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Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The intermediate-conductance calcium-activated potassium channel KCa3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and KCa3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560's intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-β1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3+, CD8+ or FoxP3+ T cells was not impacted by either irradiation or KCa3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model. [ABSTRACT FROM AUTHOR]

Purpose: In pediatric bladder/prostate-rhabdomyosarcoma, the rate of bladder preservation after neoadjuvant chemotherapy is high, with an excellent oncological outcome. Information about functional urological long-term outcomes is rare. Methods: Data of all patients who had undergone bladder-preserving surgery with or without brachytherapy at our institution between 2009 and 2020 were analyzed retrospectively. Detailed urological function was assessed focusing on age-related continence, bladder capacity and urodynamic findings. Results: We identified 40 patients, median age at surgery of 27 months (range 9–191), and 32 patients additionally received postoperative high-dose-rate brachytherapy. The median follow-up was 32.5 months (range 6–125). The bladder capacity increased from median 66.7% (21.1–180) of expected bladder capacity related to age 3 months after surgery to 87.4% (58.1–181.8) 9 months after surgery. In the group of aged > 6-year-old, continence was 94% (83% with brachytherapy, 100% without brachytherapy). Erectile function was normal in 92% (90% with brachytherapy, 100% without brachytherapy). Bladder capacity was more than 65% expected bladder capacity related to age in 70% (60% with brachytherapy, 86% without brachytherapy). 65% of all patients need neither anticholinergic drugs nor low-dose antibiotics (63% with brachytherapy, 71% without brachytherapy). Conclusions: Bladder preservation with good functional outcome can be achieved in localized bladder/prostate-rhabdomyosarcoma. In selected cases, supportive brachytherapy additionally contributes to an improvement in the oncological outcome with calculable risks for bladder and erectile function. Careful urological aftercare should be a fixed priority after oncological follow-ups. [ABSTRACT FROM AUTHOR]

While colorectal and gastroesophageal cancer represent the two gastrointestinal (GI) tumor entities with the highest incidence of brain metastatic (BM) disease, data on the clinical course of BM patients from hepatopancreatobiliary malignancies are rare. Patients with cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC) and gastroenteropancreatic neuroendocrine neoplasms (GEP NEN). Treated for BM between 1991 and 2017 at an academic care center were included. Brain metastases-free survival (BMFS) was defined as interval from first diagnosis until BM development. Overall survival (OS) was defined as interval from diagnosis of BM until death or last date of follow-up. Outcome was correlated with clinical and treatment factors. 29 patients from overall 6102 patients (0.6%) included in the Vienna Brain Metastasis Registry presented with BM from hepatopancreatobiliary primaries including 9 (31.0%) with CCA, 10 (34.5%) with HCC, 7 (24.1%) with PDAC and 3 (10.3%) with GEP NEN as primary tumor. Median BMFS was 21, 12, 14 and 7 months and median OS 4, 4, 6 and 4 months, respectively. Karnofsky Performance Status (KPS) below 80% (p = 0.08), age above 60 years (p = 0.10) and leptomeningeal carcinomatosis (LC) (p = 0.09) diagnosed concomitant to solid BM showed an inverse association with median OS (Cox proportional hazards model). In this cohort of patients with BM from hepatopancreatobiliary tumor entities, prognosis was shown to be very limited. Performance status, age and diagnosis of LC were identified as negative prognostic factors. [ABSTRACT FROM AUTHOR]

Copyright of Die Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Low-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations. Methods: We analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases. Results: 368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed. Conclusion: FGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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.Using the game Gran Turismo, an agent was trained with a combination of deep reinforcement learning algorithms and specialized training scenarios, demonstrating success against championship-level human racers. [ABSTRACT FROM AUTHOR]

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, C‑reactive 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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

GVHD, both acute and chronic, remains the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, there is still a great need for therapeutic tools for the prevention and treatment of GVHD. Several biologics have shown promising results in salvage therapies but are attendant on an increased risk for opportunistic infections, lymphoproliferative disorders, and relapse. This is partly due to efficient T cell elimination that neither dissects alloreactive from non-alloreactive T cells nor considers functional and structural distinctiveness of pathogen- and malignancy-reactive γδ and iNKT T cells. A novel, humanized monoclonal antibody, GZ-αβTCR, specific for the human αβ T cell receptor, was evaluated in a xenogeneic GVHD model for its potential to prevent or ameliorate GVHD and prolong survival. We could show that GZ-αβTCR significantly attenuated clinical signs of GVHD and prolonged survival by preferential depletion of CD4 cells and the naïve T cell compartment, the trigger and driver of GVHD. In a regimen that included a preemptive dose, GZ-αβTCR treatment sufficiently abrogated GVHD. Importantly, GZ-αβTCR's specificity spared host cell-mediated immune competence of cell types other than αβT cells: namely γδT cells. GZ-αβTCR's outstanding capacity to prevent GVHD and ameliorate an ongoing GVHD while sparing immune cells other than αβT cells strongly recommends GZ-αβTCR for the prevention and treatment of acute GVHD in clinical settings. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)