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Aim: Autoimmune colitis is a typical and possible severe side effect among patients treated with ipilimumab. Patients & methods: We prospectively included 100 patients with metastasized melanoma under ipilimumab treatment in a radiological study of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT). PET evidence of pancolitis (‘PET-colitis’) was correlated with clinical variables. Results: We observed a significant correlation between PET-colitis and clinically significant diarrhoea, although PET-colitis was more frequent (49 vs 29% of patients, respectively). Neither PET-colitis nor diarrhoea was significantly correlated with response to therapy. Other immune-related adverse events, however, such as hypophysitis and hepatitis were associated with response to therapy and overall survival. Conclusion: Increased 18F-FDG uptake in the colon correlated with clinical symptoms but did not predict clinical outcome to ipilimumab.

To access the reliability of a new dichotomous test and to capture the random variability of its results in the absence of a gold standard, two measures, the inconsistent acceptance probability (IAP) and inconsistent rejection probability (IRP), were introduced in the literature. In this paper, we first analyze the limiting behavior of both measures as the number of test repetitions increases and derive the corresponding accuracy estimates and rates of convergence. To overcome possible limitations of IRP and IAP, we then introduce a one-parameter family of refined reliability measures, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\Delta (k, s)$$\end{document}Δ(k,s). Such measures characterize the consistency of the results of a dichotomous test in the absence of a gold standard as the threshold for a positive aggregate test result varies. Similar to IRP and IAP, we also derive corresponding accuracy estimates and rates of convergence for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\Delta (k, s)$$\end{document}Δ(k,s) as the number k of test repetitions increases. Supplementary Information The online version supplementary material available at 10.1007/s00362-021-01266-9.

In this paper we address the situation where a well-established, but invasive, expensive or time-consuming diagnostic test may be replaced by multiple repetitions of a different diagnostic test which is known to be imperfect but less invasive or expensive. With an imperfect diagnostic test repeated several times on the same patient, we first introduce the sensitivity and specificity of that test for any given number of test repetitions. We also derive the corresponding asymptotic limits for sensitivity and specificity as the number n of test repetitions increases. Given those limits, we then derive sharp upper bounds for the differences between the sensitivity and specificity, obtained for a given number n of test repetitions, and the corresponding asymptotic limit. Specifically, we provide exact rates for the convergence of the empirical sensitivities and specificities. Our analysis is motivated, among other things, by the current discussion on rapid SARS-CoV-2 testing where the real-time polymerase chain reaction (RT-PCR) test may be replaced with a sequence of rapid lateral-flow antigen tests.

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors. OA gold - CA extern

Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer.

Background: Ipilimumab is a cytotoxic T-lymphocyte antigen-4 antibody that enhances T-cell activity and proliferation. Methods: In a retrospective analysis of 86 patients the clinical benefits of ipilimumab treatment were correlated with laboratory and clinical data. Results: A lactate dehydrogenase (LDH) value within the normal range before the start of therapy was significantly correlated with better OS (p ≤ 0.009). An increase in LDH level after two cycles was indicative of a poor outcome, and was significantly negatively correlated with treatment response and overall survival and progression-free survival. 42% of all patients suffered from autoimmune toxicity (CTCAE grades 2–4). The occurrence of autoimmune toxicity clearly correlated with clinical benefit. Conclusion: Changes in LDH level and side effects correlate with response to therapy and survival.

DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.

Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha (DGKA). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy., Radiotherapy can induce fibrosis in cancer patients, limiting its use in clinical settings. Here, the authors identify a differentially methylated enhancer of the lipid kinase DGKA in fibroblasts from breast cancer patients developing fibrosis after radiotherapy and they show that DGKA inhibition affects lipid homeostasis and reduces pro-fibrotic fibroblast activation.

Hydroxymethylcytosine (5hmC) methylation is a well-known epigenetic mark that is involved in gene regulation and may impact genome stability. To investigate a possible role of 5hmC in cancer development and progression, one must be able to detect and quantify its level first. In this paper, we address the issue of 5hmC detection at a single base resolution, starting with consideration of the well-established 5hmC measure Δβ and, in particular, with an analysis of its properties, both analytically and empirically. Then we propose several alternative hydroxymethylation measures and compare their properties with those of Δβ. In the absence of a gold standard, the (pairwise) resemblance of those 5hmC measures to Δβ is characterized by means of a similarity analysis and relative accuracy analysis. All results are illustrated on matched healthy and cancer tissue data sets as derived by means of bisulfite (BS) and oxidative bisulfite converting (oxBS) procedures.

The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery.We retrospectively analyzed medical records of 41 patients with TET treated with postoperative radiotherapy at our institution between 1995 and 2012. The impact of prognostic factors (e.g., Masaoka stage, histological subtype) was investigated and radiation-related toxicity was assessed.Median age was 59.8 years and median follow-up was 61 months. In 24.4 %, TETs were associated with paraneoplastic syndromes. The 5-year overall survival (OS) was 89.5 % and the 5-year disease-free survival (DFS) was 88.9 %. Masaoka stage had a significant impact on OS (p = 0.007). Locally limited stages I + II had a 5-year OS of 100 % compared to 80 % for stage III and 66.7 % for stage IV. The 5-year DFS was excellent with 100 % for both WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from B3/C-staged patients with a 5-year DFS of 63.6 %. Resection status, paraneoplastic association, radiation dose, or tumor size did not influence survival. There were no high-grade acute or late side effects caused by radiotherapy.Masaoka stage has a significant impact on OS as WHO type has on DFS in patients with TETs after surgery and adjuvant irradiation. Postoperative radiotherapy with doses around 50 Gy is safe and not likely to cause high-grade toxicity. Further prospective trials are necessary to separate patient subgroups that benefit from radiotherapy from those that do not.

The origin of the thymic epithelium, i.e. the cortical (cTEC) and medullary (mTEC) epithelial cells, from bipotent stem cells through TEC progenitors and lineage-specific progeny still remains poorly understood. We sought to obtain an unbiased view of the incipient emergence of TEC subsets by following embryonic TEC development based on co-expression of EpCAM, CD80 and MHC class II (MHCII) on non-hematopoietic (CD45- ) thymic stromal cells in wild-type BL6 mice. Using a combination of ex vivo analysis, Re-aggregate Thymic Organ Culture (RTOC) reconstitution assays and mathematical modeling, we traced emergent lineage commitment in murine embryonic TECs. Both experimental and mathematical datasets supported the following developmental sequence: MHCII- CD80- → MHCIIlo CD80- → MHCIIhi CD80- → MHCIIhi CD80hi TECs, whereby MHCIIhi CD80- and MHCIIhi CD80hi TECs bear features of cTECs and mTECs respectively. These emergent MHCIIhi CD80- cTECs directly generate mature MHCIIhi CD80hi mTECs in vivo and in vitro, thus supporting the asynchronous model of TEC lineage commitment.

We consider the linear-impact case in the continuous-time market impact model with transient price impact proposed by Gatheral. In this model, the absence of price manipulation in the sense of Huberman and Stanzl can easily be characterized by means of Bochner’s theorem. This allows us to study the problem of minimizing the expected liquidation costs of an asset position under constraints on the trading times. We prove that optimal strategies can be characterized as measure-valued solutions of a generalized Fredholm integral equation of the first kind and analyze several explicit examples. We also prove theorems on the existence and nonexistence of optimal strategies. We show in particular that optimal strategies always exist and are nonalternating between buy and sell trades when price impact decays as a convex function of time. This is based on and extends a recent result by Alfonsi, Schied, and Slynko on the nonexistence of transaction-triggered price manipulation. We also prove some qualitative properties of optimal strategies and provide explicit expressions for the optimal strategy in several special cases of interest.

BackgroundThe purpose of this study was to evaluate HPV-DNA and p16INK4a (p16) expression as prognostic markers for outcome in patients with anal cancer.MethodsFrom January 2000 to December 2011 a cohort of 105 anal cancer patients was treated with definitive chemoradiation at our institution. Tumor biopsies from 90 patients were analyzed for HPV-DNA by polymerase chain reaction and for p16 expression by immunohistochemistry.ResultsMedian follow-up was 48.6months (range 2.8–169.1months). HPV-DNA or p16-expression was found in 75 anal cancers each (83.3%), concordance was detectable in 70 tumors (77.8%). Significantly improved overall survival (OS) [77.1% vs. 51.4%, p=0.005], progression-free survival (PFS) [64.0% vs. 35.0%, p

Background Concurrent chemotherapy and radiation therapy is the preferred standard of care for patients with anal cancer. Several studies have suggested a benefit of intensity-modulated radiation therapy (IMRT) compared with 3D-conformal radiation (3D-CRT) regarding acute toxicity. This study evaluates outcome and toxicity of patients undergoing IMRT/Tomotherapy or 3D-CRT at our institution. Methods A cohort of 105 anal cancer patients was treated with chemoradiation or radiation alone (16.2%) between January 2000 and December 2011. 37 patients received 3D-CRT while 68 patients were treated with IMRT. Follow-up exams were performed every 3 to 6 months for a minimum of 3 years and then annually. Results Median follow-up was 41.4 months (2.8 – 158.4). Overall survival (OS), Progression-free survival (PFS) and local control (LC) at 3 years was 70.3%, 66.5%, 78.3% in the 3D-CRT group and 82.9%, 66.5%, 75.3% in the IMRT group without statistically significant difference. 3-year Colostomy-free survival (CFS) was 85.7% in the IMRT/Tomotherapy group and 91.8% in the 3D-CRT group (p = 0.48). No grade 4 toxicity was found in both groups. Severe (G2/3) acute skin toxicity (94.6% vs. 63.2%; p

Assuming a particular price process, it was shown by Gatheral in [6], that a model that combines nonlinear price impact with exponential decay of market impact admits price manipulation, an undesirable feature that should lead to rejection of the model. Subsequently, Alfonsi and Schied proved in [2] that their model of the order book which has nonlinear market impact and exponential resilience, is free of price manipulation. In this paper, we show how these at-first-sight incompatible results are in reality perfectly compatible.

Market impact models describe the feedback of trading strategies on the underlying asset prices. The resulting feedback effects lead to interesting questions of stability and regularity, which are closely related to the existence and behavior of strategies for optimal order execution. In this paper, we give a survey on some recent results that were obtained in this context. In the first part, we explain in particular the stochastic control approach to the maximization of the expected utility of revenues in the Almgren-Chriss framework. In the second part, we describe stability issues that arise when market impact is allowed to be transient.

Ionizing radiation is a common treatment option for cancer but its use is limited by the unpredictable and highly heterogeneous onset of late side effects, especially radiation-induced fibrosis. Clinically applicable biomarkers and effective treatments for radiation fibrosis are currently unavailable. In order to identify novel markers we ran a genome-wide DNA methylation screen in primary dermal fibroblasts obtained from breast cancer patients before intraoperative radiotherapy. Cells from patients developing fibrosis within a three-year follow up were compared to those without fibrosis (12 individuals per group). Illumina Infinium HumanMethylation450 BeadChip analysis revealed differentially methylated sites which are associated with fibrosis. Notably, we identified a differentially methylated region (DMR) at the diacylglycerol kinase alpha (DGKA) locus as a potential fibrosis marker. This DGKA DMR was confirmed using quantitative MassARRAY technology in 75 patient fibroblast samples. We first investigated whether high or low DNA methylation at this DGKA DMR affects cellular radiation response. Functional in vitro analysis showed that the methylation status of the DGKA DMR inversely correlated with its radiation-induced mRNA and protein expression as well as with its enzymatic activity. We next examined the DMR for its role as a regulatory site. The intragenically located DMR was identified as a potential enhancer sequence using chromatin immunoprecipitation (ChIP) for H3K4me1 and H3K27ac as well as luciferase reporter assays. Chromatin conformation capture (3C) analysis revealed interaction of this enhancer with the DGKA promoter in fibroblasts with low DNA methylation, and further ChIP experiments showed a DNA methylation-dependent recruitment of the profibrotic transcription factor Early Growth Response 1 (EGR1) to this site. We finally asked how epigenetically altered DGKA expression could impact on cellular processes relevant to fibrosis such as fibroblast transactivation or stress response. Results in primary fibroblasts showed that, in response to ionizing radiation and other stress factors, DGKA affects global levels of its substrate diacylglycerol, as well as expression of the fibroblast activation markers Alpha Smooth Muscle Actin (ACTA2) and collagen 1 (COL1A1). Upon overexpression of DGKA in HEK293T cells, a luciferase-based screening of 15 stress-responsive signaling reporters revealed functional consequences on several response pathways. In summary, DGKA has emerged as a novel, epigenetically regulated signaling protein that has a role in radiation fibrosis and may serve as a new biomarker and therapeutic target. Citation Format: Christoph Weigel, Marlon R. Veldwijk, Christopher C. Oakes, Petra Seibold, Alla Slynko, David B. Liesenfeld, Carsten Herskind, Elena Sperk, Axel Benner, Christoph Plass, Frederik Wenz, Jenny Chang-Claude, Peter Schmezer, Odilia Popanda. Diacylglycerol kinase alpha as a novel epigenetically regulated risk marker for radiotherapy-induced fibrosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3445. doi:10.1158/1538-7445.AM2015-3445