Validation of intensity modulation on a commercial treatment planning system

For two years now, a study on intensity modulated radiotherapy (IMRT) has been in progress at the Antoine Lacassagne Hospital Center for Cancer Therapy (in Nice) in collaboration with the University of Nice-Sophia Antipolis. The kind of intensity modulation that was used is the "step and shoot" technique in which the modulated beam is created both by adding andjoining elementary fields. Before carrying out clinical tests, several problems regarding the production of modulated beams has to be mastered. The current developments of our study enable us to dosimetrically produce (in water phantom and in the PMMA phantom) complexmodulated whose segmentation was calculated by one commercial treatment planning system (TPS). Nevertheless, we showed and studied some critical discrepancies between standard clinical calculations and the calculations using field segmentation. We showed that with nonoptimal conditions of segmentation the discrepancies, which are due to the type of algorithm used, could bring about significant errors inside the field of up to 10% of maximum dose. Another point of our study is the quantification and resolution of differences between measurements and calculations due to the internal segmentation of calculated modulated fields and their realization on Linac. Once again, in none optimal conditions of segmentation and inside the field we obtained discrepancies up to 20% of maximum dose between calculations using field segmentation and measurements. That was mainly due to the tongue and groove effect and penumbra phenomena. This study allows us to show that the discrepancies between segmentation calculations and standard clinical calculations should be solved by the use of penumbra models during segmentation calculations. We will introduce both the study and its near-future perspectives.     

Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs

Acute inhibition of NO synthesis decreases left ventricular (LV) work and external efficiency, but it is unknown whether compensatory mechanisms can limit the alterations in LV mechanoenergetics after prolonged NO deficiency. Eight chronically instrumented male mongrel dogs received 35 mg kg⁻¹ day⁻¹ of N ^ω-nitro-L-arginine methyl ester orally for 10 days to inhibit NO synthesis. At spontaneous beating frequency, heart rate, coronary blood flow, peak LV pressure, end-diastolic LV pressure and the maximum derivative of LV pressure (d P /d t _max) were not significantly different vs. baseline, whereas LV end-diastolic diameter (32.5 ± 1.0 vs. 37.6 ± 1.4 mm) and LV stroke work (515 ± 38 vs. 650 ± 44 mmHg mm), were reduced (all P < 0.05). The slope of the LV end-systolic pressure-diameter relationship was increased at 10 days vs. baseline (13.9 ± 1.0 vs. 9.6 ± 0.9 mmHg mm⁻¹, P < 0.05), while the end-diastolic LV diameter was smaller at matched LV end-diastolic pressures. At fixed heart rate (130 beats min⁻¹), cardiac oxygen consumption was increased (12.2 ± 1.5 vs. 9.9 ± 1.0 ml min⁻¹), and the ratio between stroke work and oxygen consumption was decreased by 33 ±7 % (all P < 0.05) after NO inhibition. We conclude that sustained inhibition of NO synthesis in dogs causes a decrease in LV work despite an increased contractility, which is most probably due to reduced diastolic compliance and a decrease in external efficiency. Thus, prolonged NO deficiency is not compensated for on the level of LV mechanoenergetics in vivo .     

Arrhythmogenic right ventricular cardiomyopathy versus fatty replacement of the right ventricle. An autopsy case report

We report an autopsy case of a cardiomyopathy characterized by fatty replacement of the right ventricular myocardium and compare its clinical and histologic characteristics with those of the arrhythmogenic right ventricular cardiomyopathy. A 39-year old male died suddenly in a hospital room. He had an alcoholic cirrhosis with ascitis, but the clinical examination and the biology showed no abnormalities explaining the death. Histologically, in the right ventricle, large areas of cardiomyocytes were replaced by fat, but there was no fibrosis. In contrast, fibrosis is present in association with fat in arrhythmogenic right ventricular cardiomyopathy. Fatty replacement of the right ventricle is likely to be a distinct entity. Right ventricular failure has been shown to be a possible complication. Sudden death is probably rare and is likely to occur when other arrhythmogenic factors are associated.     

Fetal RhD genotyping: A more efficient use of anti-D immunoglobulin

The most important application of blood group genotyping by molecular genetics is the prediction of fetal RhD phenotype in pregnant women with anti-D, in order to assess the risk of haemolytic disease of the fetus and newborn. This diagnostic test performed on cell-free fetal DNA in the maternal plasma, is now a routine procedure in some countries. High-throughput modifications of this form of fetal D-typing would be valuable for testing fetuses of all D-negative pregnant women to avoid unnecessary antenatal treatment with anti-D immunoglobulin in the 40% of D-negative pregnant women with a D-negative fetus. The results of trials in Bristol and Amsterdam suggest that such routine testing is feasible and accurate.     

Evaluation of the mixed lymphocyte culture (MLC) assay as a method for selecting unrelated donors for marrow transplantation

Abstract: The utility of the MLC assay as a test of HLA-D region matching and predictor of graft-versus-host disease (GvHD) was evaluated in 435 patients receiving marrow grafts from unrelated donors. Donors and recipients were phenotyped for HLA-A, B and DR antigens by serology, tested in MLC, and retrospectively genotyped for DRB1, B3, B4, B5, DQB1 and DPB1 alleles by PCR/SSOP. Of the 244 HLA-A, B, DR-identical donor-recipient pairs with evaluable MLC and DRB1 typing results available, 208 were matched for HLA-A, B and DRB1, while 36 were matched for HLA-A and B and mismatched for a DRB1 allele. Donor anti-recipient relative responses (RR) in MLC, corresponding to the GvHD vector in marrow transplantation, ranged from 7.2 to 100%, with a median of 4.0%. A comparison of reactivity in MLC between pairs matched versus mismatched for DRB1 alleles showed a significant overlap in the distribution of RRs. Using optimally-defined RR cutoffs of 4 and 16%, no correlation between MLC results and risk of developing clinically significant grades III-IV GvHD (p=0.6 and 0.5, respectively) was found when the contribution of DRB1 mismatch was accounted for. Matching for DRB1 alleles, in contrast, was a better predictor of clinically significant GvHD, with DRB1-matched transplant recipients less likely to develop grades III-IV GvHD than DRB1-mismatched recipients (p=0.14). Among the 208 patients and donors matched for DRB1 alleles, the MLC, although reactive (RR > 4.0%) in 45% of cases, did not predict GvHD. Overall, these results underscore the limitations in using the MLC to predict DRB1 matching or risk of clinically significant GvHD among patients receiving unrelated marrow grafts. The availability of DRB1 allele matching by sequence-specific oligonucleotide probes (SSOP) or by direct sequencing provides a method for donor matching that is rapid, precise and superior to the MLC for predicting clinically relevant outcome.     

The somatostatin/histaminic pathway balance on gastric secretion could be based on a competitive antagonism

Measurements of acid and pepsin secretions and of histamine release in response to food alone or in combination with graded doses of antramine (AH), a molecular form of histamine isolated from antral mucosa, with or without somatostatin were performed simultaneously in dogs equipped with a denervated pouch.AH restored somatostatin-inhibited acid and pepsin secretions but with different intensities in regard to the different inhibitory levels induced by somatostatin.AH competitively antagonized somatostatin (1 g/kg/h) inhibition of acid cecretion, but when stronger levels of inhibition were achieved, AH restored weakly acid secretion. Recovery of pepsin secretion occured through a competitive mechanism between AH and somatostatin (1 and 2 g/kg/h). There was a close relationship between the secretory outputs and the integrated histamine responses; the slopes of the regression lines might be considered as reflecting the stimulatory activity of blood histamine on secreting cells. For acid secretion, this activity is similar in control and somatostatin (1 g/kg/h) tests, while for pepsin secretion it is identical in control and 1 or 2 g/kg/h somatostatin tests.One can speculate that the suppression of the somatostatin inhibitory effects by antramine, within the limits of physiological conditions, results from a competitive mechanism.     

The glioblastoma-derived T cell suppressor factor/transforming growth factor-beta 2 inhibits T cell growth without affecting the interaction of interleukin 2 with its receptor

Human glioblastoma cells secrete a peptide termed glioblastoma-derived T cell suppressor factor (G-TsF) which inhibits T cell activation. Recently, purification and cloning of G-TsF revealed that G-TsF is identical to transforming growth factor-beta 2. As shown here, G-TsF suppresses the growth of an ovalbumin-specific mouse T helper cell clone (OVA-7T) independently of the stimulus used being either (a) antigen in the presence of antigen-presenting cells, or (b) interleukin 2 (IL2) or (c) phorbol ester and calcium ionophore. Furthermore, in the presence of antibodies against IL2 receptors, G-TsF was able to suppress the residual proliferation still observed when OVA-7T were stimulated with phorbol ester/ionophore. G-TsF failed to inhibit the release of IL3 from OVA-7T activated with IL2. Taken together, the data provide evidence that G-TsF does not directly interfere with interactions of IL2 with its receptor but rather inhibits T cell activation by interfering with an as yet unidentified pathway used by both IL2 and phorbol ester/ionophore. When analyzing different monokines and lymphokines for its effect on G-TsF-induced suppression of T cell growth the only factor found to partially neutralize the effect of G-TsF was tumor necrosis factor-alpha.