Outracing champion Gran Turismo drivers with deep reinforcement learning.

Many potential applications of artificial intelligence involve making real-time decisions in physical systems while interacting with humans. Automobile racing represents an extreme example of these conditions; drivers must execute complex tactical manoeuvres to pass or block opponents while operating their vehicles at their traction limits1. Racing simulations, such as the PlayStation game Gran Turismo, faithfully reproduce the non-linear control challenges of real race cars while also encapsulating the complex multi-agent interactions. Here we describe how we trained agents for Gran Turismo that can compete with the world's best e-sports drivers. We combine state-of-the-art, model-free, deep reinforcement learning algorithms with mixed-scenario training to learn an integrated control policy that combines exceptional speed with impressive tactics. In addition, we construct a reward function that enables the agent to be competitive while adhering to racing's important, but under-specified, sportsmanship rules. We demonstrate the capabilities of our agent, Gran Turismo Sophy, by winning a head-to-head competition against four of the world's best Gran Turismo drivers. By describing how we trained championship-level racers, we demonstrate the possibilities and challenges of using these techniques to control complex dynamical systems in domains where agents must respect imprecisely defined human norms.

KCa channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels.

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

Regional hyperthermia for soft tissue sarcoma - a survey on current practice, controversies and consensus among 12 European centers.

PURPOSE: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. METHODS: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. RESULTS: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. DISCUSSION: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. CONCLUSIONS: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

DNA as the main target in radiotherapy-a historical overview from first isolation to anti-tumour immune response.

DNA damage is one of the foremost mechanisms of irradiation at the biological level. After the first isolation of DNA by Friedrich Miescher in the 19th century, the structure of DNA was described by Watson and Crick. Several Nobel Prizes have been awarded for DNA-related discoveries. This review aims to describe the historical perspective of DNA in radiation biology. Over the decades, DNA damage has been identified and quantified after irradiation. Depending on the type of sensing, different proteins are involved in sensing DNA damage and repairing the damage, if possible. For double-strand breaks, the main repair mechanisms are non-homologous end joining and homologous recombination. Additional mechanisms are the Fanconi anaemia pathway and base excision repair. Different methods have been developed for the detection of DNA double-strand breaks. Several drugs have been developed that interfere with different DNA repair mechanisms, e.g., PARP inhibitors. These drugs have been established in the standard treatment of different tumour entities and are being applied in several clinical trials in combination with radiotherapy. Over the past decades, it has become apparent that DNA damage mechanisms are also directly linked to the immune response in tumours. For example, cytosolic DNA fragments activate the innate immune system via the cGAS STING pathway.

Hyperthermia in the treatment of high-risk soft tissue sarcomas: a systematic review.

BACKGROUND: The therapy of high-risk soft tissue sarcomas (STS) remains an interdisciplinary challenge. Regional hyperthermia (RHT) sparked interest as it has been shown to improve overall survival when added to perioperative chemotherapy (CTX). However, questions arise on how RHT should be optimally integrated into current multi-modal therapies. MATERIALS AND METHODS: We performed a systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies written in English and focused mainly on radiative RHT and superficial hyperthermia were evaluated and included. Studies including patients below the age of 18, with metastatic disease or review articles, were excluded. RESULTS: We identified 15 clinical reports from 1990 until July 2022. Three articles combined RHT + CTX, and twelve focused on combined RHT + radiotherapy (RT) or neoadjuvant chemoradiotherapy (CRT). Most treatments were based on invasive thermometry, and less on magnetic resonance imaging (MRI)-based, noninvasive thermometry for STS of the extremities. Perioperative chemotherapy was used for the combination of RHT and CTX, mostly Ifosfamide-based. The effectiveness of RT appeared to be increased by RHT, especially with two RHT sessions/week. The trimodal simultaneous approach of neoadjuvant RHT and CRT was also feasible. No significant toxicity of RHT was reported. CONCLUSIONS: The gathered data strengthen the beneficial role of RHT in the multimodal setting. Further expert consensus and clinical trials are required to determine the optimal integration of RHT in treating STS.

Patient-individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis.

Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IKCa and BKCa ). From these abundances, an mRNA signature was deduced which describes the mesenchymal-to-proneural expression profile of an individual GSC culture. To assess its functional significance, we associated the GSC mRNA signature with the clonogenic survival after irradiation with 4 Gy and the fibrin matrix invasion of the GSC cells. In addition, we compared the molecular pGSC mRNA signature with the tumor recurrence pattern and the overall survival of the glioblastoma patients from whom the pGSC cultures were derived. As a result, the molecular pGSC mRNA signature correlated positively with the pGSC radioresistance and matrix invasion capability in vitro. Moreover, patients with a mesenchymal (>median) mRNA signature in their pGSC cultures exhibited predominantly a multifocal tumor recurrence and a significantly (univariate log rank test) shorter overall survival than patients with proneural (≤median mRNA signature) pGSCs. The tumors of the latter recurred predominately unifocally. We conclude that our pGSC cultures induce/select those cell subpopulations of the heterogeneous brain tumor that determine disease progression and therapy outcome. In addition, we further postulate a clinically relevant prognostic/predictive value for the 10 mRNAs-based mesenchymal-to-proneural signature of the GSC subpopulations in glioblastoma.

Radiotherapy planning parameters correlate with changes in the peripheral immune status of patients undergoing curative radiotherapy for localized prostate cancer.

PURPOSE: The influence of radiotherapy on patient immune cell subsets has been established by several groups. Following a previously published analysis of immune changes during and after curative radiotherapy for prostate cancer, this analysis focused on describing correlations of changes of immune cell subsets with radiation treatment parameters. PATIENTS AND METHODS: For 13 patients treated in a prospective trial with radiotherapy to the prostate region (primary analysis) and five patients treated with radiotherapy to prostate and pelvic nodal regions (exploratory analysis), already published immune monitoring data were correlated with clinical data as well as radiation planning parameters such as clinical target volume (CTV) and volumes receiving 20 Gy (V20) for newly contoured volumes of pelvic blood vessels and bone marrow. RESULTS: Most significant changes among immune cell subsets were observed at the end of radiotherapy. In contrast, correlations of age and CD8+ subsets (effector and memory cells) were observed early during and 3 months after radiotherapy. Ratios of T cells and T cell proliferation compared to baseline correlated with CTV. Early changes in regulatory T cells (Treg cells) and CD8+ effector T cells correlated with V20 of blood vessels and bone volumes. CONCLUSIONS: Patient age as well as radiotherapy planning parameters correlated with immune changes during radiotherapy. Larger irradiated volumes seem to correlate with early suppression of anti-cancer immunity. For immune cell analysis during normofractionated radiotherapy and correlations with treatment planning parameters, different time points should be looked at in future projects. TRIAL REGISTRATION NUMBER: NCT01376674, 20.06.2011.

Dynamics of HMBG1 (High Mobility Group Box 1) during radiochemotherapy correlate with outcome of HNSCC patients.

PURPOSE: High Mobility Group Box 1 (HMGB1) protein has been described as a consensus marker for immunogenic cell death (ICD) in cancer. To personalize treatments, there is a need for biomarkers to adapt dose prescription, concomitant chemotherapy, and follow-up in radiation oncology. Thus, we investigated the levels of HMGB1 in plasma of patients with head and neck squamous cell carcinoma (HNSCC) during the course of radiochemotherapy and follow-up in correlation with oncologic outcome and clinical confounders. METHODS: In our pilot study, 11 patients with advanced HNSCC were treated with definitive radiochemotherapy. Blood samples were taken weekly during treatment and frequently at follow-up visits. HMGB1 levels as well as routine laboratory values were measured and clinical information was collected including tumor volume, infections, toxicity, and follow-up data. RESULTS: In total, 85 samples were analyzed. In eight patients, HMGB1 levels (baseline vs. last available sample during treatment) were increasing and in three patients HMGB1 values were decreasing toward the end of treatment. All three patients with decreasing values developed tumor recurrence. By contrast, no relapse occurred in patients that showed increasing HMGB1 levels during therapy. Moreover, a positive correlation of HMGB1 levels with tumor volumes, C­reactive protein (CRP) levels, infections, and grade three toxicity (RTOG) was observed. CONCLUSION: HMGB1 might be a promising marker to monitor ICD in HNSCC during the course of radiochemotherapy. However, HMGB1 seems to reflect complex and diverse immunogenic responses and potential confounders. Infections and treatment-associated toxicity should be considered when interpreting the dynamics of HMGB1.

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma.

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Stereotactic radiotherapy combined with immunotherapy or targeted therapy for metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the safety and efficacy of stereotactic radiotherapy (SRT) in patients with metastatic renal cell carcinoma (mRCC) concurrently receiving targeted therapy (TT) or immunotherapy. PATIENTS AND METHODS: Data on patients with mRCC were extracted from a retrospective international multicentre register study (TOaSTT), investigating SRT concurrent (≤30 days) with TT/immune checkpoint inhibitor (ICI) therapy. Overall survival (OS), progression-free survival (PFS), local metastasis control (LC) and time to systemic therapy switch were analysed using Kaplan-Meier curves and log-rank testing. Clinical and treatment factors influencing survival were analysed using multivariate Cox regression. Acute and late SRT-induced toxicity were defined according to the Common Terminology Criteria for Adverse Events v.4.03. RESULTS: Fifty-three patients who underwent 128 sessions of SRT were included, of whom 58% presented with oligometastatic disease (OMD). ICIs and TT were received by 32% and 68% of patients, respectively. Twenty patients (37%) paused TT for a median (range) of 14 (2-21) days. ICI therapy was not paused in any patient. A median (range) of 1 (1-5) metastatic tumour was treated per patient, with a median (range) SRT dose of 65 (40-129.4) Gy (biologically effective dose). The OS, LC and PFS rates at 1 year were 71%, 75% and 25%, respectively. The median OS and PFS were not significantly different among patients receiving TT vs those receiving ICIs (P = 0.329). New lesions were treated with a repeat radiotherapy course in 46% of patients. After 1 year, 62% of patients remained on the same systemic therapy as at the time of SRT; this was more frequent for ICI therapy compared to TT (83% vs 36%; P = 0.035). OMD was an independent prognostic factor for OS (P = 0.004, 95% confidence interval [CI] 0.035-0.528) and PFS (P = 0.004; 95% CI 0.165-0.717) in multivariate analysis. Eastern Cooperative Oncology Group performance status (ECOG-PS) was the other independent prognostic factor for OS (P = 0.001, 95% CI 0.001-0.351). Acute grade 3 toxicity was observed in two patients, and late grade 3 toxicity in one patient. No grade 4 or 5 toxicity was observed. CONCLUSION: Combined treatment with TT or immunotherapy and concurrent SRT was safe, without signals of increased severe toxicity. As we observed no signal of excess toxicity, full-dose SRT should be considered to achieve optimal metastasis control in patients receiving TT or immunotherapy. Favourable PFS and OS were observed for patients with oligometastatic RCC with a good ECOG-PS, which should form the basis for prospective testing of this treatment strategy in properly designed clinical trials.

Potassium Channels in Cancer.

Neoplastic transformation is reportedly associated with alterations of the potassium transport across plasma and intracellular membranes. These alterations have been identified as crucial elements of the tumourigenic reprogramming of cells. Potassium channels may contribute to cancer initiation, malignant progression and therapy resistance of tumour cells. The book chapter focusses on (oncogenic) potassium channels frequently upregulated in different tumour entities, upstream and downstream signalling of these channels, their contribution to the maintenance of cancer stemness and the formation of an immunosuppressive tumour microenvironment. In addition, their role in adaptation to tumour hypoxia, metabolic reprogramming, as well as tumour spreading and metastasis is discussed. Finally, we discuss how (oncogenic) potassium channels may confer treatment resistance of tumours against radiation and chemotherapy and thus might be harnessed for new therapy strategies, for instance, by repurposing approved drugs known to target potassium channels.

The Role of Reconstructive Surgery and Brachytherapy in Pediatric Bladder/Prostate Rhabdomyosarcoma.

PURPOSE: The surgical approach to localized bladder/prostate rhabdomyosarcoma in children may change due to a new radiotherapeutic modality. We assessed the impact of brachytherapy following surgery for local tumor control, and report surgical techniques and outcomes. MATERIALS AND METHODS: We retrospectively analyzed the records of all children who underwent surgery for bladder/prostate rhabdomyosarcoma, including tumor relapse, at our institution from 2009 onward. RESULTS: A total of 38 patients with a median age of 29 months (range 10 to 134) met inclusion criteria. Five-year overall survival was 92.8% (95% CI 72.9 to 98.1), and event-free survival at a median followup of 12 months (range 3 to 111) was 73.7% (95% CI 53.4 to 86.2). Three treatment groups were defined, ie bladder preserving surgery combined with brachytherapy, bladder preserving surgery alone and cystectomy. Five-year event-free survival rates for the 3 groups were 85.6% (95% CI 61.2 to 95.2), 66.7% (95% CI 27.2 to 88.2) and 50% (95% CI 5.8 to 84.5), respectively. Bladder preserving surgery was performed in 33 patients (87%), of whom 23 (70%) also underwent brachytherapy, while cystectomy was performed in 5 (13%). Reconstructive procedures varied depending on tumor location and spread. CONCLUSIONS: Combining brachytherapy with surgery results in a high bladder preservation rate and improves event-free survival compared to surgery alone in children with bladder/prostate rhabdomyosarcoma. The combination is also effective in treating local tumor relapse, and is associated with less extensive reconstructive procedures due to exclusion of tumors of unfavorable size and location for brachytherapy.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. TRIAL REGISTRATION: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Perioperative strategy and outcome in giant retroperitoneal dedifferentiated liposarcoma-results of a retrospective cohort study.

BACKGROUND AND OBJECTIVES: Retroperitoneal liposarcoma (RPLS) are common soft tissue sarcomas of adulthood. The aim of this study is to show resectability of even giant liposarcomas and to identify factors associated with recurrence and survival in primary retroperitoneal liposarcomas. METHODS: We retrospectively reviewed the records of patients with retroperitoneal liposarcoma. Seventy-seven patients met inclusion criteria. Out of these 10 patients with primary giant, dedifferentiated retroperitoneal liposarcomas were operated with en bloc compartment resection with intention of radical resection. Treatment consisted of neoadjuvant radiochemotherapy and surgical resection or surgical resection. RESULTS: In 6 patients, neoadjuvant radiochemotherapy was performed; 3 patients were treated with surgical resection alone and 1 patient received adjuvant chemotherapy. The median diameter of tumor size was 360 mm (300 to 440 mm). Operative outcome showed complete resection in all 10 patients. Local tumor free survival was in median 19 month. Tumor recurrence was seen in 3 of 4 patients (75%) without neoadjuvant radiochemotherapy, and in 2 of 6 patients (33%) after neoadjuvant radiochemotherapy in 2 years follow-up. CONCLUSION: Even in case of giant retroperitoneal liposarcoma, complete resection is possible and remains the principal treatment. The rate of recurrence was improved in patients with neoadjuvant radiochemotherapy.

Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model.

BACKGROUND: Tumor metastasis and immune evasion present major challenges of cancer treatment. Radiotherapy can overcome immunosuppressive tumor microenvironments. Anecdotal reports suggest abscopal anti-tumor immune responses. This study assesses abscopal effects of radiotherapy in combination with mRNA-based cancer vaccination (RNActive®). METHODS: C57BL/6 mice were injected with ovalbumin-expressing thymoma cells into the right hind leg (primary tumor) and left flank (secondary tumor) with a delay of 4 days. Primary tumors were irradiated with 3 × 2 Gy, while secondary tumors were shielded. RNA and combined treatment groups received mRNA-based RNActive® vaccination. RESULTS: Radiotherapy and combined radioimmunotherapy significantly delayed primary tumor growth with a tumor control in 15 and 53% of mice, respectively. In small secondary tumors, radioimmunotherapy significantly slowed growth rate compared to vaccination (p = 0.002) and control groups (p = 0.01). Cytokine microarray analysis of secondary tumors showed changes in the cytokine microenvironment, even in the non-irradiated contralateral tumors after combination treatment. CONCLUSION: Combined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity.

Contrast enhancement predicting survival in integrated molecular subtypes of diffuse glioma: an observational cohort study.

INTRODUCTION: To assess the predictive value of magnetic resonance imaging (MRI) gadolinium enhancement as a prognostic factor in the 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups. METHODS: Four-hundred fifty patients with histopathologically confirmed glioma were retrospectively assessed between 07/1997 and 06/2014 using gadolinium enhancement, survival, and relevant prognostic molecular data [isocitrate dehydrogenase (IDH); alpha-thalassemia/mental retardation syndrome X-linked (ATRX); chromosome 1p/19q loss of heterozygosity; and O6-methylguanine DNA methyltransferase (MGMT)]. The Kaplan-Meier method was used to assess univariate survival data. A multivariate Cox proportional hazards model was performed on significant results from the univariate analysis. RESULTS: There were significant differences in survival between patient age (p < 0.0001), WHO glioma grades (p < 0.0001), and integrated molecular profiles (p < 0.0001). Patients with IDH1/2 mutation, loss of ATRX expression, and methylated MGMT promoter showed significantly better survival than those with the IDHwild-type (p < 0.0001), retained ATRX expression (p < 0.0001), and unmethylated MGMT promoter (p = 0.019). Survival was significantly better in patients without gadolinium enhancement (p = 0.009) who were in the IDHwild-type glioma and glioma with retained ATRX expression groups (p = 0.018 and 0.030, respectively). CONCLUSIONS: In univariate analysis, the presence of gadolinium enhancement on preoperative MRI scans is an unfavorable factor for survival. Regarding the molecular subgroups, gadolinium enhancement is an unfavorable prognostic factor in gliomas with IDHwild-type and those with ATRX retention. However, in multivariate analysis only patient age, IDH1/2 mutation status, MGMT promoter methylation status, and WHO grade IV are relevant for predicting survival.

Radiotherapy and hyperthermia with curative intent in recurrent high risk soft tissue sarcomas.

PURPOSE: Radiotherapy before or after resection is one of the pillars of treatment for localised high risk soft tissue sarcomas. Treatment intensification has been described with concurrent chemotherapy and hyperthermia. The aim of this study is to assess local control after multimodal treatment, focussing on the treatment of local recurrences after surgery only. PATIENTS AND METHODS: Of 42 patients treated in a prospective protocol with radiotherapy and hyperthermia, nine were treated for isolated local recurrences without metastatic spread. Most patients were treated with trimodal therapy including chemotherapy with ifosfamide and underwent resection whenever possible. Median follow-up was 1.4 years. RESULTS: The treatment was well tolerated. Estimated disease free survival, distant metastases free survival and local control for the whole cohort after 1.5 years were 66, 73 and 88%, respectively. Neoadjuvant vs. adjuvant treatment influenced local control with a trend to statistical significance. Resection status did not influence local control. The cohort of patients treated for local recurrence after surgery alone had a significantly impaired local control compared to multimodal treatment at primary diagnosis (100 vs. 52%, p < 0.001). CONCLUSIONS: With multimodal therapy including radiotherapy and hyperthermia local tumour control is achievable even in locally recurrent tumours. The clear-cut difference of the treatment of local recurrence in contrast to primary diagnosis might either reflect difficulties in diagnosis and treatment of local recurrences or biological aggressiveness of recurrent tumours. However, we recommend to consider multimodal treatment at primary diagnosis of high risk soft tissue sarcomas.

3D vena contracta area after MitraClip© procedure: precise quantification of residual mitral regurgitation and identification of prognostic information.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is increasingly performed in patients with severe mitral regurgitation (MR). Post-procedural MR grading is challenging and an unsettled issue. We hypothesised that the direct planimetry of vena contracta area (VCA) by 3D-transoesophageal echocardiography allows quantifying post-procedural MR and implies further prognostic relevance missed by the usual ordinal scale (grade I-IV). METHODS: Based on a single-centre PMVR registry containing 102 patients, the association of VCA reduction and patients' functional capacity measured as six-minute walk distance (6 MW) was evaluated. 3D-colour-Doppler datasets were available before, during and 4 weeks after PMVR. RESULTS: Twenty nine patients (age 77.0 ± 5.8 years) with advanced heart failure (75.9% NYHA III/IV) and severe degenerative (34%) or functional (66%) MR were eligible. VCA was reduced in all patients by PMVR (0.99 ± 0.46 cm2 vs. 0.22 ± 0.15 cm2, p < 0.0001). It remained stable after median time of 33 days (p = 0.999). 6 MW improved after the procedure (257.5 ± 82.5 m vs. 295.7 ± 96.3 m, p < 0.01). Patients with a decrease in VCA less than the median VCA reduction showed a more distinct improvement in 6 MW than patients with better technical result (p < 0.05). This paradoxical finding was driven by inferior results in very large functional MR. CONCLUSIONS: VCA improves the evaluation of small residual MR. Its post-procedural values remain stable during a short-term follow-up and imply prognostic information for the patients' physical improvement. VCA might contribute to a more substantiated estimation of treatment success in the heterogeneous functional MR group.

Role of ion channels in ionizing radiation-induced cell death.

Neoadjuvant, adjuvant or definitive fractionated radiation therapy are implemented in first line anti-cancer treatment regimens of many tumor entities. Ionizing radiation kills the tumor cells mainly by causing double strand breaks of their DNA through formation of intermediate radicals. Survival of the tumor cells depends on both, their capacity of oxidative defense and their efficacy of DNA repair. By damaging the targeted cells, ionizing radiation triggers a plethora of stress responses. Among those is the modulation of ion channels such as Ca2+-activated K+ channels or Ca2+-permeable nonselective cation channels belonging to the super-family of transient receptor potential channels. Radiogenic activation of these channels may contribute to radiogenic cell death as well as to DNA repair, glucose fueling, radiogenic hypermigration or lowering of the oxidative stress burden. The present review article introduces these channels and summarizes our current knowledge on the mechanisms underlying radiogenic ion channel modulation. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models.

PURPOSE: NHS-IL12 is an immunocytokine targeting necrotic tumour areas. IL12 shows anti-tumour activity. As local irradiation might induce additional necrosis in solid tumours, we aimed to evaluate the increase in intratumoural accumulation of NHS-IL12 after irradiation and correlate the findings with diffusion-weighted MRI studies in two xenograft models. METHODS: Human rhabdomyosarcoma (A204) and prostate cancer (PC3) cells were studied in vitro and as subcutaneous xenografts. Radiation sensitivity of the cell lines was assessed in vitro by colony formation assays. In vivo tumour necrosis was assessed based on apparent diffusion coefficients (ADC). Biodistribution of NHS-IL12 was evaluated with and without tumour irradiation using in vivo small-animal PET and ex vivo biodistribution. RESULTS: A204 and PC3 differed in their intrinsic radiation sensitivity. Accordingly, radiation-induced tumour necrosis was found only in A204 xenografts. In comparison with control, ADC was significantly increased after irradiation of A204 tumours with 1 × 8.0 Gy and 5 × 2.0 Gy, whereas no change in ADC was observed in PC3 xenografts in all irradiation regimes. ADC correlated with histology. An enhanced uptake of radiolabelled NHS-IL12 in A204 tumours was detected by PET and ex vivo biodistribution after tumour irradiation. In PC3 tumours, no increase in NHS-IL12 uptake was observed. CONCLUSIONS: In dependence of the tumour model, tumour irradiation enhanced tumour necrosis measured in MRI and histology. In vivo PET and ex vivo biodistribution showed enhanced binding of NHS-IL12 in rhabdomyosarcoma xenografts. Thus, enhanced binding of necrosis-targeting immunocytokines might be a novel mechanism of additive effects in combination with irradiation.