Efficient gene editing via non-viral delivery of CRISPR-Cas9 system using polymeric and hybrid microcarriers.

CRISPR-Cas9 is a revolutionary genome-editing technology that has enormous potential for the treatment of genetic diseases. However, the lack of efficient and safe, non-viral delivery systems has hindered its clinical application. Here, we report on the application of polymeric and hybrid microcarriers, made of degradable polymers such as polypeptides and polysaccharides and modified by silica shell, for delivery of all CRISPR-Cas9 components. We found that these microcarriers mediate more efficient transfection than a commercially available liposome-based transfection reagent (>70% vs. <50% for mRNA, >40% vs. 20% for plasmid DNA). For proof-of-concept, we delivered CRISPR-Cas9 components using our capsules to dTomato-expressing HEK293T cells-a model, in which loss of red fluorescence indicates successful gene editing. Notably, transfection of indicator cells translated in high-level dTomato knockout in approx. 70% of transfected cells. In conclusion, we have provided proof-of-principle that our micro-sized containers represent promising non-viral platforms for efficient and safe gene editing.

mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5.

Homozygosity for a natural deletion variant of the HIV-coreceptor molecule CCR5, CCR5Δ32, confers resistance toward HIV infection. Allogeneic stem cell transplantation from a CCR5Δ32-homozygous donor has resulted in the first cure from HIV ('Berlin patient'). Based thereon, genetic disruption of CCR5 using designer nucleases was proposed as a promising HIV gene-therapy approach. Here we introduce a novel TAL-effector nuclease, CCR5-Uco-TALEN that can be efficiently delivered into T cells by mRNA electroporation, a gentle and truly transient gene-transfer technique. CCR5-Uco-TALEN mediated high-rate CCR5 knockout (>90% in PM1 and >50% in primary T cells) combined with low off-target activity, as assessed by flow cytometry, next-generation sequencing and a newly devised, very convenient gene-editing frequency digital-PCR (GEF-dPCR). GEF-dPCR facilitates simultaneous detection of wild-type and gene-edited alleles with remarkable sensitivity and accuracy as shown for the CCR5 on-target and CCR2 off-target loci. CCR5-edited cells were protected from infection with HIV-derived lentiviral vectors, but also with the wild-type CCR5-tropic HIV-1BaL strain. Long-term exposure to HIV-1BaL resulted in almost complete suppression of viral replication and selection of CCR5-gene edited T cells. In conclusion, we have developed a novel TALEN for the targeted, high-efficiency knockout of CCR5 and a useful dPCR-based gene-editing detection method.

Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy.

Novel cell therapies derived from human T lymphocytes are exhibiting enormous potential in early-phase clinical trials in patients with hematologic malignancies. Ex vivo modification of T cells is currently limited to a small number of centers with the required infrastructure and expertise. The process requires isolation, activation, transduction, expansion and cryopreservation steps. To simplify procedures and widen applicability for clinical therapies, automation of these procedures is being developed. The CliniMACS Prodigy (Miltenyi Biotec) has recently been adapted for lentiviral transduction of T cells and here we analyse the feasibility of a clinically compliant T-cell engineering process for the manufacture of T cells encoding chimeric antigen receptors (CAR) for CD19 (CAR19), a widely targeted antigen in B-cell malignancies. Using a closed, single-use tubing set we processed mononuclear cells from fresh or frozen leukapheresis harvests collected from healthy volunteer donors. Cells were phenotyped and subjected to automated processing and activation using TransAct, a polymeric nanomatrix activation reagent incorporating CD3/CD28-specific antibodies. Cells were then transduced and expanded in the CentriCult-Unit of the tubing set, under stabilized culture conditions with automated feeding and media exchange. The process was continuously monitored to determine kinetics of expansion, transduction efficiency and phenotype of the engineered cells in comparison with small-scale transductions run in parallel. We found that transduction efficiencies, phenotype and function of CAR19 T cells were comparable with existing procedures and overall T-cell yields sufficient for anticipated therapeutic dosing. The automation of closed-system T-cell engineering should improve dissemination of emerging immunotherapies and greatly widen applicability.

SOCS3 promotes interleukin-17 expression of human T cells.

SOCS3 is a feedback regulator of cytokine signaling that affects T-cell polarization. Human tuberculosis is accompanied by increased SOCS3 expression in T cells, and this may influence susceptibility against Mycobacterium tuberculosis. Because the role of SOCS3 in human T-cell function is not well defined, we characterized cytokine expression and proliferation of human T cells with differential SOCS3 expression in the present study. We established a flow cytometry-based method for SOCS3 protein quantification and detected higher SOCS3 levels induced by M tuberculosis specific T-cell activation and a transient decrease of SOCS3 expression in the presence of mycobacteria-infected macrophages. Notably increased SOCS3 expression was detected in IL-17-expressing T-cell clones and in CD161(+) T helper type 17 cells ex vivo. Ectopic SOCS3 expression in primary CD4(+) T cells by lentiviral transduction induced increased IL-17 production but diminished proliferation and viability. Recombinant IL-7 inhibited SOCS3 expression and reduced IL-17-expressing T-cell proportions. We concluded that higher SOCS3 expression in human T cells favors T helper type 17 cells. Therefore, increased SOCS3 expression in human tuberculosis may reflect polarization toward IL-17-expressing T cells as well as T-cell exhaustion marked by reduced proliferation.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Proton or Carbon Ion Therapy for Skull Base Chordoma: Rationale and First Analysis of a Mono-Institutional Experience.

BACKGROUND: Skull base chordomas are radio-resistant tumors that require high-dose, high-precision radiotherapy, as can be delivered by particle therapy (protons and carbon ions). We performed a first clinical outcome analysis of particle therapy based on the initial 4-years of operation. METHODS: Between August 2017 and October 2021, 44 patients were treated with proton (89%) or carbon ion therapy (11%). Prior gross total resection had been performed in 21% of lesions, subtotal resection in 57%, biopsy in 12% and decompression in 10%. The average prescription dose was 75.2 Gy RBE in 37 fractions for protons and 66 Gy RBE in 22 fractions for carbon ions. RESULTS: At a median follow-up of 34.3 months (range: 1-55), 2-, and 3-year actuarial local control rates were 95.5% and 90.9%, respectively. The 2-, and 3-year overall and progression-free survival rates were 97.7%, 93.2%, 95.5% and 90.9%, respectively. The tumor volume at the time of particle therapy was highly predictive of local failure (p < 0.01), and currently, there is 100% local control in patients with tumors < 49 cc. No grade ≥3 toxicities were observed. There was no significant difference in outcome or side effect profile seen for proton versus carbon ion therapy. Five patients (11.4%) experienced transient grade ≤2 radiation-induced brain changes. CONCLUSIONS: The first analysis suggests the safety and efficacy of proton and carbon ion therapy at our center. The excellent control of small to mid-size chordomas underlines the effectiveness of particle therapy and importance of upfront maximum debulking of large lesions.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes.

Aim: Data on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT). Material and methods: We prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8-2.3 Gy, n = 90) and hPBT (dose per fraction 2.5-3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories-mucosal, skin, and other sites-and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients. Results: Overall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (-8.33 vs -25, p = 0.016). Conclusion: Hypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

Re-structuring lentiviral vectors to express genomic RNA via cap-dependent translation.

Lentiviral (LV) vectors based on human immunodeficiency virus type I (HIV-1) package two copies of their single-stranded RNA into vector particles. Normally, this RNA genome is reverse transcribed into a double-stranded DNA provirus that integrates into the cell genome, providing permanent gene transfer and long-term expression. Integration-deficient LV vectors have been developed to reduce the frequency of genomic integration and thereby limit their persistence in dividing cells. Here, we describe optimization of a reverse-transcriptase-deficient LV vector, which enables direct translation of LV RNA genomes upon cell entry, for transient expression of vector payloads as mRNA without a DNA intermediate. We have engineered a novel LV genome arrangement in which HIV-1 sequences are removed from the 5' end, to enable ribosomal entry from the 5' 7-methylguanylate cap for efficient translation of the vector payload. We have shown that this LV-mediated mRNA delivery platform provides transient transgene expression in vitro and in vivo. This has a potential application in gene and cell therapy scenarios requiring temporary payload expression in cells and tissues that can be targeted with pseudotyped LV vectors.

Investigations on parotid gland recovery after IMRT in head and neck tumor patients.

PURPOSE: in recent years, the role of intensity-modulated radiotherapy (IMRT) for head and neck irradiation has increased. The main motivation is sparing the parotid gland and reduction of xerostomia. Generally, relative parotid volumes have been evaluated for treatment outcome and planning constraints, neglecting that absolute parotid volumes can vary significantly. The aim of the present study was to investigate changes in parotid gland function and set this in relation to absolute volumes. MATERIAL AND METHODS: 46 head and neck patients were treated by sparing at least the contralateral parotid gland. The mean dose to the contralateral gland was limited to 26 Gy. Parotid function was measured with scintigraphy before and at 3, 6, 9, and 12 months after radiotherapy. Gland recovery was correlated with absolute parotid gland volumes and mean dose. Finally the dose-effect relationship was investigated. RESULTS: the dose-volume histograms (DVHs) for the ipsi- and contralateral glands were significantly different. A correlation between absolute volumes receiving certain doses and the function loss after 3, 6, 9, and 12 months was found. The most significant correlation was found for the absolute volume that received at least 40 Gy (aV40). ED50 values of 23-38 Gy were observed for more than 50% function loss and and 52-68 Gy afor more than 75% function loss. CONCLUSION: the mean dose, aV40 or aV26, revealed similar correlations with the excretion rate and with recovery. Hence, also absolute volumes can be used for treatment planning. Longer recovery times show higher ED50 values indicating partial regeneration of gland functions.

TCRαß/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy.

T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3ε CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRαß/CD3 complex. Only transduction after disrupting assembly of TCRαß/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3ε was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/murine chimeric model, supporting the application of cellular immunotherapy strategies against T cell malignancies. 3CAR provides a bridging strategy to achieve T cell eradication and leukemic remission ahead of conditioned allogeneic stem cell transplantation.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option.

Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) and poliovirus receptor-related 2 (PVRL2) have been identified as novel immune checkpoints. In this investigation we show that acute myeloid leukemia (AML) cell lines and AML patient samples highly express the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) ligands PVR and PVRL2. Using two independent patient cohorts, we could demonstrate that high PVR and PVRL2 expression correlates with poor outcome in AML. We show for the first time that antibody blockade of PVR or PVRL2 on AML cell lines or primary AML cells or TIGIT blockade on immune cells increases the anti-leukemic effects mediated by PBMCs or purified CD3+ cells in vitro. The cytolytic activity of the BiTE® antibody construct AMG 330 against leukemic cells could be further enhanced by blockade of the TIGIT-PVR/PVRL2 axis. This increased immune reactivity is paralleled by augmented secretion of Granzyme B by immune cells. Employing CRISPR/Cas9-mediated knockout of PVR and PVRL2 in MV4-11 cells, the cytotoxic effects of antibody blockade could be recapitulated in vitro. In NSG mice reconstituted with human T cells and transplanted with either MV4-11 PVR/PVRL2 knockout or wildtype cells, prolonged survival was observed for the knockout cells. This survival benefit could be further extended by treating the mice with AMG 330. Therefore, targeting the TIGIT-PVR/PVRL2 axis with blocking antibodies might represent a promising future therapeutic option in AML.

Gene Modified T Cell Therapies for Hematological Malignancies.

This article focuses on clinical applications of T cells transduced to express recombinant T cell receptor and chimeric antigen receptor constructs directed toward hematological malignancies, and considers newer strategies incorporating gene-editing technologies to address GvHD and host-mediated rejection. Recent data from clinical trials are reviewed, and an overview is provided of current and emerging manufacturing processes; consideration is also given to new developments in the pipeline.

Digital PCR to assess gene-editing frequencies (GEF-dPCR) mediated by designer nucleases.

Genome editing using designer nucleases such as transcription activator-like effector nucleases (TALENs) or clustered regularly interspersed short palindromic repeats (CRISPR)-Cas9 nucleases is an emerging technology in basic and applied research. Whereas the application of editing tools, namely CRISPR-Cas9, has recently become very straightforward, quantification of resulting gene knockout rates still remains a bottleneck. This is particularly true if the product of a targeted gene is not easily detectable. To address this problem, we devised a novel gene-editing frequency digital PCR (GEF-dPCR) technique. GEF-dPCR exploits two differently labeled probes that are placed within one amplicon at the gene-editing target site to simultaneously detect wild-type and nonhomologous end-joining (NHEJ)-affected alleles. Taking advantage of the principle of dPCR, this enables concurrent quantification of edited and wild-type alleles in a given sample. We propose that our method is optimal for the monitoring of gene-edited cells in vivo, e.g., in clinical settings. Here we describe preparation, design of primers and probes, and setup and analysis of GEF-dPCR. The setup of GEF-dPCR requires up to 2 weeks (depending on the starting point); once the dPCR has been established, the protocol for sample analysis takes <1 d.

Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma.

PURPOSE: To determine the potential improvements in patients with paranasal sinus carcinoma by comparing proton and intensity-modulated radiotherapy (IMRT) with conventional and conformal photon treatment planning techniques. METHODS AND MATERIALS: In 5 patients, comparative treatment planning was performed by comparing proton plans and related conventional, conformal, and IMRT photon plans. The evaluations analyzed dose-volume histogram findings of the target volumes and organs at risk (OARs, i.e., pituitary gland, optical pathway structures, brain, nontarget tissue). RESULTS: The mean and maximal doses, dose inhomogeneities, and conformity indexes for the planning target volumes were comparable for all techniques. Photon plans resulted in greater volumes of irradiated nontarget tissues at the 10-70% dose level compared with the corresponding proton plans. The volumes thereby increased by a factor of 1.3-3.1 for conventional, 1.1-3.8 for conformal, and 1.1-3.7 for IMRT. Compared with conventional techniques, conformal and IMRT photon treatment planning options similarly reduced the mean dose to the OARs. The use of protons further reduced the mean dose to the OARs by up to 65% and 62% compared with the conformal and IMRT technique, respectively. CONCLUSION: Compared with conventional treatment techniques, conformal RT and IMRT similarly enabled dose reductions to the OARs. Additional improvements were obtained using proton-based treatment planning modalities.

High-dose-rate (HDR) brachytherapy with or without external beam radiotherapy in the treatment of primary vaginal carcinoma: long-term results and side effects.

PURPOSE: To report toxicity, prognostic factors, and outcome of HDR brachytherapy in the primary management of vaginal carcinoma. METHODS AND MATERIALS: A total of 86 patients receiving radiotherapy for primary vaginal carcinoma were analyzed. FIGO stages 0-IV were found in 6, 17, 38, 20, and 5 patients, respectively. Early stages of disease (Stages 0-II) were treated with intravaginal HDR brachytherapy alone (n = 26/86), whereas locally advanced diseases (Stages II-IV) received HDR brachytherapy combined with external beam therapy (n = 55/86). Teletherapy only was used in 5 of 86 cases, all of which were treated with palliative intent (i.e., advanced stage, poor general status). Recurrence-free intervals as well as overall- and disease-specific survival rates were determined for all patients. Frequencies of side effects and the influence of prognostic factors and treatment modalities on outcome were analyzed. RESULTS: Five-year overall survival rates for Stages 0-IV diseases were 83%, 41%, 43%, 37%, and 0%, respectively. Corresponding 5-year disease-specific survival rates were 100%, 92%, 57%, 59%, and 0%. Regarding 5-year recurrence-free intervals, values of 100%, 77%, 50%, 23%, and 0% (Stages 0-IV) were found, respectively. Tumor stage was the most significant prognostic factor. Chronic side effects G 1-4 were observed in

Possible impact of iridium-192 source centering on restenosis rate after femoro-popliteal angioplasty and endovascular brachytherapy in Vienna-2 study.

PURPOSE: Endovascular brachytherapy (EVBT) has been proven to significantly reduce restenosis after percutaneous transluminal angioplasty (PTA). The object of this analysis was to assess the possible correlation between iridium-192 source non-centering and angiographic-determined restenosis. MATERIALS AND METHODS: A total of 113 patients with long-segment lesions of the superficial femoro-popliteal artery (SFA) were randomized to receive either PTA alone or PTA followed by EVBT in the Vienna-2 study. This analysis was performed on a subgroup of 34 out of 57 patients, who received PTA+EVBT. Angiographic restenosis was defined as lumen reduction of more than 50%. Angiograms taken immediately after PTA (34 patients) and at follow-up (25 patients) were analyzed. The distance between the vessel wall and the actual position of the source at the time of EVBT was measured (in mm) and correlated with the follow-up vessel lumen diameter. Measurements were performed at points at a distance of 10 mm from each other. The dose was determined at the luminal surface and at the reference depth of 2 mm into the vessel wall for different distances from the source. RESULTS: Among the 622 measured points, 62 (10.0%) were within restenotic areas; 560 (90.0%) were in arterial segments without proven angiographic restenosis. As far as source centering is concerned, 7.9% of restenotic points were observed when the maximum distance to the arterial wall was <3 mm and 9.6% for 4 mm, respectively. The percentage of restenotic points increased up to 15.9% when the maximum distance to the arterial wall was 5 mm and reached 22.2% when it was >5 mm. CONCLUSIONS: The proportion of restenotic points significantly increased with source non-centering. This observation was interpreted as being related to a decrease in dose at the target. When the maximum distance between the source and the vessel surface was >5 mm, the dose at the reference depth (2 mm into the vessel wall) decreased to values lower than 5 Gy.

Epidemiological aspects of hadron therapy: a prospective nationwide study of the Austrian project MedAustron and the Austrian Society of Radiooncology (OEGRO).

BACKGROUND: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy. MATERIALS AND METHODS: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. RESULTS: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. CONCLUSION: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

The med AUSTRON/OGRO patterns of care study on radiotherapy indications in Austria.

PURPOSE: In Austria a national survey was conducted by Med AUSTRON/Osterreichische Gesellschaft for Radio--Onkologie, Radiobiologie und Medizinische Radiophysik (OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria. MATERIAL AND METHODS: At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence. RESULTS: In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90 % (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%). CONCLUSION: In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.