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Reduced expression of the cyclin kinase inhibitor p27kip1 is found in many human tumors and correlates with inferior prognosis. We tested the importance of p27 loss for the induction of genetic instability in Notch driven cholangiocarcinoma (CCA). Specifically, we asked how loss of p27 interferes with DNA repair pathway choice i.e. non-homologous-end-joining (NHEJ) or homologous recombination (HR). We detected all hallmarks of HR, in p27 deficient cells even though these cells had not undergone DNA replication. This defect in pathway choice depends on a previously unknown interaction of p27 with the RAD17 protein. In a cholangiocarcinoma mouse model loss of p27 greatly accelerated tumor formation but also resulted in a strikingly increased sensitivity against DNA damage response (DDR) targeting agents. We find that 30% of human CCC patients cluster in a group which corresponds to the DDR sensitive phenotype we have identified. In this work we show that the cyclin kinase inhibitor p27kip1 has an essential role in regulating the DNA damage response. This new activity of p27 is necessary to suppress homologous recombination-based DNA repair during the G1 phase. These findings point to a role of DDR targeting drugs in CCA with low levels of p27.

Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium’s (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0–20 years, 8.3% 21–40 years, 30.9% 41–60 years, 50.1% 61–80 years, 8.8% 81 + years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9,005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort’s data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions.

BackgroundThe clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study.Methodsmolecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data.ResultsHere, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients.ConclusionsOur study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Comprehensive genomic profiling and biomarker-based therapeutic strategies are currently used in clinical trials and in innovative health care systems including the center for personalized medicine network. Systematic assessments of patient-reported outcomes are warranted to gain insight into the perspective of patients and their relatives during biomarker-based therapies. In the present study, we focused on health-related quality of life (HRQoL), psychosocial situation, and physical symptoms in patients treated at the Center for Personalized Medicine Tübingen. First, we retrospectively evaluated symptom burden of n=265 (neuro-)oncological patients in the Molecular Tumor Board (MTB). Sixty percent of patients reported at least 1 neurological symptom, and psychosocial burden/unmet needs were high (overall 156/265; 59%, patients with malignant tumors n=86/106; 81%, Fisher’s exact, p < 0.0001). We therefore developed an app by 14 expert rounds and pretesting including validated assessments of HRoL, symptom und psychological burden and tested it in a pilot study. We conducted a structured interview with users 3 months afterwards to assess the app’s usability and feasibility. The interview was transcribed and analyzed according to a qualitative content analysis. So far, a total of 10 patients and caregivers have been enrolled in this pilot study. They reported that (i) the app is compatible with their daily routine (median 9.3, range 0-10), that (ii) they are more aware of their health status, which was rated as positive, and that (iii) completing app-based questionnaires was easier compared to paper questionnaires. Two patients reported technical problems, which were resolved timely. The pilot study proved feasibility and acceptance of the app. The app might optimize symptom burden assessment, adapted to the patients’ profiles. The next step is to prospectively compare HRQoL before and after start of targeted therapy in a multicenter study.

As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.

PurposeThis study was conducted to evaluate the role of liver sonography in patients with coronavirus disease 2019 (COVID-19) and elevated liver enzymes.Materials and methodsIn this retrospective study, patients tested positive for SARS-CoV-2 in our emergency ward between January 01 and April 24, 2020 and elevated liver enzymes were included (Cohort 1). Additionally, the local radiology information system was screened for sonographies in COVID-19 patients at the intensive care unit in the same period (Cohort 2). Liver sonographies and histologic specimen were reviewed and suspicious findings recorded. Medical records were reviewed for clinical data. Ultrasound findings and clinical data were correlated with severity of liver enzyme elevation.ResultsCohort 1: 126 patients were evaluated, of which 47 (37.3%) had elevated liver enzymes. Severity of liver enzyme elevation was associated with death (pConclusionFor most hospitalized COVID-19 patients, elevated liver enzymes cause little concern as they are only mild to moderate. However, in severely ill patients bedside sonography is a powerful tool to reveal different patterns of vascular, cholestatic or inflammatory complications in the liver, which are associated with high mortality. In addition, macrophage activation as histopathologic correlate for a hyperinflammatory syndrome seems to be a frequent complication in COVID-19.

While digital health is changing the way we perform medicine, implementation of novel diagnostic or therapeutic approaches into clinical practice remains challenging. In this paper we discuss strategies and problems that need to be addressed to enable the translation of new technologies. With its broad spectrum of diseases and procedures the field of gastroenterology offers a perfect test bed for digital innovation. Two clusters of excellence funded by the German Research Foundation focus on data driven personalized therapeutic strategies for oncological and autoimmune diseases. On experimental level digital innovations in endoscopy and for ultrasound-guided interventions are being developed. In endoscopy artificial intelligence-driven decision support systems for adenoma detection have been developed that show promising results in clinical trails. However, for future development it will be crucial to follow an interdisciplinary approach with medical professionals and patients guiding the innovation process. Therefore digital health literacy will need to be implemented in medical education. In the academic field a strong cooperation of clinicians, patients, computer scientists and engineers will be essential.Fortschritte in der genomischen Diagnostik und digitale innovative Technologien lassen die personalisierte Therapie gastrointestinaler entzündlicher und onkologischer Erkrankungen bald möglich erscheinen.In der interventionellen Gastroenterologie lassen sich neue IT-gestützte Diagnostik- und Therapieverfahren und Formen der Mensch-Technik-Kollaboration gut testen und im Versorgungalltag validieren.Um die Arzt-Patienten-Kommunikation auf Augenhöhe zu erhalten, müssen auf beiden Seiten Kompetenzen im Umgang mit digitalen Anwendungen aufgebaut werden. Qualitativ hochwertige digitale Gesundheitsprodukte im unübersichtlichen Markt zu identifizieren bleibt eine Herausforderung. WISSENSMANAGEMENT UND äRZTLICHE WEITERBILDUNG: Die Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselerkrankungen entwickelt digitale Angebote für verschiedene Interessengruppen und engagiert sich bei der Wissensvermittung über soziale Netzwerke. Die ärztliche Weiterbildung im Zeitalter der Digitalisierung ist ebenfalls ein wichtiges Thema.Um die Qualität technologischer Innovationen zu steigern und einen erfolgreichen Transfer in die Versorgung zu ermöglichen ist eine engere Kooperation zwischen Patienten, praktisch tätigen Ärzten und technischen Experten unabdingbar. Entsprechende Strukturen hierfür fehlen weitgehend.

BACKGROUND An electronic health record (EHR) is the state-of-the-art method for ensuring all data concerning a given patient are up to date for use by multidisciplinary hospital teams. Therefore, medical students need to be trained to use health information technologies within this environment from the early stages of their education. OBJECTIVE As little is known about the effects of specific training within the medical curriculum, this study aimed to develop a course module and evaluate it to offer best practice teaching for today’s students. Moreover, we looked at the acceptance of new technologies such as EHRs. METHODS Fifth-year medical students (N=104) at the University of Tübingen took part in a standardized two-day training procedure about the advantages and risks of EHR use. After the training, students performed their own EHR entries on hypothetical patient cases in a safe practice environment. In addition, questionnaires—standardized and with open-ended questions—were administered to assess students’ experiences with a new teaching module, a newly developed EHR simulator, the acceptance of the health technology, and their attitudes toward it before and after training. RESULTS After the teaching, students rated the benefit of EHR training for medical knowledge significantly higher than before the session (mean 3.74, SD 1.05). However, they also had doubts about the long-term benefit of EHRs for multidisciplinary coworking after training (mean 1.96, SD 0.65). The special training with simulation software was rated as helpful for preparing students (88/102, 86.2%), but they still did not feel safe in all aspects of EHR. CONCLUSIONS A specific simulated training on using EHRs helped students improve their knowledge and become more aware of the risks and challenges of such a system. Overall, students welcomed the new training module and supported the integration of EHR teaching into the medical curriculum. Further studies are needed to optimize training modules and make use of long-term feedback opportunities a simulated system offers.

A recent randomized study of whipworm Trichuris suis ova (TSO) in ileal Crohn’s disease failed to demonstrate a clinical benefit compared to placebo after 12 weeks. Nonetheless, it has recently been shown that the spontaneous small intestinal inflammatory changes in Nod2-/- (Nucleotide-binding oligomerization domain 2) mice could be substantially ameliorated when these mice were colonized by Trichuris muris. Those and complementary epidemiologic findings in humans lead to the hypothesis that helminths may be advantageous only in patients carrying defective NOD2 variants. Thus, 207 participants of the TSO trial were retrospectively genotyped for six functional NOD2 genetic variants to evaluate whether the treatment outcome differed in patients carrying NOD2 variants. We observed no significant association of the NOD2 variants or their haplotypes with clinical outcome after TSO treatment.

A 42-year-old woman was referred with a bleeding in the upper gastrointestinal tract, varices in the fundus of the stomach and portal hypertension of unknown primary.Ultrasound examinations showed splenomegaly as well as portal hypertension. Blood examinations revealed low levels of haemoglobin. CT imaging showed multiple arteriovenous malformations with arterioportal shunts within the liver which led to a volume-induced portal hypertension. The genetic analysis revealed no mutations in the activin receptor-like kinase (ALK) 1 or endoglin genes.The patient was clinically diagnosed with hereditary hemorrhagic teleangiectasia, also known as Osler-Weber-Rendu disease. Because of the multiple arterioportal shunts within the liver and the resulting portal hypertension with live-threatening gastrointestinal bleeding, the only therapeutic option for the patient is liver transplantation. Therefore, an application for a standard exception was made at Eurotransplant and the patient is going to be liver transplantated within the next months.Osler-Weber-Rendu disease is an autosomal dominant hereditary disease which leads to arteriovenous malformations and which can affect different organ systems. The course of the disease can be rather benign, but it can also lead to live-threatening complications requiring fast interventions.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the third most common reason for cancer-related death worldwide. Many countries either lack appropriate clinical practice guidelines for the diagnosis and treatment of HCC or the quality of their guidelines has never been evaluated. The main objective of our work was to identify published HCC guidelines and assess their quality with the Appraisal of Guidelines for Research and Evaluation instrument (AGREE) and their suitability regarding adaptation for future guidelines. METHODS: We performed a systematic literature search on HCC clinical practice guidelines of MEDLINE, National Guidelines Clearinghouse and the Guidelines International Network. Methodological quality of selected guidelines was assessed by the AGREE instrument, Version 2001. RESULTS: A total of 286 citations were screened and 32 relevant guidelines were identified. Overall, the guidelines performed well in the clarity and presentation domain with a mean score of 67%, followed by scope and purpose (55%) and rigor of development (50%). In contrast, poor scores were given for the remaining domains: stakeholder involvement (23%), applicability (28%) and editorial independence (31%). According to the AGREE instrument, four guidelines can be strongly recommended, 18 with provisos and alterations while the remaining cannot be recommended for adaptation due to poor methodological quality. CONCLUSION: Although existing HCC guidelines may accurately reflect agreed clinical practice, many guidelines lack proper methodological quality. Future guidelines should place more emphasis on these methodological shortcomings.

Before a decision is made to give a particular drug treatment, first of all the best strategy for the individual patient must be determined. In a patient with an aggressive tumour, for whom a secondary curative approach by means of metastasis resection is not an option, the preferred first-line treatment will generally be a triple combination therapy containing bevacizumab - and this is also true in KRAS/BRAF wild-type patients, since the main aim here is to achieve the longest possible survival time with a minimum of side effects. If an epidermal growth factor receptor (EGFR) antibody (cetuximab or panitumumab) is to be used in first-line or later therapy, then the presence of a KRAS mutation must be excluded beforehand. It is very likely sensible also to exclude a BRAF mutation. Second-line treatment after a first-line therapy containing bevacizumab may be a combination chemotherapy or, in patients who are KRAS wild-type (and possibly also BRAF wild-type), irinotecan plus cetuximab. Locoregional treatments such as chemoembolisation, selective internal radiation therapy (SIRT), and stereotactic

Virotherapy can potentially be used to induce tumor-specific immune responses and to overcome tumor-mediated tolerance mechanisms because apoptotic tumor cells are exposed together with viral danger signals during oncolysis. However, insufficient numbers of dendritic cells (DC) present at the site of oncolysis can limit a tumor-specific immune response and the resulting therapeutic benefit. We investigated MHC class I peptide–specific immune responses against model antigens ovalbumin (OVA) and hemagglutinin (HA) in mouse tumor models that support efficient replication of the oncolytic adenovirus hTert-Ad. Virotherapy resulted in peptide-specific cytotoxic T-cell responses against intracellular tumor antigens. Triggering of DC and T-cell infiltration to the oncolytic tumors by macrophage inflammatory protein 1α (MIP-1α, CCL3) and Fms-like tyrosine kinase-3 ligand (Flt3L) enhanced both antitumoral and antiviral immune responses. Although immune-mediated clearance of the virus can restrict therapeutic efficacy of virotherapy, MIP-1α/FLT3L–augmented hTert-Ad virotherapy inhibited local tumor growth more effectively than virotherapy alone. In agreement with the hypothesis that immune-mediated mechanisms account for improved outcome in MIP-1α/FLT3L virotherapy, we observed systemic antitumoral effects by MIP-1α/FLT3L virotherapy on uninfected lung metastasis in immunocompetent mice but not in nude mice. Furthermore, MIP-1α/FLT3L virotherapy of primary tumors was strongly synergistic with tumor DC vaccination in inhibition of established lung metastasis. Combined viroimmunotherapy resulted in long-term survival of 50% of treated animals. In summary, improvement of cross-presentation of tumor antigens by triggering of DC and T-cell infiltration during virotherapy enhances antitumoral immune response that facilitates an effective viroimmunotherapy of primary tumors and established metastases. [Cancer Res 2009;69(4):1448–58]