Feasibility of Brain Atrophy Measurement in Clinical Routine without Prior Standardization of the MRI Protocol: Results from MS-MRIUS, a Longitudinal Observational, Multicenter Real-World Outcome Study in Patients with Relapsing-Remitting MS.

BACKGROUND AND PURPOSE: Feasibility of brain atrophy measurement in patients with MS in clinical routine, without prior standardization of the MRI protocol, is unknown. Our aim was to investigate the feasibility of brain atrophy measurement in patients with MS in clinical routine. MATERIALS AND METHODS: Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States (MS-MRIUS) is a multicenter (33 sites), retrospective study that included patients with relapsing-remitting MS who began treatment with fingolimod. Brain MR imaging examinations previously acquired at the baseline and follow-up periods on 1.5T or 3T scanners with no prior standardization were used, to resemble a real-world situation. Brain atrophy outcomes included the percentage brain volume change measured by structural image evaluation with normalization of atrophy on 2D-T1-weighted imaging and 3D-T1WI and the percentage lateral ventricle volume change, measured by VIENA on 2D-T1WI and 3D-T1WI and NeuroSTREAM on T2-fluid-attenuated inversion recovery examinations. RESULTS: A total of 590 patients, followed for 16 months, were included. There were 585 (99.2%) T2-FLAIR, 425 (72%) 2D-T1WI, and 166 (28.2%) 3D-T1WI longitudinal pairs of examinations available. Excluding MR imaging examinations with scanner changes, the analyses were available on 388 (65.8%) patients on T2-FLAIR for the percentage lateral ventricle volume change, 259 and 257 (43.9% and 43.6%, respectively) on 2D-T1WI for the percentage brain volume change and the percentage lateral ventricle volume change, and 110 (18.6%) on 3D-T1WI for the percentage brain volume change and percentage lateral ventricle volume change. The median annualized percentage brain volume change was -0.31% on 2D-T1WI and -0.38% on 3D-T1WI. The median annualized percentage lateral ventricle volume change was 0.95% on 2D-T1WI, 1.47% on 3D-T1WI, and 0.90% on T2-FLAIR. CONCLUSIONS: Brain atrophy was more readily assessed by estimating the percentage lateral ventricle volume change on T2-FLAIR compared with the percentage brain volume change or percentage lateral ventricle volume change using 2D- or 3D-T1WI in this observational retrospective study. Although measurement of the percentage brain volume change on 3D-T1WI remains the criterion standard and should be encouraged in future prospective studies, T2-FLAIR-derived percentage lateral ventricle volume change may be a more feasible surrogate when historical or other practical constraints limit the availability of percentage brain volume change on 3D-T1WI.

Sphingolipid pathway enzymes modulate cell fate and immune responses.

Sphingolipids (SLs) are a class of essential, bioactive lipids. The SL family includes over 4000 distinct molecules, characterized by their sphingoid base (long-chain aliphatic amine) backbone. SLs are key components of cell membranes, yet their roles go well beyond structure. SLs are involved in many cellular processes including cell differentiation, apoptosis, growth arrest and senescence. As cancer cells routinely display increased growth properties and escape from cell death, it has been suggested that enzymes involved in SL synthesis or catabolism may be altered in cancer cells. In this review, we discuss the role of SL pathway enzymes in cancer, and in acquired resistance to therapy. The use of inhibitors and gene silencing approaches targeting these SL pathways is also explored. Finally, we elaborate on the role of SL pathway enzymes in the tumor microenvironment and their effect on immune cell function.

Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures.

Multiple patient-reported outcomes (PROs) are currently being used in multiple sclerosis (MS) but their application is inconsistent and guidance on the appropriateness of each tool is lacking. The objective of our study was to identify MS-specific PROs and systematically to assess the development process and the reliability and validity of various instruments. A systematic literature search was conducted on multiple data sources, including MEDLINE, Embase (using the Ovid platform) and Google Scholar, from 1996 to March 2015. Search terms included combinations of MS, PROs and quality of life. Randomized controlled trials or observational studies conducted on patients with MS and published in English were included. In addition, the PROQOLID database was explored. The MS-specific PROs were systematically assessed using the Evaluating the Measurement of Patient-Reported Outcomes tool. In total, 8094 articles were screened and 405 PROs were identified from 1102 relevant articles. PROs were classified into MS-specific (n = 82) and non-MS-specific (n = 323). The results for the eight PROs that are most commonly used in MS clinical trials are presented here. For these eight PROs, the overall summary scores ranged between 50.1 and 68.7. The Multiple Sclerosis Impact Scale-29 had the best overall mean score (68.7), followed by the Leeds Multiple Sclerosis Quality of Life (67.0). This is the first study to provide a standardized assessment of all PROs for MS. There is a lack of data on content validity for PROs used in MS research, which indicates the need for a robust instrument in MS developed according to the US Food and Drug Administration guidelines.

Lentivirus IL-10 gene therapy down-regulates IL-17 and attenuates mouse orthotopic lung allograft rejection.

The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.

Engineered human Tmpk fused with truncated cell-surface markers: versatile cell-fate control safety cassettes.

Cell-fate control gene therapy (CFCGT)-based strategies can augment existing gene therapy and cell transplantation approaches by providing a safety element in the event of deleterious outcomes. Previously, we described a novel enzyme/prodrug combination for CFCGT. Here, we present results employing novel lentiviral constructs harboring sequences for truncated surface molecules (CD19 or low-affinity nerve growth factor receptor) directly fused to that CFCGT cDNA (TmpkF105Y). This confers an enforced one-to-one correlation between cell marking and eradication functions. In-vitro analysis demonstrated the full functionality of the fusion product. Next, low-dose 3'-azido-3'-deoxythymidine (AZT) administration to non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice injected with transduced clonal K562 cells suppressed tumor growth; furthermore, one integrated vector on average was sufficient to mediate cytotoxicity. Further, in a murine xenogeneic leukemia-lymphoma model we also demonstrated in-vivo control over transduced Raji cells. Finally, in a proof-of-principle study to examine the utility of this cassette in combination with a therapeutic cDNA, we integrated this novel CFCGT fusion construct into a lentivector designed for treatment of Fabry disease. Transduction with this vector restored enzyme activity in Fabry cells and retained AZT sensitivity. In addition, human Fabry patient CD34(+) cells showed high transduction efficiencies and retained normal colony-generating capacity when compared with the non-transduced controls. These collective results demonstrated that this novel and broadly applicable fusion system may enhance general safety in gene- and cell-based therapies.

Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer.

Activity and specificity of chemotherapeutic agents against solid tumors can be augmented via the targeted or localized delivery of 'suicide' genes. Selective activation of specific prodrugs in cells expressing the 'suicide' gene drives their elimination by apoptosis, while also enabling the killing of adjacent bystander cells. Strong bystander effects can compensate for poor 'suicide' gene delivery, and depend on the prodrugs used and mechanisms for the acquisition of activated drug by the bystander population, such as the presence of gap junctional intercellular communications. Although a number of 'suicide' gene therapies for cancer have been developed and characterized, such as herpes simplex virus-derived thymidine kinase (HSV-tk)-based activation of ganciclovir, their limited success highlights the need for the development of more robust approaches. Limiting activation kinetics and evolution of chemoresistance are major obstacles. Here we describe 'suicide' gene therapy of cancer based on the lentivirus-mediated delivery of a thymidine-active human deoxycytidine kinase variant. This enzyme possesses substrate plasticity that enables it to activate a multitude of prodrugs, some with distinct mechanisms of action. We evaluated the magnitude and mechanisms of bystander effects induced by different prodrugs, and show that when used in combination, they can synergistically enhance the bystander effect while avoiding off-target toxicity.

Optimización de la agudeza visual en las FAS / Optimization of visual acuity in Sspanish Armed Forces

Introducción: La existencia de una agudeza visual óptima es requerida para la mayor parte de las actividades del personal de las FAS, pero se hace estrictamente necesaria en el despliegue dentro del teatro de operaciones internacional. Material y Método: Hemos realizado un estudio sobre el registro de la agudeza visual en un grupo aleatorio (n = 54) durante los reconocimientos periódicos de permanencia realizados en nuestro centro. Resultados: Sólo 3 casos (5,56%) reconocen ver mal; 20 (37,04%) han utilizado corrección en algún momento de su vida; 12 (22,22%) utilizan corrección; en 32 (60,38%) sería altamente recomendable el uso de corrección. Ningún caso (0%) de los usuarios de corrección posee corrección de repuesto (en gafas). Conclusión: Se hace incidencia en el control y registro de los parámetros visuales en el personal de las FAS, especialmente en actividades de riesgo y despliegue internacional (AU)

Introduction: The existence of an optimal visual acuity is required for most of the activities of the membrers of the Armed Forces, but it is strictly necessary in the deployment within the international theater. Materials and Methods: We conducted a study of visual acuity in a random group of periodical surveys in our center. Results: Only 3 cases (5.56%) recognize look bad; 20 (37.04%) have used correction at some point in their lives; 12 (22.22%) used correction; in 32 cases (60.38%) was highly recommended the use of correction. No cases (0%) of users of correction has a duplicate of it (in glasses). Conclusions: The study suggests the need for better surveillance and control of visual parameters of the Armed Forces members, especially in risky activities and international deployment (AU)

Topiramato: efectos secundarios a nivel ocular. Revision a propósito de un caso / Ocular side effects with topiramate: A case discussion and review of the literature

Presentamos un caso de miopización bilateral aguda asociada a hipertensión ocular por cierre angular, secundario al inicio del tratamiento con topiramato vía oral. Revisión: Revisamos los principales efectos oculares secundarios al tratamiento con topiramato, tales como cierre angular agudo asociado a glaucoma o hipertensión ocular, miopización secundaria, o toxicidad retiniana. Los síntomas aparecen típicamente en las primeras semanas tras iniciar el tratamiento, o al duplicar la dosis. El cuadro se resuelve normalmente al suspender el fármaco. Conclusión: El topiramato es un fármaco utilizado principalmente como antiepiléptico si bien es ampliamente utilizado en otros tratamientos neurológicos y cuadros variados como cefaleas, alcoholismo, espasmos infantiles, neuralgias e incluso tratamiento de la obesidad y bulimia, entre otros. Dados los efectos secundarios descritos a nivel ocular, éstos deben ser conocidos por el oftalmólogo, y considerados por el médico prescriptor, informando al paciente y a su familia al inicio del tratamiento (AU)

Clinical case: We describe a case of acute bilateral ocular myopia associate to ocular hypertension by angle-closure secondary oral treatment with topiramate. Review: We review the main ocular effects related to the treatment with topiramate, such as angle-closure glaucoma, hypertension, secondary myopia, or retinal toxicity. Symptoms typically occur in the first weeks of the topiramate therapy, or when the dose is duplicate. The disease and symtoms dissapear when the medication is discontinued. Conclusion: The topiramato is a drug used mainly as anti-epileptic, and also in other variable neurological disorders as migraines, alcoholism, spasms, neuralgias and obesity and bulimia, among others. The secondary ocular effects must be known by the ophtalmologist and communicated to the patient and his family at the beginning of the treatment (AU)

Differential immune responses mediated by adenovirus- and lentivirus-transduced DCs in a HER-2/neu overexpressing tumor model.

Recent investigations have demonstrated that adenoviral and lentiviral vectors encoding HER-2 can be utilized in cancer immunotherapy. However, it is not known whether both viral systems elicit a similar immune response. Here, we compare the immune response in mice induced by dendritic cells (DCs) infected with either recombinant adenovirus or lentivirus encoding rat HER-2 (rHER-2). Both vaccine types yielded similar control of tumor growth, but we found clear differences in their immune responses 10 days after DC immunization. Adenovirus rHER-2-transduced DCs elicited locally and systemically high frequencies of CD4+ and CD8+ T cells, while lentivirus rHER-2-transduced DCs predominantly led to CD4+ T-cell infiltration at the tumor site. Splenocytes from mice immunized with lentivirus rHER-2-transduced DCs secreted higher levels of interferon (IFN)-γ, mainly by CD4+ T cells, following stimulation by RM-1-mHER-2 tumors. In contrast, the adenovirus vaccinated group exhibited CD4+ and CD8+ T cells that both contributed to IFN-γ production. Besides an established cellular immune response, the rHER-2/DC vaccine elicited a significant humoral response that was highest in the adenovirus group. DC subsets and regulatory T cells in the spleen were also differentially modulated in the two vaccine systems. Finally, adoptive transfer of splenocytes from both groups of immunized mice strongly inhibited in vivo tumor growth. Our results suggest that not only the target antigen but also the virus system may determine the nature and magnitude of antitumor immunity by DC vaccination.

Novel application of lentiviral vectors towards treatment of graft-versus-host disease.

Allogeneic transplantation of hematopoietic stem cells and lymphocytes is a curative treatment for malignant and non-malignant disease. However, the primary complication limiting the safety of transplantation is graft-versus-host disease (GvHD), which is mediated by donor T cells. Strategies for pre- and post-transplant manipulation of graft cells are not yet optimal for balancing GvHD severity with beneficial Graft-versus-Leukemia (GvL) effects. Emerging cell fate control gene therapy (CFCGT)-based strategies, such as 'suicide' gene therapy for donor T cell regulation, can supplement existing transplantation approaches by providing a safety element to reduce GvHD. Past uses of CFCGT in the clinic have provided proof-of-principle that GvHD can be controlled by such a strategy. However, there exists a need for improved transgene delivery and suicide control systems. Recently, lentiviral vectors (LVs) have emerged as effective gene delivery vehicles for the clinic. Combining lentiviral gene delivery with newer generations of 'suicide' systems that possess improved enzyme/prodrug specificities, activities, and reduced immunogenicity, could provide the necessary degree of control required to more successfully manage GvHD. Improving the safety of transplantation through successful CFCGT will serve to expand the potential donor pool and the spectrum of disorders that can be treated by this therapeutic schema.

Transduction and transplantation of spermatogonia into the testis of ram lambs through the extra-testicular rete.

Spermatogonial transplantation will provide a new way to study spermatogenesis in domestic animals, disseminate male genetics and produce transgenic animals, if efficiency can be improved. We evaluated a 'surgical' method for transplanting donor cells into testes of ram lambs, where the head of the epididymis is reflected, and a catheter introduced into the extra-testicular rete testis. We also tested transduction of ram spermatogonia with a lentiviral (LV) vector as a means to identify permanent colonization, and introduce genes into donor cells. Eight ram lambs, 11- to 13-week olds, were the recipients: in five, spermatogonia were injected into one testis, and the contralateral testis was an un-manipulated control: in two, spermatogonia were injected into one testis and the contralateral was sham-injected: in one, both testes were injected. Six lambs received spermatogonia labelled with a cell-tracking dye and these were collected 1 or 2 weeks after transplantation; three lambs received spermatogonia transduced with a LV vector driving the expression of enhanced Green Fluorescence Protein and these were collected after 2 months. Donor cells were detected by immunohistochemistry in tubules of seven of nine recipient testes. Approximately 22% of tubule cross-sections contained donor cells immediately after transplantation, and 0.2% contained virally transduced cells 2 months after transplantation. The onset of spermatogenesis was delayed, and there were lesions in both injected and sham-injected testes. Despite the effects of the surgery, elongated spermatids were present in one recipient testis 2 months after surgery. The results suggest that, after modifying the surgical and transduction techniques, this approach will be a means to produce good colonization by donor spermatogonia in sheep testes.

Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells.

Adoptively transferred T cells possess anticancer activities partially mediated by T-cell FasL engagement of Fas tumor targets. However, antigen-induced T-cell activation and clonal expansion, which stimulates FasL activity, is often inefficient in tumors. As a gene therapy approach to overcome this obstacle, we have created oncoretroviral vectors to overexpress FasL or non-cleavable FasL (ncFasL) on murine T cells of a diverse T-cell receptor repertoire. Expression of c-FLIP was also engineered to prevent apoptosis of transduced cells. Retroviral transduction of murine T lymphocytes has historically been problematic, and we describe optimized T-cell transduction protocols involving CD3/CD28 co-stimulation of T cells, transduction on ice using concentrated oncoretrovirus, and culture with IL-15. Genetically modified T cells home to established prostate cancer tumors in vivo. Co-stimulated T cells expressing FasL, ncFasL and ncFasL/c-FLIP each mediated cytotoxicity in vitro against RM-1 and LNCaP prostate cancer cells. To evaluate the compatibility of this approach with current prostate cancer therapies, we exposed RM-1, LNCaP, and TRAMP-C1 cells to radiation, mitoxantrone, or docetaxel. Fas and H-2(b) expression were upregulated by these methods. We have developed a novel FasL-based immuno-gene therapy for prostate cancer that warrants further investigation given the apparent constitutive and inducible Fas pathway expression in this malignancy.

Nanodosimetry in a clinical neutron therapy beam using the variance-covariance method and Monte Carlo simulations.

Nanodosimetric single-event distributions or their mean values may contribute to a better understanding of how radiation induced biological damages are produced. They may also provide means for radiation quality characterization in therapy beams. Experimental nanodosimetry is however technically challenging and Monte Carlo simulations are valuable as a complementary tool for such investigations. The dose-mean lineal energy was determined in a therapeutic p(65)+Be neutron beam and in a (60)Co gamma beam using low-pressure gas detectors and the variance-covariance method. The neutron beam was simulated using the condensed history Monte Carlo codes MCNPX and SHIELD-HIT. The dose-mean lineal energy was calculated using the simulated dose and fluence spectra together with published data from track-structure simulations. A comparison between simulated and measured results revealed some systematic differences and different dependencies on the simulated object size. The results show that both experimental and theoretical approaches are needed for an accurate dosimetry in the nanometer region. In line with previously reported results, the dose-mean lineal energy determined at 10 nm was shown to be related to clinical RBE values in the neutron beam and in a simulated 175 MeV proton beam as well.

Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells.

A deficiency in alpha-galactosidase A (alpha-gal A) activity causes Fabry disease. Virus-based delivery of genes can correct cells and establish a sustained supply of therapeutic proteins. Recombinant lentiviral vectors (LVs) show promise in this context. We first demonstrate LV-mediated marking of peripheral blood (PB) cells by transduction/transplantation of hematopoietic stem/progenitor cells. Stable enGFP expression was observed in PB for 37 weeks. Next, we transplanted Fabry mice with bone marrow mononuclear cells (BMMNCs) transduced a single time with a LV encoding the human alpha-gal A cDNA. Sustained expression of functional alpha-gal A in Fabry mice was observed over 24 weeks. Plasma alpha-gal A activity from treated Fabry mice was two-fold higher than wild-type controls. Increased alpha-gal A activity, often to supra-normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed. In secondary bone marrow transplantations, Fabry mice showed multilineage marking of PB, splenocytes and BMMNCs, along with therapeutic levels of alpha-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34(+) cells from a Fabry patient and observed corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease.

An algorithm for real-time dosimetry in intensity-modulated radiation therapy using the radioluminescence signal from Al2O3:C.

Although the radioluminescence (RL) signal from optical fibre Al(2)O(3):C dosemeters used in medical applications is essentially proportional to dose rate, the crystals used so far are imperfect in the sense that their RL sensitivity changes with accumulated dose. A computational algorithm has been developed that corrects for these sensitivity changes. We further report on a new system that effectively separates the RL signal generated in the crystal from fluorescence and Cerenkov emission generated in the optical fibre cable using a gating technique in connection with pulsed linear accelerator radiation beams. The dosimetry system has been used for dose measurements in a phantom during an intensity-modulated radiation therapy (IMRT) treatment with 6 MV photons. The RL measurement results are in excellent agreement (i.e. within 1%) with both the OSL results and the dose delivered according to the treatment planning system. RL signals from Al(2)O(3):C can be used for real-time dose rate measurements with a time resolution of approximately 0.1 s and a spatial resolution only limited by the size of the detector (<0.5 mm).

Can the average glandular dose in routine digital mammography screening be reduced? A pilot study using revised image quality criteria.

There is a need for tools that in a simple way can be used for the evaluation of image quality related to clinical requirements in mammography. The aim of this work was to adjust the present European image quality criteria to be relevant also for digital mammography images, and to use as simple and as few criteria as possible. A pilot evaluation of the new set of criteria was made with mammograms of 28 women from a General Electric Senographe 2000D full-field digital mammography system. One breast was exposed using the standard automatic exposure mode, the other using about half of that absorbed dose. Three experienced radiologists evaluated the images using visual grading analysis technique. The results indicate that the new quality criteria can be used for the evaluation of image quality related to clinical requirements in digital mammography in a simple way. The results also suggest that absorbed doses for the mammography system used may be substantially reduced.

Clinical evaluation of a new set of image quality criteria for mammography.

The European Commission (EC) quality criteria for screen-film mammography are used as a tool to assess image quality. A new set of criteria was developed and initially tested in a previous study. In the present study, these criteria are further evaluated using screen-film mammograms that have been digitised, manipulated to simulate different image quality levels and reprinted on film. Expert radiologists have evaluated these manipulated images using both the original (EC) and the new criteria. A comparison of three different simulated dose levels reveals that the new criteria yield a larger separation of image criteria scores than the old ones. These results indicate that the new set of image quality criteria has a higher discriminative power than the old set and thus seems to be more suitable for evaluation of image quality in mammography.

A Monte Carlo study of the energy dependence of Al2O3:C crystals for real-time in vivo dosimetry in mammography.

In a previous experimental study, a novel method for in vivo dosimetry has been investigated, based on radioluminescence (RL) and optically stimulated luminescence (OSL). However, because of the large difference in atomic composition between the detector material and the breast tissue, relatively large energy dependence in low-energy X-ray beams can be expected. In the present work, the energy dependence of Al2O3:C crystals was modelled with the Monte Carlo code EGSnrc using three types of X-ray spectra. The results obtained (5.6-7.3%) agree with a previously determined experimental result (9%) within the combined standard uncertainty of the two methods. The influence of the size of the crystal on the energy dependence was investigated together with the effect of varying the thickness of the surrounding light-protective material. The results obtained indicate a minor effect owing to the thickness of the light-protective material, and a somewhat larger effect from reducing the diameter of the crystal. The outcome of this study can be used to improve the future design of the RL/OSL dosimetry system for use in mammography.

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer.

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

In vivo absorbed dose measurements in mammography using a new real-time luminescence technique.

A dosimetry system based on radioluminescence (RL) and optically stimulated luminescence (OSL) from carbon doped aluminium oxide (Al2O3:C) crystals was developed for in vivo absorbed dose measurements in mammography. A small cylindrical crystal of Al2O3:C (diameter 0.48 mm and length 2 mm) was coupled to the end of a 1 mm diameter optical fibre cable. Owing to their small size and characteristic shape, these probes can be placed on the body surface in the field of view during the examination, without compromising the reading of the mammogram. Our new technique was tested with a mammography unit (Siemens Mammomat 3000) and screen-film technique over a range of clinically relevant X-ray energies. The results were compared with those obtained from an ionization chamber usually used for the determination of absorbed dose in mammography. The reproducibility of measurements was around 3% (1 standard deviation) at 4.5 mGy for both RL and OSL data. The dose response was found to be linear between 4.5 mGy and 30 mGy. The energy dependence of the system is around 18% between 23 kV and 35 kV. In vivo measurements were performed during three patient examinations. It was shown that entrance and exit doses could be measured. The presence of the small probes did not significantly interfere with the diagnostic quality of the images. Entrance doses estimated by RL/OSL results agreed within 3% with entrance surface dose values calculated from the ionization chamber measurements. These results indicate a considerable potential for use in routine control and in vivo dose measurements in mammography.