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Biomedical subjects

L Dewit

Publications and source records attributed to L Dewit.

At least 19 recordsLinked to original sources
PubMed2005

Prolonged low dose IL-2 and thalidomide in progressive metastatic renal cell carcinoma with concurrent radiotherapy to bone and/or soft tissue metastasis: a phase II study.

Metastatic renal cell cancer is one of the immuno-sensitive tumors. Apart from the immuno-modulating agents IFNalpha and IL-2, thalidomide has been reported to be effective in this type of cancer. However, bone metastases and bulky metastases, show limited response to immunotherapy, are often site of recurrent disease and are therefore often treated later with radiotherapy. In this phase II study, we evaluated toxicity and efficacy of the combination of continuous low dose (1 mIU/m2) s.c. IL-2 and thalidomide (200 mg once daily) in 22 patients with progressive metastatic renal cell cancer. In addition, 13 soft tissue lesions and two bone metastases in 13 patients were concurrently treated with fractionated radiotherapy. T cell number and activation in blood was measured by immunoflowcytometry. Nearly all patients developed grade 1-2 toxicity consisting of fatigue, sensory neuropathy, constipation and dizziness. Five patients had a grade 3-4 toxic event: four patients with deep venous thrombosis requiring anticoagulant therapy, and one patient who developed radiation myelopathy. On systemic response evaluation ten patients showed ongoing SD with a mean progression free survival of 9 months. One patient showed a PR (at an irradiated site). Regarding local response to irradiation, seven lesions showed a PR for a mean time period of 8.7 months, whereas seven were stable for 6 months. The radiation response of one lesion was not evaluable. Immunoflowcytometry showed an increase in number and activation of lymphocytes (mainly Natural Killer--NK-cells), which was absent or even decreased in irradiated patients. The combination of sc. low dose IL-2, thalidomide and radiotherapy is feasible, but relatively toxic and does not lead to higher responses at non-irradiated sites. The combination of immunotherapy and concurrent radiotherapy is effective at 60% of the relatively large evaluable sites. Progressive myelopathy developed in one patient, possibly due to radiotherapy in combination with thalidomide.

Adult↗
PubMed2000

In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation.

Previous investigations have demonstrated an increased release of von Willebrand factor (VWF; also known as vWF) in endothelial cells after high single-dose irradiation in vitro. We have also found increased levels of Vwf protein in mouse glomeruli after a high single dose of renal irradiation in vivo. In addition, increased numbers of leukocytes were observed in the renal cortex after irradiation in vivo. The aim of the present study was to investigate and quantify these biological processes after clinically relevant fractionated irradiation and to relate them to changes in renal function. A significantly greater increase in release of VWF was observed in cultured human umbilical vein endothelial cells (HUVECs) after fractionated irradiation (20 x 1.0 Gy) than after a single dose of 20 Gy (147% compared to 115% of control, respectively, P < 0.0005). In contrast with the in vitro observations, glomerular Vwf staining was lower after fractionated irradiation in vivo (20 x 2.0 Gy or 10 x 1.6 Gy +/- re-irradiation) than after a single dose of 16 Gy. The number of leukocytes accumulating in the renal cortex was also lower after fractionated in vivo irradiation than after a single radiation dose. The onset of these events preceded renal functional and histopathological changes by approximately 10 weeks. These data indicate that radiation-induced changes in endothelial VWF expression after in vivo irradiation may be distinct from the in vitro observations. Increased VWF expression may reflect pivotal processes in the pathogenesis of late radiation nephropathy and provide a clue to appropriate timing of pharmacological intervention.

Animals↗
PubMed1995

Amelioration of radiation nephropathy by acetylsalicylic acid.

This investigation was carried out to assess the amelioration by two antithrombotic drugs of radiation nephropathy in mice. Mouse kidneys were given split-dose irradiation to total doses between 17 and 22 Gy. A first group of animals was given acetylsalicylic acid (ASA) in drinking water, a second received daltroban, a thromboxane A2/prostaglandin H2 receptor antagonist, and a third received normal tap water, serving as a control. Both antithrombotic drugs were started 1 week prior to the irradiation and were given throughout the whole follow-up period. Renal function was assessed every 4 weeks from 18 weeks after the start of irradiation onwards by measuring the [51Cr] EDTA retention and haematocrit. The dose of ASA (600 mg/kg/day) caused an inhibition of thromboxane A2 and prostacyclin biosynthesis to 19 +/- 10 (mean +/- SEM) and 85 +/- 22%, respectively, as assessed by the excretion of their urinary metabolites. A significant sparing effect on the renal function after irradiation was observed in the ASA-treated animals. Using the latency time to reach 4% residual plasma activity of [51Cr] EDTA, a dose-modifying factor of 1.19 was calculated. No effect was seen with daltroban (10 mg/kg/day). Histopathological analysis of the kidneys at 12 months after irradiation demonstrated a substantially lower level of damage in the ASA-treated mice compared with daltroban-treated and radiation-only animals. These data indicate that long-term treatment with ASA is effective in reducing renal functional impairment after irradiation.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Monitoring of blood-10B concentration for boron neutron capture therapy using prompt gamma-ray analysis.

The aim of the present study was to monitor the blood-10B concentration of laboratory dogs receiving boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry and showed good agreement. A substantial variation in 10B clearance pattern after administration of borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement was adjusted to the individually determined boron elimination curve. Mean blood-10B concentrations during irradiation of 25.8 +/- 2.2 micrograms/g (1 SD, n = 18) and 49.3 +/- 5.3 micrograms/g (1 SD, n = 17) were obtained for intended concentrations of 25 micrograms/g and 50 micrograms/g, respectively. These variations are a factor of two smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful blood-10B monitoring procedure is a prerequisite for accurately obtaining such steep dose-response curves as observed during the dog study.

Animals↗
PubMed1994

Radiation reduces cyclooxygenase activity in cultured human endothelial cells at low doses.

The effect of radiation on prostaglandin (PG) production was investigated in cultured human umbilical vein endothelial cells. It was found that 48 hours after irradiation the endothelial cell capacity to synthesize prostacyclin (PGI2), Prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) from exogenous arachidonic acid (AA) was strongly reduced in a radiation dose-dependent way, with 50% of the maximal inhibition at approximately 2 Gy. By incubating the endothelial cells between 24 and 48 hours after irradiation with 50 U/ml interleukin-2 (IL-2), which is known to selectively stimulate de novo synthesis of cyclooxygenase, the PGI2 synthesis from exogenous AA was nearly completely restored. Basal PGI2 release was not influenced by radiation (up to 25 Gy), nor was there increased cell damage as measured by LDH release during 72 hours after irradiation compared with controls. Clonogenic cell survival after irradiation showed a typical exponential radiation dose-response curve with a fairly broad initial shoulder. The data presented in this study suggest that the reduction of endothelial PGI2 synthesis after low doses of radiation is primarily due to a reduction in the activity of the enzyme cyclooxygenase.

Arachidonic Acid↗
PubMed1993

Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney.

Renal function was prospectively analysed in 26 patients treated with radiotherapy for various types of malignancies. In patients with gastric non-Hodgkin's lymphoma stage I-II (gNHL, n = 5), the 99mTc-diethylene-triamine-penta-acetic acid (99mTc-DTPA) renal uptake and the relative 99mTc-dimercapto-succinyl acid (99mTc-DMSA) accumulation decreased gradually and concomitantly in the high-dose, whole-volume irradiated left kidney (40 Gy/5, 5 weeks), down to 25 +/- 10% (mean +/- 1 S.E.M.) and 31 +/- 11%, respectively, after 6-9 years. The absolute 99mTc-DMSA uptake in the left kidney declined down to 33 +/- 12% whereas in the low-dose, whole-volume irradiated right kidney (12-13 Gy/3 weeks) it increased up to 187 +/- 11%. When considering renal volume changes with single photon emission computed tomography, the left kidney in the gNHL patients was reduced to 30 +/- 13%, with, surprisingly, a contralateral enlargement up to only 119 +/- 7% (P < 0.05). The overall renal function in this group of patients, as assessed by creatinine clearance and by [125I]iothalamate/[131I]hippuran clearance was reduced to 48-68%. In the Hodgkin's disease patients (HD, n = 7) given 40 Gy in 4 weeks to 30-50% of the left kidney, the 99mTc-DTPA filtration and the relative 99mTc-DMSA uptake in the left kidney was reduced to 75 +/- 4% and 81 +/- 3%, respectively. The absolute 99mTc-DMSA changes were 78 +/- 10% and 135 +/- 13%, respectively. No significant renal functional alterations were observed in patients with either ovarian carcinoma (n = 7) or seminoma (n = 7). These data suggest a significant, compensatory response of the non-irradiated or low-dose irradiated kidney which, however, appears to be incomplete after contralateral, whole-volume, high-dose irradiation. Such compensatory response might be overestimated when considering only relative or absolute changes in radioactivity uptake.

Blood Pressure↗
PubMed1992

Identification of the aadB gene coding for the aminoglycoside-2"-O-nucleotidyltransferase, ANT(2"), by means of the polymerase chain reaction.

The polymerase chain reaction (PCR) was used to identify the gene encoding the aminoglycoside-2"-O-nucleotidyltransferase, ANT(2"). Two primers, delineating a DNA fragment of 188 bp, and a specific probe within this fragment were constructed, based on the nucleotide sequence of the aadB gene encoding this enzyme. Reference strains producing different aminoglycoside-modifying enzymes were used to evaluate the specificity and the sensitivity of the test. Strains producing the ANT(2") enzyme showed the expected 188 bp DNA fragment after amplification. The oligonucleotide primers did not interact with genes encoding other aminoglycoside-modifying enzymes. Evaluation of a one-step single colony technique demonstrated that it was an acceptable alternative to the classic PCR test. The PCR method was used successfully to detect the presence of the aadB gene in 17 gentamicin-resistant clinical isolates.

Bacillus↗
PubMed1990

Radiation injury in the human kidney: a prospective analysis using specific scintigraphic and biochemical endpoints.

Renal function was prospectively analyzed in 26 evaluable patients, irradiated to various doses on their kidneys for neoplastic disease. Glomerular function was assessed by 99mTc-DTPA renography, creatinine clearance, and serum beta 2-microglobulin, whereas tubular function was monitored by 99mTc-DMSA scintigraphy, urine beta 2-microglobulin, urine N-acetyl glucosaminidase, and alanine aminopeptidase and a urine concentration test. In the patients given the highest irradiation dose to the entire left kidney, that is, 40 Gy in 5 1/2 weeks, glomerular and tubular functional impairment, as assessed scintigraphically, progressed at a rate of 2.0 +/- 1.0% (+/- 1 SD) and 2.0 +/- 0.5% per month, respectively, down to 30-40% after 3 to 5 years. The overall glomerular function, as assessed by creatinine clearance, decreased by only 20%. In the patients irradiated unilaterally on the upper pole to 40 Gy in 4 weeks, glomerular and tubular function in the left kidney deteriorated at 0.75 +/- 0.33% and 0.75 +/- 0.20% per month in the first 2 years, down to 75-80% at 5 years. This smaller reduction was due to shielding of a part of the left kidney. No changes were observed, thus far, after bilateral whole kidney irradiation to 17-18 Gy in 3 1/2 weeks. The concentration capacity of the kidney after total volume irradiation was not impaired. There was a trend for an increase in diastolic blood pressure in 3 out of 5 patients given the high dose irradiation to the entire left kidney and in 2 out of 7 patients irradiated on the upper pole of the left kidney. The progressive nature of the radiation nephropathy stresses the need for long term follow-up to determine more accurately the "tolerance dose" of the human kidney for irradiation.

Acetylglucosaminidase↗
PubMed1989

The effect of cis-diamminedichloroplatinum(II) on radiation damage in mouse rectum after fractionated irradiation.

The influence of cis-diamminedichloroplatinum(II) (c-DDP) on radiation injury in the rectum of mice was investigated after single dose and fractionated irradiation. Mice were exposed to single doses, or 2, 4 or 8 fractions of X-rays given daily (or twice a day for the 8 fractions) with or without 8 mg/kg of c-DDP. The incidence of rectal stenosis and of anal discharge were scored and a direct analysis of the data for linear-quadratic dose-dependence of damage was performed with correction for censoring. For each endpoint, c-DDP did not significantly change the dose-response curves after fractionated irradiation. Subtile modifications in the coefficients of the linear-quadratic relationship were observed. The drug appeared to increase the alpha term by a factor of 2.3 and the beta term by a factor of 1.5, but the differences did not reach statistical significance. For the rectal stenosis endpoint, the alpha/beta was 4.4 Gy after irradiation alone and 6.9 Gy after combination treatment. Again the differences were not significant. These data suggest that c-DDP did not reduce the repair capacity in the mouse rectum during fractionated irradiation. Combined modality therapy with c-DDP and radiation would therefore not be expected to cause an increase in late damage in the large bowel.

Animals↗
PubMed1989

Direct estimation of latent time for radiation injury in late-responding normal tissues: gut, lung, and spinal cord.

Mixture models are proposed for simultaneous analysis of the latency and fractionation characteristics of radiation injury in late-responding normal tissues. The method is an extension of the direct analysis for quantal response data. Conceptually, the application of the mixture model is based on the biological observation that over a wide range of doses a proportion of the irradiated subjects will never express damage. Mixture models allow the time of occurrence to be utilized in the analysis. Furthermore, this type of model takes time-censored observations into account in a natural way and provides an adequate framework for modelling and analysis of effect-dependent latency. Mixture models with complete and incomplete repair are applied to dose-incidence data for four late endpoints in rodents: death from radiation-induced pneumonitis, leg paralysis after spinal-cord irradiation, and radiation-induced rectal stenosis and anal discharge. Radiation-induced pneumonitis had an effect-dependent latency. The modelling of this phenomenon correlates well with the results of histologic studies. Interestingly, the ratio of hazard rates was not constant for this endpoint. The dominating feature in the latency of radiation injury to the spinal cord was a strong dependency on dose per fraction. After correction for this effect a tendency towards a longer latent time for lower effect levels was observed. For the rectal complications, there was no difference between latency with radiation only vs. radiation combined with cis-platin.

Animals↗
PubMed1989

Radionuclide assessment of right ventricular regional wall motion abnormalities in anterior left ventricular infarction.

Because of its potential use in the detection of right ventricular myocardial infarction, we performed radionuclide ventriculography in 80 consecutive cases of electrocardiographically anterior acute MI. Regional wall motion of both ventricles was studied on amplitude-phase images. Forty-five patients (56%) showed normal right ventricular function and 35 (44%) regional right ventricular dyskinesia: 19 in the septal, 14 in the apical and 2 in the free wall region. Right ventricular septal, respectively apical asynergy were virtually always associated with asynergy in the homologous parts of the left ventricle. This could be a consequence of the proximity of these regions, or alternatively be due to a common vascular supply. Thus it remains uncertain if asynergy in these regions signifies necrosis of part of the right ventricular wall. Free wall asynergy was considered as evidence of right ventricular wall necrosis. Thus, in our study group the prevalence of right ventricular myocardial infarction in anterior left ventricular myocardial infarction was at least 2.5%.

Adult↗
PubMed1988

Renal damage in mice after treatment with cisplatin and x-rays: comparison of fractionated and single-dose studies.

Functional kidney damage in mice was measured after bilateral irradiation with x-rays alone or in combination with cisplatin (c-DDP). A single drug dose (6 mg/kg) was injected 30 minutes before the first of four or eight x-ray doses, given as four fractions per day with a minimum interval of 5 hours between treatments. A 30-fraction schedule was also investigated, with 15 fractions given in the first week (3 fractions per day), followed by a 2-week rest period and another 15 fractions in the fourth week. The c-DDP (4 mg/kg) was administered 30 minutes before the first fraction of each week, giving a total drug dose of 8 mg/kg. Renal function was assessed monthly from 10 to 37 weeks after the start of treatment by the clearance of 51Cr-labeled EDTA. The combined treatment caused more kidney damage than either agent alone for all fractionation schedules. Enhancement of the radiation damage by c-DDP changed only slightly with fractionation; dose enhancement factors were 1.2 for 1 fraction to 1.3 for 30 fractions. Modeling studies showed that this was consistent with the additive toxic effects of the two agents. There was no change in the alpha/beta for renal damage after x-rays plus c-DDP, compared with x-rays alone (alpha/beta = 1.9 Gy), implying that there was no reduction in repair and no modification of the x-ray response by c-DDP.

Animals↗
PubMed1987

Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data.

Cis-diamminedichloroplatinum (II) (c-DDP), a highly effective cytostatic drug, is increasingly used in combination with irradiation both in the laboratory and in patients. This review aims at a critical reassessment of the potential role of this drug as a "radiosensitizer." The opinion about c-DDP being an effective hypoxic cell radiosensitizer in bacteria was substantiated in some studies on mammalian cells in culture but not in others. More powerful mechanisms of radiation enhancement, which are not yet fully explored, may be depletion of endogenous thiols, inhibition of cellular repair processes, and proliferation inhibition. The effects of c-DDP in combination with irradiation in experimental tumors seem to vary between different investigators and between different tumor systems. Occasionally, supra-additive effects have been observed in some animal tumors. This stresses the need for testing this combination treatment in various tumor types, preferentially of human origin. In normal tissues, the effects are, to a large extent, explained by independent cell killing by each agent. A substantial number of clinical pilot studies have shown that the combination treatment is feasible, but the results of ongoing phase III trials will be needed to assess the potential therapeutic benefit of this combined treatment modality.

Animals↗
PubMed1987

Repair of sublethal radiation injury after multiple small doses in mouse kidney: an estimate of flexure dose.

Functional kidney damage in mice was measured after a series of fractionated X-irradiations. Doses per fraction of 0.75-12.5 Gy were given as 2, 5, 10, 30, 40, 60, or 80 equal doses in a total treatment time of 4 weeks. Renal function (measured by clearance of 51CrEDTA or hematocrit levels) deteriorated progressively, in a dose related manner, from 20 to 46 weeks after the start of treatment. The changes in renal function versus time were fitted by a polynomial regression through all data and interpolated values for 51CrEDTA clearance were then calculated at 30 and 40 weeks after treatment. Steep dose response curves were obtained and these were used to calculate isoeffective doses for the different fractionation schedules. There was a marked increase in total isoeffective doses from 2-30 fractions and these data were well described by a linear quadratic (L.Q.) expression for damage with an alpha/beta ratio of 2.3 +/- 0.2 Gy. There was only a slight increase in the total isoeffect dose as the size of the dose per fraction was decreased below 2 Gy and the measured isoeffect doses after 40 to 80 fractions were lower than predicted on the basis of an L.Q. model assuming complete repair between successive irradiations. The flexure dose for mouse kidneys irradiated 3 times per day was, effectively, 1 to 2 Gy and hyperfractionation using lower doses per fraction did not lead to significant, additional repair.

Animals↗