Quality assurance in stereotactic radiosurgery/radiotherapy according to DIN 6875-1

The new DIN (' Deutsche Industrie- Norm') 6875- 1, which is currently being finalised, deals with quality assurance ( QA) criteria and tests methods for linear accelerator and Gamma Knife stereotactic radiosurgery/ radiotherapy including treatment planning, stereotactic frame and stereotactic imaging and a system test to check the whole chain of uncertainties. Our existing QA program, based on dedicated phantoms and test procedures, has been refined to fulfill the demands of this new DIN. The radiological and mechanical isocentre corresponded within 0.2 mm and the measured 50% isodose lines were in agreement with the calculated ones within less than 0.5 mm. The measured absorbed dose was within 3%. The resultant output factors measured for the 14-, 8- and 4- mm collimator helmet were 0.9870 +/- 0.0086, 0.9578 +/- 0.0057 and 0.8741 +/- 0.0202, respectively. For 170 consecutive tests, the mean geometrical accuracy was 0.48 +/- 0.23 mm. Besides QA phantoms and analysis software developed in- house, the use of commercially available tools facilitated the QA according to the DIN 6875- 1 with which our results complied. Copyright (C) 2004 S. Karger AG, Basel

Induction of CD4+ regulatory T cells by soluble HLA-G isoforms.

Purpose/Objective: The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto-maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule, which participates to the control of the immune response. HLA-G inhibits a wide array of immune cells and has long-term immune- modulatory effects since it can induce the generation of suppressor/ regulatory cells. We recently demonstrated that tolerogenic DC, termed DC-10, promote the differentiation of Tr1 cells via the IL10-dependent membrane bound HLA-G1/ILT4 pathway. The role of membrane-bound HLA-G1 in promoting Tr1 cells via DC-10, raise the question whether soluble shed HLA-G1 or HLA-G5 can promote Tr1 cell differentiation. Materials and methods: Human naı¨ve CD4+ T cells were stimulated via anti-CD3 mAbs cross-linked on artificial APC consisting in murine L-cells co-transfected with human CD32, CD80, and CD58 in the presence of shed sHLA-G1 or HLA-G5 alone or in combination with IL-10. As control, we used Th0 and Tr1 cells differentiated with artificial APC alone or in the presence of IL-10 and IFN-a, respectively. Results: We showed that repetitive stimulation of human naı¨ve CD4+ T cells in the presence of shed HLA-G1 or HLA-G5, alone or in combination with IL-10, induced the differentiation of a population of CD4+ T cells that are phenotypically different from both Th0 and Tr1 cells. T cells differentiated with soluble HLA-Gs secrete lower levels of IFN-g and IL-2 as compared to Th0 cells. Interestingly, HLA-Ginduced T cells secrete low amounts of IL-10, which is slightly increased when IL-10 is present in culture, but never reach the levels produced by Tr1 cells. Despite the ability to proliferate upon polyclonal activation, HLA-G-induced T cells suppress the proliferation of autologous CD4+ T cells in vitro. Conclusions: We showed that activation of human CD4+ T cells in the presence of both soluble shed HLA-G1 or HLA-G5, alone or in combination with IL-10, promotes the induction of a population of suppressor CD4+ T cells, which are distinct from Tr1 cells

First application of a pixel-wise analysis on bladder dose-surface maps in prostate cancer radiotherapy

PURPOSE: To develop a method for investigating local dose effects on the bladder after prostate cancer radiotherapy based on dose-surface maps (DSMs). BACKGROUND AND PURPOSE: DSMs of patients included in a prospective study (DUE01) were generated by virtually cutting bladder contours at the points intersecting the sagittal plane passing through its center-of-mass: maps were laterally normalized and aligned at the posterior inferior point. The average DSMs of patients with/without toxicity, the DSMs of differences and t statistic were used to select regions better discriminating patients with toxicity. A total of 72 patients with no/mild urinary symptoms before radiotherapy and who were treated with moderate hypo-fractionation (2.5-2.65Gy/fr, 70-74Gy) were considered, and the endpoint was an International Prostate Symptoms Score (IPSS)\u2a7e15 at the end of therapy (IPSSend\u2a7e15, n=25/72). RESULTS: The DSMs of patients with/without toxicity were significantly different (p50-70Gy at 5-7mm from the base was associated with an IPSSend\u2a7e15 (odds ratios: 1.03-1.07). Different patterns were recognized for specific symptoms. With frequency/urgency, a quasi-threshold effect on the absolute posterior dose at 5-12mm from the base (2Gy equivalent doses=80-82Gy, \u3b1/\u3b2=3-5Gy) was observed. CONCLUSIONS: Local-dose effects for acute symptoms were detected in a group of patients treated within a moderately hypo-fractionated protocol. The results for frequency/urgency were consistent with a threshold effect on the trigone

Correlation between surrogates of bladder dosimetry and dose-volume histograms of the bladder wall defined on MRI in prostate cancer radiotherapy

The correlation between bladder dose-wall-histogram (DWH) and dose-volume-histogram (DVH), dose-surface-histogram (DSH), and DVH-5/10 was investigated in a group of 28 patients; bladder walls were drawn on T2-MRI. DVH showed the poorest correlation with DWH; DSH or DVH-5/10 should be preferred in planning; absolute DVH may be used for radical patients, although less robust

Contouring variability of the penile bulb on CT images : quantitative assessment using a generalized concordance index

Purpose: Within a multicenter study (DUE-01) focused on the search of predictors of erectile dysfunction and urinary toxicity after radiotherapy for prostate cancer, a dummy run exercise on penile bulb (PB) contouring on computed tomography (CT) images was carried out. The aim of this study was to quantitatively assess interobserver contouring variability by the application of the generalized DICE index. Methods and Materials: Fifteen physicians from different Institutes drew the PB on CT images of 10 patients. The spread of DICE values was used to objectively select those observers who significantly disagreed with the others. The analyses were performed with a dedicated module in the VODCA software package. Results: DICE values were found to significantly change among observers and patients. The mean DICE value was 0.67, ranging between 0.43 and 0.80. The statistics of DICE coefficients identified 4 of 15 observers who systematically showed a value below the average (p value range, 0.013 - 0.059): Mean DICE values were 0.62 for the 4 "bad" observers compared to 0.69 of the 11 "good" observers. For all bad observers, the main cause of the disagreement was identified. Average DICE values were significantly worse from the average in 2 of 10 patients (0.60 vs. 0.70, p < 0.05) because of the limited visibility of the PB. Excluding the bad observers and the "bad" patients," the mean DICE value increased from 0.67 to 0.70; interobserver variability, expressed in terms of standard deviation of DICE spread, was also reduced. Conclusions: The obtained values of DICE around 0.7 shows an acceptable agreement, considered the small dimension of the PB. Additional strategies to improve this agreement are under consideration and include an additional tutorial of the so-called bad observers with a recontouring procedure, or the recontouring by a single observer of the PB for all patients included in the DUE-01 study

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a longterm asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the α-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV- 1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection

Independent Validation of Rectal Dose-volume Constraints using MRC RT01 (ISRCTN47772397) Trial Data

Introduction: Treatment plan evaluation requires knowledge of the effect of the plan, not only on the intended target, but also the surrounding normal tissues that are unavoidably irradiated. Recent literature has provided estimations of tolerance doses and proposed dose-volume constraints for many of the organs at risk. However, very few of these recommendations have been independently validated. This study details how constraints proposed for the rectum were tested using data from the RT01 randomised prostate radiotherapy trial. Method: An independent validation of the rectal dose-volume constraints used in the CHHiP trial and proposed recently by Fiorino et al. was performed. The constraints were applied retrospectively to the treatment plans collected from the RT01 trial. Odds ratios (OR) were calculated to compare the reported incidence of specific late rectal toxicity end points in the group of patients whose treatment plan met a specified dose-volume constraint compared to the group of patients who failed that constraint. Results: Statistically significant ORs were observed for every constraint tested (except 75 Gy) for at least one clinical end point. For the CHHiP constraints between 60 and 70 Gy, the ORs calculated for rectal bleeding (RMH score defined in protocol) exceeded 2.5 (P!0.02). Similarly the ORs for CHHiP constraints between 30 and 65 Gy exceeded 2.4 (P!0.021) for urgency (UCLA PCI). The Fiorino constraints between 40 and 60 Gy resulted in ORs O2 (P!0.02) for loose stools (UCLA PCI) Conclusion: Implementing rectal dose-volume constraints from 30 Gy up to the prescription dose will result in a decrease in the incidence of late rectal toxicity. Constraints for doses as low as 30 Gy were statistically significant, further challenging the concept that the rectum is a serial structure where the maximum dose to the organ is the only consideration

Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis

GABAergic transmission regulates adult neurogenesis by exerting negative feedback on cell proliferation and enabling dendrite formation and outgrowth. Further, GABAergic synapses target differentiating dentate gyrus granule cells prior to formation of glutamatergic connections. GABA(A) receptors (GABA(A) Rs) mediating tonic (extrasynaptic) and phasic (synaptic) transmission are molecularly and functionally distinct, but their specific role in regulating adult neurogenesis is unknown. Using global and single-cell targeted gene deletion of subunits contributing to the assembly of GABA(A) Rs mediating tonic (α4, δ) or phasic (α2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABA(A) Rs containing α4, but not δ, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, α2-GABA(A) Rs cell-autonomously signal to control positioning of newborn neurons and regulate late maturation of their dendritic tree. In particular, we observed pruning of distal dendrites in immature granule cells lacking the α2 subunit. This alteration could be prevented by pharmacological inhibition of thrombospondin signaling with chronic gabapentin treatment, shown previously to reduce glutamatergic synaptogenesis. These observations point to homeostatic regulation of inhibitory and excitatory inputs onto newborn granule cells under the control of α2-GABA(A) Rs. Taken together, the availability of distinct GABA(A) R subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain