal cord after combined treatment of x-rays and hyperthermia showed necrosis of nerve roots. Irradiation with 16, 20, 24, and 28 Gy (n = 77) alone led to tumor induction in 17 +/- 8% of the animals (pooled data). If followed by hyperthermia (n = 96), it was increased to 33 +/- 12% (p < 0.01). Most tumors induced by radiation and hyperthermia were sarcomas. CONCLUSION: First, the radiation response of rat lumbosacral spinal cord was enhanced by heat. Second, latency for paralysis was shortened in the lower dose range. Third, no difference in pathology between x-rays alone or in combination with hyperthermia. Fourth, hyperthermia did increase radiation carcinogenesis.

Animals↗
PubMed1993

Feasibility of curative radiotherapy with a concomitant boost technique in 33 patients with non-small cell lung cancer (NSCLC)

Thirty-three patients with an inoperable NSCLC were treated with a dose of 60 Gy/20 fractions/25 days, using a concomitant boost technique. A dose of 40 Gy/2 Gy/25 days was given to the tumor area and a part (15 patients) or the whole (18 patients) mediastinum. During each session a simultaneous boost to the tumor of 1 Gy was administered. Moderate acute oesophageal toxicity was observed in 7/33 patients (22%). One out of 33 patients developed serious late oesophageal toxicity. A correlation between the oesophageal toxicity, absorbed oesophageal dose of irradiation and length of the elective field was observed. Five out of 33 patients developed subacute radiation pneumonitis grade 2 or 3. In selected patients with inoperable NSCLC radiotherapy, with a dose of 60 Gy/20 fractions/25 days, using a concomitant technique is feasible.

Adult↗
PubMed1993

Long-term observation of the rat skin after fractionated local X irradiation: development of secondary tumors.

Data from previous animal experiments were analyzed retrospectively with a view to the induction of secondary tumors. The skin of 86 rats was exposed locally to multiple fractions of 200 kV p X rays at doses of 60 to 82 Gy applied in 30 or 35 fractions in 6 weeks, i.e., in the clinically relevant range of 1.9 to 2.7 Gy per fraction. The course of the early skin reaction was scored and compared to the late carcinogenic effects of the treatment using Kaplan-Meier data analysis. With increasing total dose the median duration of the early skin reaction increased, while median latency of tumor induction in the irradiated area of skin decreased from 381 days after 60 Gy to 274 days after 82 Gy. Independent of the total dose, number of fractions, and operative intervention, 84 to 100% of the animals cured by irradiation developed a secondary neoplasm inside the treated area. The majority of induced tumors were squamous cell carcinomas. In the skin covering the thorax, which had received a dose of 15 Gy in 10 fractions for elective irradiation of the lungs, no tumors were induced.

Animals↗
PubMed1992

The influence of hyperthermia on the uptake of cisplatin in the rat cervical spinal cord.

The influence of local hyperthermia on the uptake of cisplatin in the rat cervical spinal cord was investigated. After single intraperitoneal or intravenous injection of cisplatin (5 mg/kg body weight), the spinal cord region cervical 5-thoracic 2 was heated for 60 min at mean (S.D.) 41.2 (0.4) degrees C or 40 min 42.4 (0.3) degrees C using a 434 MHz microwave heating device. One day after treatment with either hyperthermia alone, cisplatin alone or the combination, none of the animals expressed neurological symptoms. The spinal cord was dissected and platinum levels were measured by flameless atomic absorption spectroscopy. No difference was found in uptake of platinum in the spinal cord between control- and heat treated animals. In a second series of experiments, the spinal cord was heated for 30-60 min. during a 2 h infusion of cisplatin. One day after treatment at 42.3 degrees C for 60 min, neither motor nor sensory functions were affected and platinum levels did not differ significantly between control and treated animals. Also, platinum levels measured in the spinal cord immediately after cisplatin infusion were not influenced by heat treatment at 42.1 or 43.0 degrees C for 30 min. However, after a heat dose of 60 min 43 degrees C, cisplatin uptake was significantly increased (P less than 0.001) by a factor of 2.8 (1.3). The data demonstrate that mild hyperthermia has no effect on the uptake of cisplatin in the spinal cord, while an injurious heat dose leads to a significant increase in cisplatin uptake. The present findings indicate that, in case of treatment of tumours of the central nervous system with hyperthermia and cisplatin, a treatment which might be toxic for the tumour is well tolerated by the normal nervous tissue.

Animals↗
PubMed1992

Neurological complications after 434 MHz microwave hyperthermia of the rat lumbar region including the spinal cord.

Hyperthermia was applied in the region of the vertebral column from the second to the fifth lumbar vertebra using a ring-shaped 434 MHz microwave radiator. In all experiments temperatures were measured at a 'reference' thermocouple which was placed against the fourth lumbar vertebra. After 60 min of heat treatment at 'reference' temperatures of 43.0 degrees C, 44.0 degrees C and 45.0 degrees C (+/- 0.05 degrees C) the average maximal temperature inside the vertebral canal were 42.6 degrees C, 43.0 degrees C and 43.8 degrees C (+/- 0.3 degrees C), respectively. At all 'reference' temperatures the maximal core temperature of the animal did not exceed 40.5 +/- 0.3 degrees C after 60 min of heat treatment. Dorsal skin and muscle temperatures in the treatment area reached 'reference' temperature, and transient skin and muscle necrosis was observed after treatment for 1 h at 'reference' temperatures at 44 degrees C and 45 degrees C. Temperatures in the peritoneal cavity approximately 1 mm ventrally of the vertebral column rose to 41.8 degrees C after 60 min at reference 43.0 degrees C. Treatment at spinal cord temperature 42.6 degrees C for 60 min did not induce any significant neurological effects. Motoric dysfunction of the hind legs, such as difficulties with walking, was observed after 60 min treatment at spinal cord temperatures of 43.0 degrees C or 43.8 degrees C. In addition, 24 h after treatment at 43.8 degrees C for 60 min loss of tail tonus was observed, as well as loss of sensory function in the hind limbs. Recovery from the neurological disorders, except for the loss of tail tonus, occurred within 2 weeks after treatment. Histopathological examination revealed necrosis in the central areas of the spinal cord at 3 days and complete necrosis at 7 days after treatment at 43.8 degrees C for 60 min.

Animals↗
PubMed1991

Effects of hyperthermia applied to previously irradiated cervical spinal cord in the rat.

Rat cervical spinal cord was X-ray irradiated at doses of 15, 18, 20 and 26 Gy. Ninety days later, approximately the same part of the spinal cord was heated at 42.3 +/- 0.4 degrees C for 50, 60, 75 or 90 min by means of a 434 MHz microwave applicator. After treatment, animals were observed over a period of 18 months for expression of neurological complications. These complications could either be the result of the heat or of the radiation treatment. The time course showed three distinct peaks in the incidence of neurological symptoms. The first peak was due to the acute response to hyperthermia. The ED50 value for neurological complications one day after treatment at 42.3 +/- 0.4 degrees C was 74 +/- 2 min. Previous X-ray irradiation of the spinal cord with 18, 20 and 26 Gy reduced the ED50 to 57 +/- 7, 65 +/- 4 and 55 +/- 5 min (12-26% of control), respectively. Recovery from heat-induced neurological complications was diminished in previously irradiated animals. The second peak (150-300 days after X-rays) concerned the expression of "early delayed" radiation damage. Hyperthermia given 90 days after irradiation did not influence either the percentage of animals with paralysis or the latent period. Neurological symptoms developing after day 300 were due to the "late delayed" radiation response. No significant difference was observed in the data on paralysis induced by radiation alone or radiation followed by heat. The late radiation-induced minor neurological symptoms were, however, influenced by retreatment with heat.

Animals↗
PubMed1991

Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats.

The purpose of this study was to optimise intraperitoneal chemotherapy by combining this modality with regional hyperthermia. In vitro data demonstrated that both the uptake of cisplatin into CC531 tumour cells and cytotoxicity were increased at temperatures of 40 degrees C (factor 4) and 43 degrees C (factor 6) compared to 37 degrees C. The increase of intracellular platinum concentration correlated well with the decrease in survival of these cells. In vivo, rats were treated intraperitoneally with cisplatin (5 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3) degrees C and outside the peritoneal cavity 40.5 (0.3) degrees C. Enhanced platinum concentrations were found in peritoneal tumours (factor 4.1) and kidney, liver, spleen and lung (all around a factor 2.0), after combined cisplatin-hyperthermia treatment. The platinum distribution in peritoneal tumours was more homogeneous after the combined treatment than after cisplatin alone, possibly due to increased penetration of cisplatin into peritoneal tumours. Pharmacokinetic data demonstrated an increased tumour exposure for unfiltered platinum in the peritoneal cavity (area under the curve [AUC] increased from 339 mumol/l/min to 486 mumol/l/min at 37 degrees C and 41.5 degrees C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 mumol/min and for ultrafiltered platinum from 22.2 to 107 mumol/l/min at 37 degrees C and 41.5 degrees C respectively. The latter might be due to a slower elimination of platinum from the blood. The combined treatment, intraperitoneal cisplatin and regional hyperthermia, also increased toxicity. The thermal enhancement ratio (TER) using lethality as endpoint was 1.8.

Animals↗
PubMed1991

Enhancement by hyperthermia of the 'early delayed' and 'late delayed' radiation response of the rat cervical spinal cord.

The cervical spinal cord (C5-T5) of female Wistar WU rats was irradiated with 250 kV X-rays (15-32 Gy). Heat was applied at approximately the same site 7 +/- 1 min after X-rays. 'Early delayed' paralysis of the forelegs was observed 5-10 months after treatment. The ED50 (+/- SE) after single-dose irradiation alone was 25.8 +/- 0.4 Gy. 'Late delayed' paralysis and paresis were observed 11-21 months after irradiation with an ED50 (X-rays alone) of 22.7 +/- 0.6 Gy. The data for late paralysis, late paresis and minor neurological symptoms were pooled resulting in an ED50 (+/- SE) of 20.6 +/- 0.7 Gy. Hyperthermia enhanced the radiation response. Thermal enhancement ratios (TER) in the 'early delayed' response after a 30 min treatment with 41.1 +/- 0.4 degrees C 42.1 +/- 0.4 degrees C and 42.9 +/- 0.4 degrees C were 1.07 +/- 0.08, 1.17 +/- 0.08 and 1.12 +/- 0.04, respectively. For the 'late delayed' radiation response concerning paralysis and paresis the TER after 30 min at 41.1 degrees C and 42.1 degrees C were 1.25 +/- 0.10 and 1.31 +/- 0.07, respectively. The latent period for paralysis was not significantly affected. Pathological examination of the spinal cord after combined treatment of X-rays and hyperthermia showed focal demyelination with white matter necrosis and vascular injury in animals as an indication of 'early delayed' and 'late delayed' paralysis, respectively. This was not different from histopathological changes observed after irradiation alone.

Animals↗