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Ca Schildhaus Background: MET amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in MET amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or MET amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup. Methods: A total of 373 unselected patients with NSCLC were consecutively tested for MET gene copy number (GCN) by FISH. Mean GCN, MET/CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data. Results: Based on the variability of obtained data a top-level category of MET amplification was newly defined (>90th percentile of average GCN; >= 10 MET gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected (KRAS mutation or MET exon 14 skipping mutation). In this top-level group, there were no EGFR mutations or ALK or ROS1 alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 vs. 23.6 months). Worse prognosis did not depend on initial stage or treatment. Conclusions: The newly defined top-level category of MET amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of MET gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.

Immune checkpoint inhibitors (ICIs) can induce immunity-related adverse events. We demonstrate the clinical use of cardiac magnetic resonance and endomyocardial biopsy in the diagnosis and subsequent monitoring of ICI-associated myocarditis, suggesting the need to establish and evaluate a cardiac monitoring protocol for patients under ICI therapy. (Level of Difficulty: Intermediate.), Graphical abstract, Immune checkpoint inhibitors (ICIs) can induce immunity-related adverse events. We demonstrate the clinical use of cardiac magnetic resonance…

Aims Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. Methods and results One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson’s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF−) median percentage MF (≥11% or Conclusion Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Eosinophilic fasciitis (EF) and generalized morphea (GM) are rare and difficult-to-treat sclerosing skin diseases which may occur in association with hematologic disorders. We present a 66-year-old man with EF and associated Waldenström macroglobulinemia who received combination therapy with rituximab (375mg/m2 every other week, gradually extended to every eight weeks), prednisolone (1.25-30mg/d), and methotrexate (7.5-15mg/w). Three months after rituximab initiation, his skin condition improved steadily accompanied by a significant improvement in joint mobility with only mild and transitory flares (observation period: 59 months under treatment with rituximab). To date, there are five case reports on rituximab treatment of EF/GM with an association to hypergammaglobulinemia in three of those cases. Therapy effected significant improvement in four patients. Our case adds to the hitherto limited evidence that rituximab may be a promising therapeutic strategy for EF/GM in association with hypergammaglobulinemia.

Background/aim Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated. Patients and methods A systematic review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis. Results A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a two-fold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, three-fold elevated risk of death. This higher mortality is independent of tumour stage. Conclusion Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care.

Brain metastases (BMs) are the most frequent malignancy of the central nervous system. Previous research suggested that some metastases show infiltrative behavior rather than sharp demarcation. We hypothesized that three magnetic resonance (MR) imaging parameters—(a) tumor size, (b) extent of peritumoral edema, and (c) presence of multiple BMs—are predictors of cellular invasion beyond the surgically identifiable tumor margins. We performed a post hoc analysis on prospectively collected data of patients with BMs. Biopsies beyond the resection margin and immunohistochemistry were performed to assess infiltration status. The three MR imaging parameters were dichotomized into diameters ≤ 30 mm (“small”) and > 30 mm (“large”), amount of peritumoral edema “extended” and “limited,” and “multiple BMs” and “single BMs,” respectively. The association between infiltration status and imaging parameters was calculated using chi-square test. Biopsy beyond the resection margin was performed in 77 patients; 49 (63.6%) had supramarginal infiltration and 28 patients (36.4%) showed no infiltration. Histological evidence of tumor infiltration was found in 25/41 patients with smaller lesions (61%) and in 24/36 with larger lesions (66.7%, p = 0.64), in 28/44 patients with limited (63.6%) and in 21/33 patients with extended edema (63.6%, p = 1.0), in 28/45 patients (62.2%) with single BM and in 21/32 patients (65.6%) with multiple BMs (p = 0.81). Based on the post hoc analysis of our prospective trial data, we could not confirm the hypothesis that infiltration of brain parenchyma beyond the glial pseudocapsule is associated with the MR imaging parameters tumor size, extent of edema, or multiplicity of metastases.

Simple Summary Glycolysis is one of the hallmarks of cancer. Therefore, the development of novel therapeutical strategies for colorectal cancer targeting glycolysis may improve treatment responses. PFKFB3 expression has been directly associated with enhanced glycolysis, not only in cancer cells but also within the tumor environment. The aim of this study was to evaluate PFKFB3 expression and its correlation with outcome in rectal and colon tumors and to assess the effects of the newly developed PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and intestinal patient-derived organoids. Our results showed that KAN0438757 efficiently targets PFKFB3 expression and was able to affect cancer cell motility, invasion and survival. Additionally, a tumor specific cytotoxic-effect was observed in patient-derived organoids. In vivo, KAN0438757 showed to be well tolerated by mice without systemic toxicity. Our work re-enforces the concept that targeting of glycolysis may be a promising therapeutical approach for colorectal cancer. Abstract Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.

MotivationContemporary deep learning approaches show cutting-edge performance in a variety of complex prediction tasks. Nonetheless, the application of deep learning in healthcare remains limited since deep learning methods are often considered as non-interpretable black-box models. Layer-wise Relevance Propagation (LRP) is a technique to explain decisions of deep learning methods. It is widely used to interpret Convolutional Neural Networks (CNNs) applied on image data. Recently, CNNs started to extend towards non-euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Graph-CNNs can be applied to structured gene expression data, for example, to predict metastatic events in breast cancer. Therefore, there is a need for explanations showing which part of a molecular network is relevant for predicting an event, e.g. distant metastasis in cancer, for each individual patient.ResultsWe extended the procedure of LRP to make it available for Graph-CNN and tested its applicability on a large breast cancer dataset. We present Graph Layer-wise Relevance Propagation (GLRP) as a new method to explain the decisions made by Graph-CNNs. We demonstrate a sanity check of the developed GLRP on a hand-written digits dataset, and then applied the method on gene expression data. We show that GLRP provides patient-specific molecular subnetworks that largely agree with clinical knowledge and identify common as well as novel, and potentially druggable, drivers of tumor progression. As a result this method could be potentially highly useful on interpreting classification results on the individual patient level, as for example in precision medicine approaches or a molecular tumor board.Availabilityhttps://gitlab.gwdg.de/UKEBpublic/graph-lrphttps://frankkramer-lab.github.io/MetaRelSubNetVis/Contacttim.beissbarth@bioinf.med.uni-goettingen.de

Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines, inducing a BRCAness-like phenotype and rendering them resistant to PARP inhibition. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 is indeed a novel ligand for ROR2 that interacts with its cysteine-rich domain and triggers the invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.

Objectives/hypothesis Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment. Study design Case series. Methods To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected. Results To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated. Conclusions Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials. Level of evidence 4 Laryngoscope, 131:E1926-E1933, 2021.

About 40% of non‐small lung cancer (NSCLC) patients have metastatic disease at the time of diagnosis. However, metastatic NSCLC in the biliary duct system is extremely rare. A high proportion of patients with acute liver failure due to advanced NSCLC do not receive any treatment due to organ dysfunction or poor performance status. Here, we report a case of successful treatment with chemoimmunotherapy in a young woman with obstructive jaundice and acute hepatic failure due to multiple intrahepatic bile duct metastases. Key points Significant findings of the study Chemotherapy in NSCLC patients with liver failure is a therapeutic challenge. Acute hepatic failure are often exclusion criteria for therapy of NSCLC. Some reports showed a benefit of ICIs plus chemotherapy for NSCLC with liver metastases. What this study adds Combination of ICIs and chemotherapy is effective and safe in critically ill patients with lung cancer and impaired liver function., We report a case of successful treatment with chemimmunotherapy in a young woman with obstructive jaundice and acute hepatic failure due to multiple intrahepatic bile duct metastases of NSCLC.

Extracellular vesicles (EV) are secreted by all cell types in a tumor and its microenvironment (TME), playing an essential role in intercellular communication and the establishment of a TME favorable for tumor invasion and metastasis. They encompass a variety of vesicle populations, among them the well-known endosomal-derived small exosomes (Exo), but also larger vesicles (diameter > 100 nm) that are shed directly from the plasma membrane, the so-called microvesicles (MV). Increasing evidence suggests that MV, although biologically different, share the tumor-promoting features of Exo in the TME. Due to their larger size, they can be readily harvested from patients’ blood and characterized by routine methods such as conventional flow cytometry, exploiting the plethora of molecules expressed on their surface. In this review, we summarize the current knowledge about the biology and the composition of MV, as well as their role within the TME. We highlight not only the challenges and potential of MV as novel biomarkers for cancer, but also discuss their possible use for therapeutic intervention.

Background Metastatic brain disease continues to have a dismal prognosis. Previous studies achieved a reduction of local recurrence rates by aggressively resecting the peritumoral zone (supramarginal resection) or using 5-aminolaevulinic acid (5-ALA) fluorescence. The aim of the present study is to assess whether the use of 5-ALA has an impact on local recurrence or survival compared to conventional white light microscopic tumor resection. Materials and methods We included consecutive patients who underwent surgical resection of brain metastases. Two groups were compared: In the "white light" group, resection was performed with conventional microscopy. In the 5-ALA group, fluorescence guided peritumoral resection was additionally performed after standard microscopic resection. In-brain recurrence and mortality were compared between groups. Results N = 175 patients were included in the study. All baseline parameters were similarly distributed with no significant difference between surgical groups. Local in-brain recurrence occurred in 21/175 patients (12%) with a rate of 15/119 (12.6%) in the white light and 6/56 (10.7%) in the 5-ALA group (p = 0.720). The use of 5-ALA influenced neither in-brain recurrence (OR 0.59 [CI = 95% 0.18; 1.99], p = 0.40) nor mortality (OR 0.71 [CI = 95% 0.27; 1.85], p = 0.49). Conclusions The use of 5-ALA did not result in lower in-brain recurrence or mortality compared to the use of white light microscopy. The most prominent predictors of survival remain favorable preoperative performance status, a low tumor diameter and the absence of multiple cerebral lesions.

Veno-venous extracorporeal membrane oxygenation (ECMO) can be a lifesaving therapy for patients with severe acute respiratory distress syndrome (ARDS). ECMO is a technically complex and challenging procedure and should therefore only be performed in specialized centers. Transporting ARDS patients to ECMO centers for treatment can be dangerous because of the risk of hypoxemia during transport. This raises the question if ECMO should not be already initiated in the transferring hospital before transport. Over a 5-year period, we studied ARDS patients who had been transported to our department by our mobile ECMO team for further treatment after ECMO had already been initiated at the referring hospital. Data for analysis were obtained from our patient data management system (PDMS), the referral documents, and from the referring hospitals. Seventy-five patients meeting the selection criteria were studied. All had been successfully cannulated in the transferring hospitals. They were transported to our ECMO center by helicopter (n = 34) or mobile intensive care units (n = 41). No patient died during transport. Forty four of the patients were transported at night. Twenty-six patients (35%) died in our intensive care unit due to a therapy refractory course, comorbidities or limitation of therapy. Patients on ECMO therapy can be safely transferred to a specialist center. Setting up ECMO in an unfamiliar location and the subsequent patient transport can be very challenging and should only be performed by a highly trained, experienced team.

// Julia Elisabeth Fromme 1, * , Katja Schmitz 1, * , Astrid Wachter 2 , Marius Grzelinski 3 , Dirk Zielinski 3 , Christina Koppel 3 , Lena-Christin Conradi 4 , Kia Homayounfar 4 , Tabea Hugo 1 , Sara Hugo 1 , Laura Lukat 1 , Josef Ruschoff 3 , Philipp Strobel 1 , Michael Ghadimi 4 , Tim Beisbarth 2 , Kirsten Reuter-Jessen 1, ** , Annalen Bleckmann 2, 5, ** and Hans-Ulrich Schildhaus 1, 3, ** 1 Institute of Pathology, University Hospital Gottingen, Gottingen, Germany 2 Department of Medical Statistics, University Medical Center Gottingen, Gottingen, Germany 3 Targos Molecular Pathology Inc., Kassel, Germany 4 Department of General, Visceral and Pediatric Surgery, University Medical Center Gottingen, Georg-August-University, Goettingen, Germany 5 Department for Hematology and Medical Oncology, University Hospital Gottingen, Gottingen, Germany * These authors have contributed equally to this work ** KRJ, AB, HUS share senior authorship Correspondence to: Hans-Ulrich Schildhaus, email: Hans-Ulrich.Schildhaus@med.uni-goettingen.de Keywords: colorectal cancer; metastases; FGFR3; fibroblast growth factor receptors; RNA in situ hybridization Received: March 26, 2018 Accepted: July 12, 2018 Published: August 14, 2018 ABSTRACT Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established. Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors ( FGFR1-4 ) and their ligands ( FGF3, 4 and 19 ) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ . Results were correlated with clinico-pathologic data and molecular subtypes. Results: Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111). Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.

The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid-treated PCNSL (ST-PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST-PCNSL patients were older than MS patients (mean age: ST-PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST-PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow-up of the patient to detect recurrent lymphoma.

More than half of all brain metastases show infiltrating rather than displacing growth at the macro-metastasis/brain parenchyma interface (MMPI), a finding associated with shorter survival. The Lymphoid Enhancer-binding Factor-1 (LEF1) is an epithelial-mesenchymal transition (EMT) transcription factor that is commonly overexpressed in brain-colonizing cancer cells. Here, we overexpressed LEF1 in an in vivo breast cancer brain colonization model. It shortened survival, albeit without engaging EMT at the MMPI. By differential proteome analysis, we identified a novel function of LEF1 as a regulator of the glutathione (GSH) system, the principal cellular redox buffer. LEF1 overexpression also conferred resistance against therapeutic GSH depletion during brain colonization and improved management of intracellular ROS. We conclude that besides EMT, LEF1 facilitates metastasis by improving the anti-oxidative capacity of epithelial breast cancer cells, in particular during colonization of the brain parenchyma. This article is protected by copyright. All rights reserved.

The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

Therapeutic regimens in chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL) are undergoing tremendous changes. In 2014, the Bruton tyrosine kinase inhibitor (TKI) ibrutinib was approve...

Background: In glioma surgery, 5-aminolevulinic acid (5-ALA) fluorescence reflects tumor infiltration, and fluorescence-assisted resection correlates with higher removal rates and improved progression-free survival. Recent studies report that a sizable proportion of brain metastases exhibit peritumoral infiltration on the cellular level. There is little information regarding whether 5-ALA is useful to guide surgery in the peritumoral zone in metastases. The aim of this study was to assess histologically whether 5-ALA fluorescence accurately reflects metastatic brain infiltration. Methods and Materials: Fluorescence-assisted tumor resection was performed in 27 patients with brain metastases. Patients received 20 mg/kg 5-ALA 3 hours before anesthesia. After resection, biopsy specimens of the surrounding parenchyma were analyzed for 5-ALA fluorescence and histologic evidence of infiltrating tumor cells. The correlation between 5-ALA positivity and immunohistochemical evidence of tumor in the peritumoral zone was also assessed. Results: Of 27 metastases, 23 (85%) were 5-ALA positive. For qualitative tissue analysis, 110 of 125 samples were collected. Metastatic infiltration was present in 49 samples with faint or red fluorescence; 33 samples without fluorescence were tumor-free. The presence of metastatic infiltration correlated with fluorescence (P < 0.001). Tumor infiltration correlated with fluorescence (blue fluorescence 0.09% ± 0.04% and red or faint fluorescence 3.26%; P = 0.003). Conclusions: Infiltration of surrounding brain tissue is a common finding in brain metastases in selected primary tumors. 5-ALA fluorescence correlates with tumor cell infiltration and might guide more radical resection. Key words: 5-ALA, Brain metastasis, Brain tumor, Fluorescence-guided surgery, Histology, Tumor infiltration

Positive results of MitraClip in terms of improvement in clinical and left ventricular parameters have been described in detail. However, long-term effects on secondary pulmonary hypertension were not investigated in a larger patient cohort to date. 70 patients with severe mitral regurgitation, additional pulmonary hypertension, and right heart failure as a result of left heart disease were treated in the heart centers Hamburg and Göttingen. Immediately after successful MitraClip implantation, a reduction of the RVOT diameter from 3.52 cm to 3.44 cm was observed reaching a statistically significant value of 3.39 cm after 12 months. In contrast, there was a significant reduction in the velocity of the tricuspid regurgitation (TR) from 4.17 m/s to 3.11 m/s, the gradient of the TR from 48.5 mmHg to 39.3 mmHg, and the systolic pulmonary artery pressure (PAPsyst) from 58.6 mmHg to 50.0 mmHg. This decline continued in the following months (Vmax TR 3.09 m/s, peak TR 38.6 mmHg, and PAPsyst 47.4 mmHg). The tricuspid annular plane systolic excursion (TAPSE) increased from 16.5 mm to 18.9 mm after 12 months. MitraClip implantation improves pulmonary artery pressure, tricuspid regurgitation, and TAPSE after 12 months. At the same time, there is a decrease in the RVOT diameter without significant changes in other right ventricular and right atrial dimensions.

// Laila Siam 1 , Annalen Bleckmann 2, 3 , Han-Ning Chaung 2 , Alexander Mohr 4 , Florian Klemm 2 , Alonso Barrantes-Freer 5 , Raquel Blazquez 2 , Hendrik A. Wolff 6 , Florian Luke 7 , Veit Rohde 1 , Christine Stadelmann 5 , Tobias Pukrop 2, 7 1 Department of Neurosurgery, University Medical Center, Gottingen, Germany 2 Department of Hematology and Medical Oncology, University Medical Center, Gottingen, Germany 3 Department of Medical Statistics, University Medical Center, Gottingen, Germany 4 Department of Neuroradiology, University Medical Center, Gottingen, Germany 5 Institute of Neuropathology, University Medical Center, Gottingen, Germany 6 Department of Radiotherapy and Radiation Oncology, University Medical Center, Gottingen, Germany 7 Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany Correspondence to: Tobias Pukrop, e-mail: tobias.pukrop@ukr.de Keywords: astrocytes, brain metastasis, glial-pseudo capsule, metastatic infiltration, organ-specific defense Received: April 11, 2015 Accepted: June 08, 2015 Published: June 17, 2015 ABSTRACT The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.

// Eva Rietkotter 1 , Annalen Bleckmann 1 , Michaela Bayerlova 2 , Kerstin Menck 1 , Han-Ning Chuang 1 , Britta Wenske 1 , Hila Schwartz 3 , Neta Erez 3 , Claudia Binder 1 , Uwe-Karsten Hanisch 4 , Tobias Pukrop 1, 5 1 Department of Hematology and Medical Oncology, University Medical Center, 37075 Gottingen, Germany 2 Department of Medical Statistics, University Medical Center, 37075 Gottingen, Germany 3 Department of Pathology, Sackler School of Medicine, 69978 Tel Aviv University, Israel 4 Institute of Neuropathology, University Medical Center, 37075 Gottingen, Germany 5 Department of Hematology and Medical Oncology, University Clinic Regensburg, 93053 Regensburg, Germany Correspondence to: Tobias Pukrop, e-mail: tobias.pukrop@ukr.de Keywords: anti-CSF-1, colonization, monocyte-derived cells, microglia, metastasis Received: January 5, 2015 Accepted: April 29, 2015 Published: May 12, 2015 ABSTRACT The mononuclear phagocytic system is categorized in three major groups: monocyte-derived cells (MCs), dendritic cells and resident macrophages. During breast cancer progression the colony stimulating factor 1 (CSF-1) can reprogram MCs into tumor-promoting macrophages in the primary tumor. However, the effect of CSF-1 during colonization of the brain parenchyma is largely unknown. Thus, we analyzed the outcome of anti-CSF-1 treatment on the resident macrophage population of the brain, the microglia, in comparison to MCs, alone and in different in vitro co-culture models. Our results underline the addiction of MCs to CSF-1 while surprisingly, microglia were not affected. Furthermore, in contrast to the brain, the bone marrow did not express the alternative ligand, IL-34. Yet treatment with IL-34 and co-culture with carcinoma cells partially rescued the anti-CSF-1 effects on MCs. Further, MC-induced invasion was significantly reduced by anti-CSF-1 treatment while microglia-induced invasion was reduced to a lower extend. Moreover, analysis of lung and breast cancer brain metastasis revealed significant differences of CSF-1 and CSF-1R expression. Taken together, our findings demonstrate not only differences of anti-CSF-1 treatment on MCs and microglia but also in the CSF-1 receptor and ligand expression in brain and bone marrow as well as in brain metastasis.

Genomic high-throughput technologies (GHTT) such as next-generation sequencing represent a fast and cost-effective tool toward a more comprehensive understanding of the molecular background of complex diseases. However, technological advances contrast with insufficient application in clinical practice. Thus, patients, physicians, and other professionals are faced with tough challenges that forestall the efficient and effective implementation. With the increasing application of genetic testing, it is of paramount importance that physicians and other professionals in healthcare recognize the restrictions and potential of GHTT, in order to understand and interpret the complex data in the context of health and disease. At the same time, the growing volume and complexity of data is forever increasing the need for sustainable infrastructure and state-of-the-art tools for efficient data management, including their analysis and integration. The large pool of sensitive information remains difficult to interpret and fundamental questions spanning from billing to legal, social, and ethical issues have still not been resolved. Here we summarize and discuss these obstacles in an interdisciplinary context and suggest ways to overcome them. Continuous discussion with clinicians, data managers, biostatisticians, systems medicine experts, ethicists, legal scholars, and patients illuminates the strengths, weakness, and current practices in the pipeline from biomaterial to sequencing and data management. This discussion also highlights the new, cross-disciplinary working collaborations to realize the wide-ranging challenges in clinical genomics including the exceptional demands placed on the staff preparing and presenting the data, as well as the question as to how to report the data and results to patients.

// Nathalie Zatula 1,4 , Maria Wiese 1,4 , Jens Bunzendahl 1,4 , Walter Birchmeier 2 , Christina Perske 3 , Annalen Bleckmann 4 and Felix H. Brembeck 1,4 1 Tumor Biology and Signal Transduction, Georg-August-University Gottingen, Germany 2 Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany 3 Dept. of Pathology, Georg-August-University Gottingen, Germany 4 Dept. of Hematology and Medical Oncology, Georg-August-University Gottingen, Germany Correspondence: Felix H. Brembeck, email: // Keywords : mouse model; primary cell culture; human breast cancer; canonical Wnt signaling; estrogen receptor pathway; Pygo2; Sp1 Received : April 04, 2014 Accepted : July 24, 2014 Published : July 25, 2014 Abstract The majority of human breast cancers express estrogen receptor alpha (ER), which is important for therapy with anti-estrogens. Here we describe the role of BCL9-2, a proto-oncogene previously characterized as co-activator of Wnt/s-catenin signaling, for mammary tumorigenesis in mice and human. ER positive human breast cancers showed overexpression of BCL9-2 and tamoxifen treated patients with high BCL9-2 demonstrated a better survival. BCL9-2 was upregulated during puberty and pregnancy in normal mammary epithelia, but downregulated in the involuted gland. BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia. Moreover, aged BCL9-2 transgenic mice developed ductal-like mammary tumors with high nuclear ER expression. We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment. Moreover, BCL9-2 regulated the expression of ER and the proliferation of human breast cancer cells independently of s-catenin. Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter. In summary, BCL9-2 induces ER positive breast cancers in vivo , regulates ER expression by a novel s-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.

AIMS MitraClip implantation is evolving as a potential alternative treatment to conventional surgery in high-risk patients with significant mitral regurgitation (MR). However, outcome predictors are under-investigated. The aim of this study was to identify predictors of midterm mortality and heart failure rehospitalisation after percutaneous mitral valve repair with MitraClip. METHODS AND RESULTS A total of 150 consecutive patients were followed for a median of 463 days. Survival analyses were performed for baseline characteristics, risk scores and failure of acute procedural success (APS) defined as persisting MR grade 3+ or 4+. Univariate significant risk stratifiers were tested in multivariate analyses using a Cox proportional hazards model. Overall survival was 96% at 30 days, 79.5% at 12 months, and 62% at two years. Multivariate analysis identified APS failure (HR 2.13, p=0.02), NYHA Class IV at baseline (HR 2.11, p=0.01) and STS score ≥12 (HR 2.20, p

Background Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment. Methods Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants. Results Overall, 630 answers (21 × 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56·8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41·3 per cent) at TB1, compared with only 171 answers (27·1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0·006). Postoperative chemotherapy was included in 51·9 and 52·4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0·980). Conclusion Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy.

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01–0.56) and high Ki67 (HR 3.68, 95 % CI 1.12–12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11–5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02–4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis. Electronic supplementary material The online version of this article (doi:10.1007/s10585-016-9780-3) contains supplementary material, which is available to authorized users.

Purpose Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections. Methods Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts. Results Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (p

Objective: To systematically assess the informational value, quality, intention, source and bias of web 2.0 footage whose aim is peer-to-peer education about oral implantology. Methods: YouTube (http://www.youtube.com) was scanned on 15 October 2010 for oral implantology-related videos using an adequately pre-defined search query. Search results were filtered with the system-generated category ‘education’ and the additional criterion ‘most viewed’. Only those videos with at least 1000 views were included (total 124, of which 27 were excluded because they were not related to implantology). Filtered videos were discussed and rated with particular regard to the educational needs of potential groups of addressees [(i) undergraduates and laymen, (ii) dentists without or currently undergoing a specialisation in oral implantology and (iii) dentists who have completed a specialisation in the field of oral implantology] by a jury consisting of (i) an accredited post-graduate university instructor with 22 years of professional teaching experience in the field of implantology, (ii) a university lecturer in dentistry/orthodontics with 10 years teaching experience and (iii) a university haematologist/oncologist. They were required to fill out a questionnaire for each video. The data were statistically analysed using non-parametric ANOVA (α = 5%) and a sign test (α = 0.05/3 = 0.017). Results: The YouTube scan produced 1710 results in the category ‘EDU’. The analysis revealed that there is a wide range of instructional footage on this topic, but with highly variable range in quality and informational value. Footage intention was to large proportions (47.4%) a mixture of education and advertisement. Its usefulness differed significantly for the three groups of addressees, offering greater novelty to undergraduates and post-graduates. Conclusion: YouTube and similar social media websites may have a potential capacity and value in complementing continuing education in the technique of oral implantology. As a means of achieving an acceptable level of knowledge about the topic when used alone, it should not be considered to be suitable at this point in time.

Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN. peerReviewed

Design Prospective, randomized, clinical trial. Setting University hospital operation room. Patients 104 patients scheduled for elective dental or maxillofacial surgery were randomized to two groups: GlideScope® classic (GSc) and GlideScope® direct (GSd). Interventions We compared the video laryngoscopes GSc and GSd with each other and with direct laryngoscopy (DL) for nasotracheal intubation with regard to visualization of the glottis, intubation success rate, and required time for and ease of intubation. The aim of the study was to determine whether the use of the video monitor alone reduced the difficulty of nasotracheal intubation, and also to investigate whether the GSc, with its blade designed for difficult airways, had an additional advantage over the video-assisted Macintosh blade (GSd). In both groups the investigators first performed laryngoscopy using the GSd blade, first with the monitor concealed and then with it visible. In the GSd group the tube was then inserted into the trachea with the video monitor screen visible. In the GSc group, the GSd blade was exchanged for the GSc blade, which was then used when inserting the tube with the screen visible. Results The success rates and the times required for the video-assisted nasotracheal intubation did not differ significantly between the groups. A better view was obtained more often in the GSc group. In both groups there was a significant difference between direct laryngoscopy and the video-assisted intubation technique. Overall, using the video monitor improved the C-L scores by one grade in 52% and by two grades in 11% of the patients. Conclusions Video laryngoscopes increase the ease of nasotracheal intubation. The GSc blade might provide a better view of the laryngeal structures in case of a difficult airway than the GSd blade. Video laryngoscopy per se gives a better view of the glottis than direct laryngoscopy.

AIMS: Transcatheter aortic valve implantation (TAVI) represents a less invasive treatment option for elderly patients. Therefore, we aimed to determine the impact of frailty measured by the Katz Index of activities of daily living (ADL) on short- and long-term mortality after TAVI. METHODS AND RESULTS: Our study included 300 consecutive patients (mean age, 82±5 years) who had undergone TAVI at our institution (158 transapical, 142 transfemoral procedures). At baseline, 144 patients were impaired in at least one ADL and therefore defined as frail (Katz Index

Aims Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. Methods and results Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility. Conclusions Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.

// Eva Rietkotter 1 , Kerstin Menck 1 , Annalen Bleckmann 1,2 , Katja Farhat 3 , Meike Schaffrinski 1 , Matthias Schulz 1 , Uwe-Karsten Hanisch 4 , Claudia Binder 1 , Tobias Pukrop 1 1 Department of Hematology/Oncology, University Medical Center, 37099 Gottingen, Germany 2 Department of Medical Statistics, University Medical Center, 37099 Gottingen, Germany 3 Department of Cardiovascular Physiology, University Medical Center, 37099 Gottingen, Germany 4 Institute of Neuropathology, University Medical Center, 37099 Gottingen, Germany Correspondence: Tobias Pukrop, email: // Keywords : Zoledronic acid, macrophages, microglia, metastasis, tumor microenvironment Received : July 23, 2013 Accepted : August 17, 2013 Published : August 19, 2013 Abstract The bisphosphonate zoledronic acid (ZA) significantly reduces complications of bone metastasis by inhibiting resident macrophages, the osteoclasts. Recent clinical trials indicate additional anti-metastatic effects of ZA outside the bone. However, which step of metastasis is influenced and whether thisis due to directtoxicity on cancer cells or inhibition of the tumor promoting microenvironment, is unknown. In particular, tumor-associated and resident macrophages support each step of organ metastasis and could be a crucial target of ZA. Thus, we comparatively investigate the ZA effects on: i) different types of macrophages, ii) on breast cancer cells but also iii) on macrophage-induced invasion. We demonstrate that ZA concentrations reflecting the plasma level affected viability of human macrophages, murine bone marrow-derived macrophages as well as their resident brain equivalents, the microglia, while it did not influence the tested cancer cells. However, the effects on the macrophages subsequently reduced the macrophage/microglia-induced invasiveness of the cancer cells. In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma cells. The characterization of human macrophages after ZA treatment revealed a phenotype/response shift, in particular after external stimulation. In conclusion, we show that therapeutic concentrations of ZA affect all types of macrophages but not the cancer cells. Thus, anti-metastatic effects of ZA are predominantly caused by modulating the microenvironment. Most importantly, our findings demonstrate that ZA reduced microglia-assisted invasion of cancer cells to the brain tissue, indicating a potential therapeutic role in the prevention of cerebral metastasis.

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis. peerReviewed

Purpose Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60 % of patients develop secondary metastatic recurrence (SMR) after R0-resection of CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR. Methods From 01/2001 to 11/2011, 104 out of 178 consecutive patients with R0-resection of CRC-LM developed SMR and were evaluated. The impact of surgical and Ctx re-interventions on recurrence free (RFS) and cancer-specific survival (CSS) was analyzed. Median follow-up was 28.0 (95 %CI: 19.4–37.4) months. Results SMR occurred in 81 patients at a single site (49× liver, 18× lung, 14× other) and in 23 patients at multiple sites. Forty-two patients were scheduled for primary surgery. Fifty-three patients were classified as non-resectable and treated with median 5.0 [IQR, 3.0–10.0] cycles of Ctx, combined with an EGFR/VEGF-antibody in 27 patients. Nine patients received best supportive care only. R0/R1 resection could be achieved in 35 patients primarily and even in 8 patients secondarily after Ctx. Surgical morbidity and mortality were 16 and 0 %, respectively. The 5-year RFS rates for patients with R0 versus R1-resection were 22 and 24 % (p = 0.948). The 5-year CSS rate for R0/R1-resected patients was 38 % versus 10 % for those patients treated by Ctx alone (p

Habitual mouth breathing is often accompanied by habitual anterior tongue thrust, instead of a lip closure, in order to create the anterior seal necessary for the initiation of physiological deglutition. We tested the null hypothesis of no significant influence of oral maneuver and the use of oral screens on tongue coordination and position during deglutition in 29 subjects (age = 6-16; mean = 9.69 years; 13/16 female/male) with habitual open-mouth posture using intraoral polysensography. The target parameters for swallowing were swallowing-associated nasal airflow interruption (NAI) and coordination of tongue-palate contact during NAI. Conventional myofunctional maneuvers could be facilitated and made more efficient, in terms of increasing the numbers of favorable early tongue-palate contacts typical of somatic swallowing, if accompanied by the application of an oral screen. Habitual open-mouth breathing does not necessarily coincide with distinctively pronounced proportions of late tongue-palate contact. peerReviewed

An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/β-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, β-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear β-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear β-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/β-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not β-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of β-catenin in this setting. Electronic supplementary material The online version of this article (doi:10.1007/s10585-012-9552-7) contains supplementary material, which is available to authorized users.

The objective of this study was to systematically assess the informational value, intention, source, and bias of videos related to dentistry available on the video-sharing Internet platform YouTube. YouTube (www.youtube.com) was searched for videos related to dentistry, using the system-generated sorts "by relevance" and "most viewed" and two categories (All and Education). Each of the first thirty results was rated by two assessors filling out a questionnaire for each (total: 120). The data were subjected to statistical analysis using Cohen's kappa, Pearson's correlation coefficient tau, Mann-Whitney U-tests, and a nonparametric three-way ANOVA, including an analysis of the interaction between the sorting and category effect, with an α-level of 5 percent. The scan produced 279,000 results in the category All and 5,050 in the category Education. The analysis revealed a wide variety of information about dentistry available on YouTube. The purpose of these videos includes entertainment, advertising, and education. The videos classified under Education have a higher degree of usefulness and informational value for laypersons, dental students, and dental professionals than those found in a broader search category. YouTube and similar social media websites offer new educational possibilities that are currently both underdeveloped and underestimated in terms of their potential value. Dentists and dental educators should also recognize the importance of these websites in shaping public opinion about their profession.

A correct prehospital diagnosis of emergency patients is crucial as it determines initial treatment, admitting specialty, and subsequent treatment. We evaluated the diagnostic accuracy of emergency physicians.All patients seen by six emergency physicians staffing the local emergency ambulance and rescue helicopter services during an 8-month period were studied. The ambulance and helicopter physicians had 3 and 4 years, respectively, training in anesthesia and intensive care medicine. The admission diagnoses were compared with the discharge diagnoses for agreement. Time of day of the emergency call, patients' age, and sex, living conditions, and presenting symptoms were evaluated as contributing factors.Three hundred and fifty-five ambulance and 241 helicopter deployment protocols were analyzed. The overall degree of agreement between initial and discharge diagnoses was 90.1% with no difference attributable to years of experience. The lowest agreement rate was seen in neurological disorders (81.5%), with a postictal state after an unobserved seizure often being diagnosed as a cerebrovascular accident. Inability to obtain a complete medical history (e.g. elderly patients, patients in nursing homes, neurological impairment) was associated with a lower agreement rate between initial and discharge diagnoses (P0.05).Medical history, physical examination, ECG, and blood glucose enabled a correct diagnosis in most cases, but some were impossible to resolve without further technical and laboratory investigations. Only a few were definitively incorrect. A detailed medical history is essential. Neurological disorders can present with misleading symptoms and when the diagnosis is not clear it is better to assume the worst case.

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.

3600 Background: Even though the implementation of multimodal treatment strategies including neoadjuvant radiochemotherapy (RCT) has led to improved survival distant metastases are still limiting the prognosis of rectal cancer patients. In this context, we investigated the HER-2 status in rectal cancer patients, UICC stages II and III. Our aim was to assess the HER-2 positivity rate in primary tumors and metachronous metastases. Methods: In this study 264 rectal cancer patients (192 male, 72 female; median age 64 years) from phase-II/-III-trials of the German Rectal Cancer Study Group (CAO/ARO/AIO-94 and 04) were included. HER-2 status was determined pretherapeutically in tumor biopsies as well as resection specimens and metachronous metastases (n=27) using immunohistochemistry (IHC0 to IHC3+) scoring and S-ISH-amplification detection. Tumors with IHC3+ or S-ISH ratio ?2.0 were classified as HER-2 positive; results were correlated with clinicopathological parameters and long-term survival. Results: A positive HER-2 status was found in 12.4% of pre-treatment biopsies, in 29.3% of the resection specimens and 22.2% (n=6) of metastases. With a median follow-up of 46.5 months patients with HER-2-positivity showed better disease free survival (p=0.06) and cancer-specific survival (CSS, p=0.05). The 5-years survival rate was 96.4% (HER-2-positive) versus 79.5% (HER-2-negative). In multivariate analyses HER-2 status was as an independent (p=0.0053) predictor for CSS along with (y)pN-status (p

e14167 Background: Multidisciplinary treatment in patients with colorectal liver metastases (CRLM) is standard in modern oncology. However, for interdisciplinary discussion assessing complimentary disciplines' potential and changes in personal views is crucial. We evaluated experienced medical oncologists' (MO) and surgeons' (SG) assessment of resectability and indication for chemotherapy (CTx) in patients with CRLM. Methods: Thirty patients who underwent R0-resection of CRLM between 2001 and 2011 at our department were selected. Medical history and staging data were presented to MO (n=10) and SG (n=11) in a virtual tumor board (TB1). Standardized blinded TED-voting answers (9 options) included assessment of resectability and the indication for pre- and/or postoperative CTx. The virtual tumor board was followed by training in terms of state-of-the-art lectures on potential of CTx and surgery. Assessment was then repeated in a second virtual tumor board (TB2). Results: 630 (21x30) answers were obtained per tumor board. In TB1 resectability, borderline resectability and definite unresectability were expected in 433, 161 and 36 answers, respectively. Resectability was significantly more often expected by SG (p

Purpose For years, 5-fluorouracil (5-FU) has been the backbone of radiochemotherapy (RCT) of locally advanced rectal cancer. Its main target, thymidylate synthase (TS), is speculated to be an important biomarker for response prediction and long-term prognosis. In this study, we analyzed TS expression in the rectal cancer tissue of 208 patients to evaluate its predictive/prognostic potential. Methods All patients included were diagnosed with locally advanced adenocarcinoma of the rectum (UICC II and III) and were treated within randomized clinical trials of the German Rectal Cancer Study Group. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 167 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. TS levels and further clinicopathological parameters were assessed in univariate and multivariate analyses. Additionally, a TS gene polymorphism was analyzed with respect to the intratumoral protein levels. Results Low TS expression in pretreatment biopsies correlated with impaired patient survival (p = 0.015). Analysis of a 28-bp repeat revealed a correlation between the *3/*3 genotype and high TS expression in pretherapeutic biopsies. In this study, a correlation of TS expression and grade of RCT-induced tumor regression was not found. Histopathological examination confirmed a complete tumor remission in 16 patients (9.6%). Analyses of the resection specimen indicated an unfavorable prognosis for patients with low intratumoral TS expression in case of detected lymph node metastases (p = 0.04). Conclusions TS can serve as a prognostic biomarker indicating an unfavorable prognosis for patients with low TS expression. Electronic supplementary material The online version of this article (doi:10.1245/s10434-011-1608-4) contains supplementary material, which is available to authorized users.