The Swiss IMRT dosimetry intercomparison using a thorax phantom.

PURPOSE: In 2008, a national intensity modulated radiation therapy (IMRT) dosimetry intercomparison was carried out for all 23 radiation oncology institutions in Switzerland. It was the aim to check the treatment chain focused on the planning, dose calculation, and irradiation process. METHODS: A thorax phantom with inhomogeneities was used, in which thermoluminescence dosimeter (TLD) and ionization chamber measurements were performed. Additionally, absolute dosimetry of the applied beams has been checked. Altogether, 30 plan-measurement combinations have been used in the comparison study. The results have been grouped according to dose calculation algorithms, classified as "type a" or "type b," as proposed by Kntis et al. ["Comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations," Phys. Med. Biol. 51, 5785-5807 (2006)]. RESULTS: Absolute dosimetry check under standard conditions: The mean ratio between the dose derived from the single field measurement and the stated dose, calculated with the treatment planning system, was 1.007 +/- 0.010 for the ionization chamber and 1.002 +/- 0.014 (mean+/- standard deviation) for the TLD measurements. IMRT Plan Check: In the lung tissue of the planning target volume, a significantly better agreement between measurements (TLD, ionization chamber) and calculations is shown for type b algorithms than for type a (p <0.001). In regions outside the lungs, the absolute differences between TLD measured and stated dose values, relative to the prescribed dose, [(Dm-Ds)/Dprescribed], are 1.9 +/- 0.4% and 1.4 +/- 0.3%, respectively. These data show the same degree of accuracy between the two algorithm types if low-density medium is not present. CONCLUSIONS: The results demonstrate that the performed intercomparison is feasible and confirm the calculation accuracies of type a and type b algorithms in a water equivalent and low-density environment. It is now planned to offer the intercomparison on a regular basis to all Swiss institutions using IMRT techniques.

Open low-field magnetic resonance imaging for target definition, dose calculations and set-up verification during three-dimensional CRT for glioblastoma multiforme.

AIMS: To assess the effect on target delineation of using magnetic resonance simulation for planning of glioblastoma multiforme (GBM). Dose calculations derived from computed tomography- and magnetic resonance-derived plans were computed. The accuracy of set-up verification using magnetic resonance imaging (MRI)-based digital reconstructed radiographs (DRRs) was assessed. MATERIALS AND METHODS: Ten patients with GBM were simulated using computed tomography and MRI. MRI was acquired with a low-field (0.23 T) MRI unit (SimMRI). Gross tumour volumes (GTVs) were delineated by two radiation oncologists on computed tomography and MRI. In total, 30 plans were generated using both the computed tomography, with (planbathoCT) and without (planCT) heterogeneity correction, and MRI data sets (planSimMRI). The minimum dose delivered (Dmin) to the GTV between computed tomography- and MRI-based plans was compared. The accuracy of set-up positioning using MRI DRRs was assessed by four radiation oncologists. RESULTS: The mean GTVs delineated on computed tomography were significantly (P<0.001) larger than those contoured on MRI. The mean (+/-standard deviation) Dmin difference percentage was 0.3+/-0.8, 0.1+/-0.6 and -0.2+/-1.0% for the planCT/planbathoCT-, planCT/planSimMRI- and planbathoCT/planSimMRI-derived plans, respectively. The set-up differences observed with the computed tomography and MRI DRRs ranged from 1.0 to 4.0 mm (mean 1.5 mm; standard deviation+/-1.4). CONCLUSIONS: GTVs defined on computed tomography were significantly larger than those delineated on MRI. Compared with computed tomography-derived plans, MRI-based dose calculations were accurate. The precision of set-up verifications based on computed tomography- and MRI-derived DRRs seemed similar. The use of MRI only for the planning of GBM should be further assessed.

Contouring workload in adjuvant breast cancer radiotherapy.

PURPOSE: To measure the impact of contouring on worktime in the adjuvant radiation treatment of breast cancer, and to identify factors that might affect the measurements. MATERIAL AND METHODS: The dates and times of contouring clinical target volumes and organs at risk were recorded by a senior and by two junior radiation oncologists. Outcome measurements were contour times and the time from start to approval. The factors evaluated were patient age, type of surgery, radiation targets and setup, operator, planning station, part of the day and day of the week on which the contouring started. The Welch test was used to comparatively assess the measurements. RESULTS: Two hundred and three cases were included in the analysis. The mean contour time per patient was 34minutes for a mean of 4.72 structures, with a mean of 7.1minutes per structure. The clinical target volume and organs at risk times did not differ significantly. The mean time from start to approval per patient was 29.4hours. Factors significantly associated with longer contour times were breast-conserving surgery (P=0.026), prone setup (P=0.002), junior operator (P<0.0001), Pinnacle planning station (P=0.026), contouring start in the morning (P=0.001), and contouring start by the end of the week (P<0.0001). Factors significantly associated with time from start to approval were age (P=0.038), junior operator (P<0.0001), planning station (P=0.016), and contouring start by the end of the week (P=0.004). CONCLUSION: Contouring is a time-consuming process. Each delineated structure influences worktime, and many factors may be targeted for optimization of the workflow. These preliminary data will serve as basis for future prospective studies to determine how to establish a cost-effective solution.

Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells.

G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.

Isoxicam and related 4-hydroxy-N-isoxazolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides. Potent nonsteroidal antiinflammatory agents.

A novel series of antiinflammatory agents, N-isoxazolyl-3-carboxamides of 4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide, was synthesized and evaluated as antiinflammatory agents in the carrageenin-induced rat paw edema (CIRPE) assay and adjuvant-induced polyarthritis (AIP) assay. Several analogues were found to be equipotent or more potent than aspirin and phenylbutazone. Structure-activity relationships are discussed. One of the compounds, 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine 3-carboxamide 1,1-dioxide (3a; isoxicam), was found to be 3 times as potent as phenylbutazone in the CIRPE and in the therapeutic AIP assays. Isoxicam (3a) is presently undergoing phase III clinical trial as an antiarthritic drug.

Proteoglycan degradation by a chondrocyte metalloprotease. Effects of synthetic protease inhibitors.

Synthetic inhibitors of a chondrocyte metalloprotease (CMP) were assessed for potency. Proteoglycan core protein was used as substrate. The IC50 values were between 2 X 10(-6) and 7 X 10(-6) M for two types of inhibitors, thiol tripeptides and N-carboxyalkyl peptides. Hydroxamic acid peptides were more potent, with IC50 values of 3.2 X 10(-8) to 6.0 X 10(-8) M. These results confirm inhibitory concentrations reported using a proteoglycan-polyacrylamide bead assay. The slopes of the dose-response curves for the thiol compounds were steeper than the slopes for the other two types of compounds. All of the culture media tested inhibited CMP to some extent. Some media also interfered with inhibitor activity. In Ham's F10 nutrient medium, minimum CMP inhibition occurred, and all four hydroxamic acid peptides retained their activity for 1-2 days at 37 degrees. One thiol peptide compound assayed lost activity in 1 hr in thiocyanate-treated serum. All four hydroxamic acid peptides assayed retained activity in thiocyanate-treated serum after 3 days at 37 degrees. The hydroxamic acid peptides may provide a way to block endogenous CMP activity in vivo and to assess the role of CMP in normal and experimentally altered cartilage. They are more potent than other known CMP inhibitors. They retain activity in culture media and serum conditions used for in vivo and in vitro tests of CMP activity and toxicity.

Protease inhibitors decrease rabbit cartilage degradation after meniscectomy.

In vitro proteoglycan (PG) synthesis and release were measured on cartilage removed from rabbit knees within 1 week of meniscectomy. Three days following partial lateral meniscectomy, 72% of the femurs and 82% of the tibias had visible ulcers. Cartilage from the weight-bearing areas incorporated 2.0-2.9 times more 35S-sulfate in vitro than cartilage from the opposite, unoperated knees. 3H-thymidine incorporation was 2.5-3.4 times higher for surgical than control groups. 35S-sulfate incorporation by the surgical group was inhibited by 22% in the presence of 10(-4) M U24522, an inhibitor of rabbit chondrocyte metalloprotease (CMP). 3H-thymidine incorporation by the surgical group was inhibited by 28% by 10(-4) M U24522. In vitro PG release from cartilage removed 2 days after surgery was 1.6-3.7 times higher for the surgical than the control group. PG release by the surgical group after 22 h of incubation was reduced to the control level by three CMP inhibitors, U24278, U24279, and U24522. PG release by cartilage from the nonsurgical group was also reduced by these compounds at 22 h. These results suggest that both the anabolic and catabolic processes that are stimulated by surgery can be isolated in vitro and that CMP may be involved in the catabolic process.

LTB4-induced transient neutropenia in the rat: a model for evaluating efficacy and bioavailability of LTB4 receptor antagonists.

An animal model of leukotriene B4- (LTB4) induced neutropenia has been developed to evaluate LTB4 receptor antagonists in vivo. LTB4, a potent chemotactic inflammatory mediator, when administered intravenously, induces a profound, rapid, and transient redistribution of blood neutrophils from the circulating pool to the marginated pool. This phenomenon is applied in the neutropenia model whereby circulating blood neutrophil counts prior to and after intravenous infusion of LTB4 are compared. Kinetics of LTB4-induced neutrophil responses are determined through the use of a Technicon H*1 automated blood cell analyzer. LTB4 receptor antagonists are identified by inhibition of LTB4-induced neutropenia. Standard antiinflammatory compounds including BW-755C, Abbott A-64077 (zileuton), dexamethasone-21-acetate, indomethacin, and naproxen did not affect LTB4-induced neutropenia. A potent LTB4 receptor antagonist, designated "RPR," inhibited LTB4-induced neutropenia following oral administration in a dose-dependent fashion.

Comparison of spontaneous and retinoic acid stimulated rabbit articular cartilage degradation in vitro.

The in vitro degradation of rabbit articular cartilage explants was evaluated with and without the addition of retinoic acid under various experimental conditions. Retinoic acid at nontoxic concentrations ranging from 1 X 10(-7) to 1 X 10(-5) M significantly increased cartilage degradation. The addition of phenanthroline or cycloheximide, but not pepstatin, significantly inhibited spontaneous and retinoic-acid-stimulated cartilage degradation at pH 7. When the pH was reduced to 5, only pepstatin inhibited spontaneous and retinoic-acid-stimulated cartilage degradation. No chondroitin sulphate release was observed when the temperature was reduced to 4 degrees C. The different inhibitory profiles observed at pH 7 and pH 5 suggest that cartilage degradation at pH 7 is associated with the presence and synthesis of a neutral metalloproteinase.

Regrowth of the rabbit meniscus after lateral and medial meniscectomies.

The rate of regrowth of the meniscus was compared after medial and lateral meniscectomies. Articular cartilage ulcers were observed 21 days after lateral meniscectomies and femoral pitting was observed after either procedure. Histologically, lesions were observed only after the lateral procedure. Regrowth of the meniscus was evident within 1 week of surgery as increased 3H-thymidine uptake and increased collagen synthesis by meniscal tissue from both surgical groups. These parameters returned to normal sooner after the medial than the lateral procedure. The excised meniscus was completely replaced by new tissue within 3 weeks of either procedure. In conclusion, the meniscus heals quickly following surgery and the small differences in the rate of regrowth between the two procedures do not seem to be adequate to explain the significant differences in femoral and tibial lesions.

Inhibition of arachidonic acid induced mortality in rabbits with several non-steroidal anti-inflammatory agents.

The intravenous administration of arachidonic acid to rabbits is an effective in vivo model for evaluating potential anti-thrombotic drugs. Most of the non-steroidal anti-inflammatory agents (NSAIFA) inhibit this arachidonic acid induced mortality (except sodium salicylate and acetaminophen). However, there is a lack of correlation between the relative potencies from various assays (rabbit anti-thrombotic, anti-inflammatory, alalgesic, ulcerogenic and inhibition of prostaglandin synthetase evaluations). These studies imply other actions with NSAIFA than an effect solely on the prostaglandin biosynthetic pathway.