Tumor-Stroma Interaction in PDAC as a New Approach for Liquid Biopsy and its Potential Clinical Implications.

The extremely poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) has remained unchanged for decades. As a hallmark of PDAC histology, the distinct desmoplastic response in the tumor microenvironment is considered a key factor exerting pro- and antitumor effects. Increasing emphasis has been placed on cancer-associated fibroblasts (CAFs), whose heterogeneity and functional diversity is reflected in the numerous subtypes. The myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs) and antigen presenting CAFs (apCAFs) are functionally divergent CAF subtypes with tumor promoting as well as repressing effects. Precise knowledge of the underlying interactions is the basis for a variety of treatment approaches, which are subsumed under the term antistromal therapy. Clinical implementation is still pending due to the lack of benefit-as well as paradoxical preclinical findings. While the prominent significance of CAFs in the immediate environment of the tumor is becoming clear, less is known about the circulating (c)CAFs. cCAFs are of particular interest as they seem not only to be potential new liquid biopsy biomarkers but also to support the survival of circulating tumor cells (CTC) in the bloodstream. In PDAC, CTCs correlate with an unfavorable outcome and can also be employed to monitor treatment response, but the current clinical relevance is limited. In this review, we discuss CTCs, cCAFs, secretomes that include EVs or fragments of collagen turnover as liquid biopsy biomarkers, and clinical approaches to target tumor stroma in PDAC.

Annotation and initial evaluation of a large annotated German oncological corpus.

OBJECTIVE: We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts. MATERIALS AND METHODS: BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research. RESULTS: The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72-0.90 for named entity recognition, 0.10-0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection. DISCUSSION: Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important. CONCLUSION: To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.

[Gastrointestinal complications of the new immune checkpoint inhibitor therapies]. / Gastroenterologische Komplikationen der neuen Immuncheckpoint-Inhibitor-Therapien.

In recent years, immune checkpoint inhibitors (ICPI) have become established as an integral part of drug tumor therapy. They belong to a group of monoclonal antibodies that promote anti-cancer cell immune response. Inhibitory signaling pathways are interrupted by binding to CTLA-4 and PD-1 or PD-L1, which increases the activity of cytotoxic T lymphocytes and reduces the immunological tolerance to tumor cells.Diarrhea - a symptom of enterocolitis - is the most common side effect of ICPI therapy after dermatological phenomena. A combined CTLA-4 and PD-1 blockade may affect up to 44 % of patients. The symptoms of ICPI-associated colitis are similar to the clinical appearance of inflammatory bowel disease.The treatment of affected patients should follow a standardized approach. Both the European and American Oncology Societies offer specific recommendations for the diagnosis and treatment of ICPI-associated adverse reactions. Rapid immunosuppressant treatments, to include steroids and biologics, are necessary to reduce morbidity once differential diagnoses are excluded. It may then be possible to subsequently resume ICPI therapy.Immune-mediated hepatitis is a potential side effect which occurs about 6 to 14 weeks after initiation of therapy. It is usually asymptomatic and characterized by an increase in serum transaminases. Lipasemia, without clinical signs of acute pancreatitis, is a common laboratory finding, which usually has no therapeutic consequence.

VIST - a Variant-Information Search Tool for precision oncology.

BACKGROUND: Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient's genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile. RESULTS: VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST's ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document's content. CONCLUSION: Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/.

Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44+ Gastric Cancer Stem Cells.

Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44+ CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44+ CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44+ CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44+ CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44+ CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44+ CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. Stem Cells Translational Medicine 2017;6:819-829.

Correction: Capsaicin Treatment Attenuates Cholangiocarcinoma Carcinogenesis.

[This corrects the article DOI: 10.1371/journal.pone.0095605.].

Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma.

Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small-molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p-MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines. MET inhibition was achieved by blocking phosphorylation of MET with LY2801653 and subsequent down regulation of c-MET downstream targets. Treatment showed in a xenograft model potent anti-tumor activity. LY2801653 is an effective inhibitor and suppress the proliferation of CCC cells as well as the growth of xenograft tumors. Therefore, inhibition of c-MET could be a possible alternative approach for the treatment of human CCC. © 2016 Wiley Periodicals, Inc.

Capsaicin treatment attenuates cholangiocarcinoma carcinogenesis.

UNLABELLED: Capsaicin, the most abundant pungent molecule produced by pepper plants, represents an important ingredient in spicy foods consumed throughout the world. Studies have shown that capsaicin can relieve inflammation and has anti-proliferative effects on various human malignancies. Cholangiocarcinoma (CC) is a cancer disease with rising incidence. The prognosis remains dismal with little advance in treatment. The aim of the present study is to explore the anti-tumor activity of capsaicin in cultured human CC cell lines. Capsaicin effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. Further, we show that capsaicin treatment of CC cells regulates the Hedgehog signaling pathway. CONCLUSION: Our results provide a basis for capsaicin to improve the prognosis of CCs in vivo and present new insights into the effectiveness and mode of action of capsaicin.