RESUMEN

BACKGROUND: 5­Fluoruracil (5-FU) and its oral prodrug capecitabine are mainstays in combined chemoradiotherapy regimens. They are metabolized by dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants of the DPYD gene cause a reduction in DPYD activity, leading to possibly severe toxicities. Therefore, patients receiving 5­FU-/capecitabine-based chemoradiotherapy should be tested for DPYD variants. However, there are limited clinical data on treatment adjustments and tolerability in patients with decreased DPYP activity receiving combined chemoradiotherapy. Therefore, a retrospective analysis of the toxicity profiles of patients with decreased DPYD activity treated at our center was conducted. MATERIALS AND METHODS: For all patients receiving 5­FU-/capecitabine-based chemo(radio)therapy at our department, DPYD activity was routinely tested. Genotyping of four DPYD variants (DPYD*2A, DPYD*13, c.2846A > T, and haplotype B3) was conducted according to the recommendation of the German Society for Hematooncology (DGHO) using TaqMan hydrolysis polymerase chain reaction (PCR; QuantStudy 3, Thermo FisherScientific, Darmstadt). DPYD variants and activity score as well as clinical data (tumor entity, treatment protocol, dose adjustments, and toxicity according to the Common Terminology Criteria for Adverse Events [CTCAE]) were assessed and reported. RESULTS: Of 261 tested patients, 21 exhibited DPYD variants, 18 of whom received chemoradiotherapy. All but one patient was treated for rectal or anal carcinoma. The observed rate of DPYD variants was 8.0%, and heterozygous haplotype B3 was the most common (5.75%). One patient exhibited a homozygous DPYD variant. DPYD activity score was at least 0.5 in heterozygous patients; chemotherapy dose was adjusted accordingly, with an applied dose of 50-75%. CTCAE grade 2 skin toxicity (50%) and grade 3 leukopenia (33.3%) were most common. One patient experienced a transient grade 4 increase in transaminases. All high-grade toxicities were manageable with supportive treatment and transient. No CTCAE grade 5 toxicities related to 5­FU administration were observed. CONCLUSION: With dose reduction in heterozygous patients, toxicity was within the range of patients without DPYD variants. Our clinical data suggest that dose-adapted 5­FU-/capecitabine-chemoradiotherapy regimens can be safely considered in patients with heterozygous clinically relevant DPYD variants, but that the optimal dosage still needs to be determined to avoid both increased toxicity and undertreatment in a curative setting.

RESUMEN

Research in the field of local and locoregional breast cancer radiotherapy aims to maintain excellent oncological outcomes while reducing treatment-related toxicity. Adaptive radiotherapy (ART) considers variations in target and organs at risk (OARs) anatomy occurring during the treatment course and integrates these in re-optimized treatment plans. Exploiting ART routinely in clinic may result in smaller target volumes and better OAR sparing, which may lead to reduction of acute as well as late toxicities. In this review MR-guided and CT-guided ART for breast cancer patients according to different clinical scenarios (neoadjuvant and adjuvant partial breast irradiation, whole breast, chest wall and regional nodal irradiation) are reviewed and their advantages as well as challenging aspects discussed.

RESUMEN

PURPOSE: For patients treated with partial breast irradiation (PBI), potential long-term treatment-related toxicities are important. The 1.5 T magnetic resonance guided linear accelerator (MRL) offers excellent tumor bed visualization and a daily treatment plan adaption possibility, but MRL-specific electron stream and return effects may cause increased dose deposition at air-tissue interfaces. In this study, we aimed to investigate the projected risk of radiation-induced secondary malignancies (RISM) in patients treated with PBI at the 1.5 T MRL. METHODS: Projected excess absolute risk values (EARs) for the contralateral breast, lungs, thyroid and esophagus were estimated for 11 patients treated with PBI at the MRL and compared to 11 patients treated with PBI and 11 patients treated with whole breast irradiation (WBI) at the conventional linac (CTL). All patients received 40.05 Gy in 15 fractions. For patients treated at the CTL, additional dose due to daily cone beam computed tomography (CBCT) was simulated. The t­test with Bonferroni correction was used for comparison. RESULTS: The highest projected risk for a radiation-induced secondary cancer was found for the ipsilateral lung, without significant differences between the groups. A lower contralateral breast EAR was found for MRL-PBI (EAR = 0.89) compared to CTL-PBI (EAR = 1.41, p = 0.01), whereas a lower thyroid EAR for CTL-PBI (EAR = 0.17) compared to MRL-PBI (EAR = 0.33, p = 0.03) and CTL-WBI (EAR = 0.46, p = 0.002) was observed. Nevertheless, when adding the CBCT dose no difference between thyroid EAR for CTL-PBI compared to MRL-PBI was detected. CONCLUSION: Better breast tissue visualization and the possibility for daily plan adaption make PBI at the 1.5 T MRL particularly attractive. Our simulations suggest that this treatment can be performed without additional projected risk of RISM.

Asunto(s)

RESUMEN

INTRODUCTION: The hybrid magnetic resonance linear accelerator (MRL) has the potential to test novel concepts in breast cancer patients such as daily MR-guided real-time plan adaptation. Before starting clinical trials, preparatory studies for example of the MR-dependent electron stream effect (ESE) are necessary. MATERIAL AND METHODS: To prospectively investigate the ESE, data from 11 patients treated with partial breast irradiation (PBI) at the 1.5 T MRL were evaluated. A bolus was placed on the chin and in vivo dosimetry results were compared with the dose simulated by the treatment planning system (TPS). The same measurements were carried out for three patients treated at a conventional linac. Toxicity and cosmesis were evaluated. RESULTS: Median doses measured and simulated on top/ underneath the bolus were 1.91 / 0.62 Gy and 2.82 / 0.63 Gy, respectively. Median differences between calculations and measurements were 0.8 Gy and 0.1 Gy. At the conventional linac, median measured doses on top/ underneath the bolus were 0.98 and 1.37 Gy. No acute toxicity exceeding grade 2 was recorded. Cosmesis was good or excellent and patient reported outcome measures were mostly scored as none or mild. CONCLUSION: The dose due to the ESE is low, correctly predicted by the TPS and effectively minimized by a bolus.

RESUMEN

PURPOSE: To prospectively investigate the role of re-irradiation (re-RT) combined with hyperthermia (HT) in a contemporary cohort of patients affected by recurrent breast cancer (RBC). METHODS: Within the prospective registry HT03, patients with resected RBC and previous irradiation were included. Re-RT was applied to the recurrence region with doses of 50-50.4 Gy, with a boost up to 60-60.4 Gy to the microscopically or macroscopically positive resection margins (R1/R2) region. Concurrent HT was performed at 40-42 ℃. Primary endpoint was LC. Acute and late toxicity, overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) were also evaluated. RESULTS: 20 patients and 21 RBC were analyzed. Median re-RT dose was 50.4 Gy and a median of 11 HT fractions were applied. Re-RT+HT was well tolerated, with three patients who experienced a grade (G) 3 acute skin toxicity and no cases of ≥G3 late toxicity. With a median follow up of 24.7 months, two local relapses occurred. Ten patients experienced regional and/or distant disease progression. Five patients died, four of them from breast cancer. PFS was favorable in patients treated with re-RT+HT for the first recurrence with doses of 60 Gy. A trend towards better CSS was found in patients with negative or close margins and after doses of 60 Gy. CONCLUSION: Full-dose re-RT+HT for RBC is well tolerated, provides good LC, and seems to be more effective when applied at the time of the first relapse and after doses of 60 Gy. The registry will be continued for validation in a larger cohort and with longer follow-up.

Asunto(s)

RESUMEN

Apart from radiocaesium and radiostrontium, there have been few studies on the foliar transfer of radionuclides in plants. Consequently, specific translocation factor (ftr) values for (129)I, (79)Se and (36)Cl are still missing from the IAEA reference databases. The translocation of short - lived isotopes, (125)I and (75)Se, and of (36)Cl to wheat grain were measured under field conditions following acute and chronic wet foliar contamination at various plant growth stages in the absence of leaching caused by rain. The translocation factors ranged from 0.02% to 1.1% for (125)I (a value similar to Sr), from 0.1% to 16.5% for (75)Se, and from 1% to 14.9% for (36)Cl. Both (36)Cl and (75)Se were as mobile as Cs. The phenomenological analysis showed that each element displayed a specific behavior. Iodide showed the lowest apparent mobility because of its preferential fixation in or on the leaves and a significant amount probably volatilized. Selenite internal transfer was significant and possibly utilized the sulphur metabolic pathway. However bio - methylation of selenite may have led to increased volatilization. Chloride was very mobile and quickly diffused throughout the plant. In addition, the analysis underlined the importance of plant growth responses to annual variations in weather conditions that can affect open field experiments because plant growth stage played a major role in ftr values dispersion. The chronic contamination results suggested that a series of acute contamination events had an additive effect on translocated elements. The highest translocation value obtained for an acute contamination event was shown to be a good conservative assessment of chronic contamination if data on chronic contamination translocation are lacking. The absence of rain leaching during the experiment meant that this investigation avoided potential radionuclide transfer by the roots, which also meant that radionuclide retention on or in the leaves was maximized. This study was therefore able to obtain accurate translocation factors, which are probably among the highest that could be recorded.

Asunto(s)

RESUMEN

A review of the published literature about foliar transfer radionuclides to cereal grains was carried out with a special interest for translocation factors. Translocation describes the distribution of radionuclides within the plant after foliar deposition and radionuclide absorption onto the surface of leaves. It mainly depends on elements and the plant growth stage. The collected data were derived from both in-field and greenhouse experiments. They were analysed in order to select those coming from a contamination simulating a sprinkling irrigation or a rain. The data set contains 307 values. For each radionuclide the translocation factor values were sorted according to 5 characteristic stages of the cereal vegetative cycle: leaf development-tillering, stem elongation, earing-flowering, grain growth and ripening. Wheat, barley and rye have been treated together, independently of rice. For mobile elements such as cesium, the translocation factor is maximum when the contamination occurred at the earing-flowering stage. For less mobile elements such as strontium this maximum occurred for a foliar contamination at the grain growth stage. This review enabled us to propose the most probable value as well as the range of variation of translocation factors for some radionuclides according to the cereal vegetative cycle. Moreover, from these results, a radionuclide classification is proposed according to three mobility groups.

Asunto(s)

RESUMEN

Cl-36 is an important component of nuclear waste. The concentrations of stable chlorine (Cl) in pig and cow tissues were measured to provide information which can be used to parameterize models of (36)Cl transfer into agricultural animals. The concentration of stable Cl in cows' milk was 1.0 +/- 0.2 g L(-1), in cow muscle it was 0.7 +/- 0.2 g kg(-1) wet mass (wm) and in pig muscle 0.4 +/- 0.1 g kg(-1) wm. The concentration of stable Cl in cow and pig liver was 0.9 +/- 0.3 g kg(-1) wm, which was about two-fold higher than that in the kidney and lung. Due to homeostatic control, stable Cl concentrations in animal tissues are not related to the amount ingested daily in herbage at intake rates in the normal physiological range of up to 188 g day(-1) for cows and up to 40 g day(-1) for pigs. Therefore, the commonly used transfer coefficient is not suitable for use in quantifying the transfer of (36)Cl to milk and meat. Since the metabolism of stable Cl and (36)Cl in an animal's body is identical, the average equilibrium ratios of (36)Cl to stable Cl in the daily ration ((36)Cl (g kg(-1))/Cl (g kg(-1))) and animal tissues will be the same. We therefore conclude that the average equilibrium Cl isotopic ratio in the dietary daily intake should be used to predict the contamination of meat and milk with (36)Cl.

Asunto(s)

RESUMEN

Long-term field experiments have been carried out in the Chernobyl exclusion zone in order to determine the parameters governing radiochlorine ((36)Cl) transfer to plants from four types of soil, namely, Podzoluvisol, Greyzem, Phaeozem and Chernozem. Radiochlorine concentration ratios (CR=concentration of (36)Cl in the fresh plant material divided by its concentration in the dried soil in the upper 20 cm layer) were obtained in green peas (2.6+/-0.4), onions (1.5+/-0.5), potatoes (8+/-1), clover (90+/-26) and ryegrass (158+/-88) hay, oat seeds (36+/-23) and straw (305+/-159), wheat seeds (35+/-10) and straw (222+/-82). These values correlate with the stable chlorine values for the same plants. It was shown that (36)Cl plant/soil CR in radish roots (CR=9.7+/-1.4) does not depend on the stable chlorine content in the soil (up to 150 mgkg(-1)), soil type and thus, that stable chlorine CR values (9.4+/-1.2) can also be used for (36)Cl. Injection of additional quantities of stable chlorine into the soil (100 mgkg(-1) of dry soil) with fertilizer does not change the soil-to-plant transfer of (36)Cl. The results from a batch experiment showed that chlorine is retained in the investigated soils only by live biota and transfers quickly (in just a few hours) into the soil solution from dry vegetation even without decomposition of dead plants and is integrated in the migration processes in soil.

Asunto(s)

RESUMEN

The factors governing chlorine transfer from Phaeozem and Greyzem soils to various important crop species (foodstuff and forage) were determined in natural conditions in the Kiev region of Ukraine. The stable chlorine concentration ratio (CR) values were the lowest in apple (0.5+/-0.3) and strawberry (2+/-1), higher in vegetables (5+/-3), seeds (15+/-7) and reached a maximum in straw (187+/-90). The average CR values of 36Cl were estimated for the most important crops using all experimental data on 36Cl and stable chlorine transfer into plants from various soils. It was experimentally shown that boiling potatoes in water leads to an equilibrium between 36Cl specific content in the water and moisture in the cooked potato. The 36Cl processing factor (PF) for boiling various foodstuffs is equal to the ratio of water mass in the cooked foodstuff to the total water mass (in the food and the decoction). 36Cl PF for cereal flour can be estimated as 1. The 36Cl processing factor for dairy products is equal to the ratio of residual water mass in the product to initial water mass in milk. At a 36Cl specific activity in soil of 1 Bq kg-1, the estimated annual dietary 36Cl intake into human organism (adult man) is about 10 kBq. Sixty to seventy percent of the above amount will be taken in via milk and dairy products, 7-16% via meat, 14-16% via bread and bakery items and 8-12% via vegetables. The highest annual 36Cl intake, 10.7 kBq, is predicted for 1-year-old children. The expected effective doses from annual 36Cl intake are higher for younger age groups, increasing from 0.008 mSv in adults to 0.12 mSv in 1-year-old children.

Asunto(s)

RESUMEN

Foliar transfer of 241Am, 239,240Pu, 137Cs and 85Sr was evaluated after contamination of bean plants (Phaseolus vulgaris) at the flowering development stage, by soaking their first two trifoliate leaves into contaminated solutions. Initial retentions of 241Am (27%) and 239,240Pu (37%) were higher than those of 137Cs and 85Sr (10-15%). Mean fraction of retained activity redistributed among bean organs was higher for 137Cs (20.3%) than for 239,240Pu (2.2%), 241Am (1%) or 85Sr (0.1%). Mean leaf-to-pod translocation factors (Bq kg(-1) dry weight pod/Bq kg(-1) dry weight contaminated leaves) were 5.0 x 10(-4) for 241Am, 2.7 x 10(-6) for 239,240Pu, 5.4 x 10(-2) for 137Cs and 3.6 x 10(-4) for 85Sr. Caesium was mainly recovered in pods (12.8%). Americium and strontium were uniformly redistributed among leaves, stems and pods. Plutonium showed preferential redistribution in oldest bean organs, leaves and stems, and very little redistribution in forming pods. Results for americium and plutonium were compared to those of strontium and caesium to evaluate the consistency of the attribution of behaviour of strontium to transuranium elements towards foliar transfer, based on translocation factors, as stated in two radioecological models, ECOSYS-87 and ASTRAL.

Asunto(s)

RESUMEN

Long-term controlled experiments under natural conditions in the field have been carried out in the Chernobyl Exclusion zone in order to determine the parameters governing radioiodine transfer to plants from four types of soils (podzoluvisol, greyzem and typical and meadow chernozem) homogeneously contaminated in the 20-cm upper layer with an addition of (125)I. An absence of (125)I depletion in arable soil layers due to volatilization was noted up to one year after contamination. During one year, depletion due to the vertical migration of radioiodine from the arable layer of each of the soils did not exceed 4% of the total (125)I content. Radioiodine concentration ratios (CR) were obtained in radish roots, lettuce leaves, bean pods, and wheat grain and straw. The highest CR values were observed in podzoluvisol: 0.01-0.03 for radish roots and lettuce leaves, 0.003-0.004 for bean pods and 0.001 for wheat grains. In the other three soils, these values were one order of magnitude lower. The parameters relating to changes in radioiodine bioavailability were determined, based on the contamination dynamics of plants in field conditions.

Asunto(s)

RESUMEN

Long-term field experiments have been carried out in the Chernobyl exclusion zone in order to determine the parameters governing radiochlorine (36Cl) transfer to plants from four types of soil, namely, podzoluvisol, greyzem, and typical and meadow chernozem. Radiochlorine concentration ratios (CR) in radish roots (15+/-10), lettuce leaves (30+/-15), bean pods (15+/-11) and wheat seed (23+/-11) and straw (210+/-110) for fresh weight of plants were obtained. These values correlate well with stable chlorine values for the same plants. One year after injection, 36Cl reached a quasi-equilibrium with stable chlorine in the agricultural soils and its behavior in the soil-plant system mimicked the behavior of stable chlorine (this behavior was determined by soil moisture transport in the investigated soils). In the absence of intensive vertical migration, more than half of 36Cl activity in arable layer of soil passes into the radish, lettuce and the aboveground parts of wheat during a single vegetation period.

Asunto(s)

RESUMEN

Hypertonic saline solution (HSS) has been investigated in the treatment of intracranial hypertension (ICH) in a limited number of studies, usually after failure of conventional treatment. HSS, used in concentrations that vary from 3% to 23.4%, seems to be effective in reducing refractory ICH and to be devoid of adverse effects. We treated a patient with refractory ICH with a small-volume infusion of 18% HSS, and performed magnetic resonance imaging (MRI) before and after HSS infusion. MRI showed a marked reduction in cerebral water content 1 h after the infusion. To our knowledge, this is the first MRI study in a patient with brain injury to evaluate the effect of HSS on brain water content. Further studies are necessary to test HSS efficacy and to identify, through MRI or computed tomography (CT) scan imaging, a subgroup of patients with brain injury who would be best treated with HSS.

Asunto(s)

RESUMEN

The behaviour of radioactive aerosols released from a severely damaged nuclear reactor and deposited on cereals was simulated under controlled conditions. 137Cs- and 90Sr-labelled aerosols were generated by volatilisation at high temperature of an artificially spiked pellet of depleted UO2. After cooling and maturation the aerosols were allowed to deposit on spring wheat (Triticum aestivum L. var. Arbon) cultures grown on lysimeters under greenhouse conditions. At the time of contamination the wheat plants were at different stages of development, from early vegetative growth (two leaves) until nearly mature (end of flowering). The estimated interception coefficient (micro) amounted to 13.1 m2 kg(-1); such a high value may be explained by the experimental conditions that created an over-saturated atmosphere during the contamination process and wet leaf surfaces. The first simulated rain, applied 6 days after the contamination, removed four times more 137Cs (54%+/-12 of the intercepted radionuclides) than 90Sr (15%+/-20) from the aerial parts. At harvest approximately 2% of the Sr and less than 1% of the Cs initially intercepted by the aerial parts is recovered for plants contaminated during the early development stages. A significantly higher proportion of the intercepted activity is still present for plants contaminated in the late development stages. The translocation to grains (TLF) increases when deposit occurs closer to the mature stage of the plant. The initial decrease of TLF values that we observed for strontium contamination in the earliest development stages is most probably due to the contribution of root uptake. Ploughing and re-sowing after the first rain, applied as a countermeasure reduced the 137Cs content in leaves and stems at harvest approximately 3 times but had no effect on the 90Sr content in vegetative organs. It reduced the 137Cs-contamination level in edible parts (grain) by a factor of 2 compared to the unploughed control, but doubled the 90Sr content.

Asunto(s)

RESUMEN

In the brain, group-III metabotropic glutamate (mGlu) receptors mGlu(4), mGlu(7) and mGlu(8) receptors play a critical role in controlling the release process at many glutamatergic synapses. The pharmacological profile of mGlu(4) receptor has been studied extensively, allowing us to propose a pharmacophore model for this receptor subtype. Surprisingly, the activity of only a few compounds have been reported on mGlu(7) and mGlu(8) receptors. In order to identify new possibilities for the design of selective compounds able to discriminate between the members of the group-III mGlu receptors, we have undertaken a complete pharmacological characterization of mGlu(8) receptor and compared it with that of mGlu(4) receptor, using the same expression system, and the same read out. The activities of 32 different molecules revealed that these two mGlu receptors subtypes share a similar pharmacological profile. Only small differences were noticed in addition to that previously reported with S-carboxyglutamate (S-Gla) being a partial agonist at mGlu(4) receptor and a full antagonist at mGlu(8) receptor. These include: a slightly higher relative potency of the agonists 1S,3R and 1S,3S-aminocyclopentane-1,3-dicarboxylic acid (ACPD), S-4-carboxyphenylglycine (S-4CPG) and S-4-carboxy-3-hydroxyphenylglycine (S-4C3HPG), and a slightly higher potency of the antagonists 2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY354740) and RS-alpha-methyl-4-phosphonophenylglycine (MPPG) on mGlu(8) receptor. When superimposed on the mGlu(4) receptor pharmacophore model, these molecules revealed three regions that may be different between the ligand binding sites of mGlu(8) and mGlu(4) receptors.

Asunto(s)

RESUMEN

Metabotropic glutamate receptors (mGluRs) belong to the family 3 of G-protein-coupled receptors. On these proteins, agonist binding on the extracellular domain leads to conformational changes in the 7-transmembrane domains required for G-protein activation. To elucidate the structural features that might be responsible for such an activation mechanism, we have generated models of the amino terminal domain (ATD) of type 4 mGluR (mGlu4R). The fold recognition search allowed the identification of three hits with a low sequence identity, but with high secondary structure conservation: leucine isoleucine valine-binding protein (LIVBP) and leucine-binding protein (LBP) as already known, and acetamide-binding protein (AmiC). These proteins are characterized by a bilobate structure in an open state for LIVBP/LBP and a closed state for AmiC, with ligand binding in the cleft. Models for both open and closed forms of mGlu4R ATD have been generated. ACPT-I (1-aminocyclopentane 1,3,4-tricarboxylic acid), a selective agonist, has been docked in the two models. In the open form, ACPT-I is only bound to lobe I through interactions with Lys74, Arg78, Ser159, and Thr182. In the closed form, ACPT-I is trapped between both lobes with additional binding to Tyr230, Asp312, Ser313, and Lys317 from lobe II. These results support the hypothesis that mGluR agonists bind a closed form of the ATDs, suggesting that such a conformation of the binding domain corresponds to the active conformation.

Asunto(s)

RESUMEN

The metabotropic glutamate receptors are GTP-binding-protein (G-protein) coupled receptors that play important roles in regulating the activity of many synapses in the central nervous system. As such, these receptors are involved in a wide number of physiological and pathological processes. Within the last few years, new potent and selective agonists and antagonists as well as radioligands acting on these receptors have been developed. Molecular modeling studies revealed the structural features of the glutamate binding site, and will be useful for the design of more selective and potent ligands. More interestingly, recent data revealed new regulatory sites on the receptor protein, able either to decrease or potentiate the action of the endogenous ligand. No doubt that in the near future a multitude of new tools to modulate the activity of these receptors will be discovered, enabling the identification of the possible therapeutic applications for these new neuroactive molecules.

Asunto(s)

RESUMEN

PURPOSE: To evaluate if the use of inhomogeneous target-dose distributions, obtained by 3D conformal radiotherapy plans with or without beam intensity modulation, offers the possibility to decrease indices of toxicity to normal tissues and/or increase indices of tumor control stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Ten patients with stage III NSCLC were planned using a conventional 3D technique and a technique involving noncoplanar beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic tumor volume. Virtual simulation defined the beam shapes and incidences as well as the wedge orientations (3D) and segment outlines (BIM). Weights of wedged beams, unwedged beams, and segments were determined by optimization using an objective function with a biological and a physical component. The biological component included tumor control probability (TCP) for PTV1 (TCP1), PTV2 (TCP2), and normal tissue complication probability (NTCP) for lung, spinal cord, and heart. The physical component included the maximum and minimum dose as well as the standard deviation of the dose at PTV1. The most inhomogeneous target-dose distributions were obtained by using only the biological component of the objective function (biological optimization). By enabling the physical component in addition to the biological component, PTV1 inhomogeneity was reduced (biophysical optimization). As indices for toxicity to normal tissues, NTCP-values as well as maximum doses or dose levels to relevant fractions of the organ's volume were used. As indices for tumor control, TCP-values as well as minimum doses to the PTVs were used. RESULTS: When optimization was performed with the biophysical as compared to the biological objective function, the PTV1 inhomogeneity decreased from 13 (8-23)% to 4 (2-9)% for the 3D-(p = 0.00009) and from 44 (33-56)% to 20 (9-34)% for the BIM plans (p < 0. 00001). Minimum PTV1 doses (expressed as the lowest voxel-dose) were similar for both objective functions. The mean and maximum target doses were significantly higher with biological optimization for 3D as well as for BIM (all p values < 0.001). Tumor control probability (estimated by TCP1 x TCP2) was 4.7% (3D) and 6.2% (BIM) higher for biological optimization (p = 0.01 and p = 0.00002 respectively). NTCP(lung) as well as the percentage of lung volume exceeding 20 Gy was higher with the use of the biophysical objective function. NTCP(heart) was also higher with the use of the biophysical objective function. The percentage of heart volume exceeding 40 Gy tended to be higher but the difference was not significant. For spinal cord, the maximum dose as well as NTCP(cord) were similar for 3D plans (D(max): p = 0.04; NTCP: p = 0.2) but were significantly lower for BIM (D(max): p = 0.002; NTCP: p = 0.008) if the biophysical objective function was used. CONCLUSIONS: When using conventional 3D techniques, inhomogeneous dose distributions offer the potential to further increase the probability of uncomplicated local control. When using techniques as BIM that would lead to large escalation of the median and maximum target doses, it seems indicated to limit target-dose inhomogeneity to avoid dose levels that are so high that the safety becomes questionable.

Asunto(s)

RESUMEN

In a previous study we reported that the addition of a carboxylic group to the mGlu receptor agonist aminocyclopentane-1,3-dicarboxylate (ACPD) changes its properties from agonist to antagonist at both mGlu1 and mGlu2 receptors, and resulted in an increase in affinity at mGlu4 receptors, with isomers being either agonists or antagonists. In the present study, the effect of gamma-carboxy-L-glutamic acid (Gla) and (2S,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), two carboxylic derivatives of non-selective agonists, were examined on all cloned mGlu receptors. We found that this additional carboxylic group on glutamate prevents its interaction with group-I mGlu receptors and generates a potent group-II antagonist (K(B) = 55 microM on mGlu2). At group-III mGlu receptors, Gla was found to be either an antagonist (mGlu7 and mGlu8 receptors) or a partial agonist (mGlu4 and mGlu6 receptors). We show here that L-CCG-I is a general mGlu receptor agonist activating all cloned receptors. We also confirm that DCG-IV, which corresponds to L-CCG-I with an additional carboxylic group, is a selective group-II agonist. However, this additional COOH group changes the properties of L-CCG-I from an agonist to an antagonist at all group-III receptors, making this compound one of the most potent group-III mGlu receptor antagonist known so far. These observations will be useful for the development of more potent and selective mGlu receptor agonists and antagonists.

Asunto(s)