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Zusammenfassung Hintergrund Die Diagnose Krebs fuhrt bei vielen Patient*innen zu einem emotionalen Ausnahmezustand. Die Lebensqualitat ist in diesem Zusammenhang ein wichtiges Therapieziel. Daher wurde in der onkologischen Tagesklinik (ICT) am Universitatsklinikum Regensburg (UKR) eine LQ-Lotsin implementiert, um die ambulanten Patient*innen hinsichtlich ihrer Fragen und Bedurfnisse individuell zu unterstutzen, um so die Lebensqualitat zu erhohen. Methode Fur die strukturierte Erhebung der Lebensqualitat/Bedurfnisse in der Routine der Tumortherapie und -nachsorge ist ein Screeningtool notwendig. Im Rahmen einer mixed-methods Studie wurden Fokusgruppen mit Gesundheitsexpert*innen/Patient*innen organisiert, um die Bedurfnisse von Krebspatient*innen zu ergrunden. Darauf basierend wurden Fragebogen in der Literatur gesichtet, welche diese Bedurfnisse abdecken, um folglich einen ICT-spezifischen Fragebogen zu adaptieren und diesen mithilfe eines Workflow zu integrieren. Ergebnisse Insgesamt 333 einzelne Wortmeldungen wurden von den Teilnehmer*innen der Fokusgruppen zu den Bedurfnissen von Krebspatient*innen in verschiedenen Phasen der Behandlung/Tumorentitaten hervorgebracht. Keiner der Fragebogen in der Literatur erfullte alle gewunschten Anforderungen, weshalb ein neuer Bogen u.a. mit Elementen verschiedener standardisierter Bogen und den Ergebnissen der Fokusgruppen entstand. Ein Workflow wurde erstellt, um den Fragebogen in der Routineversorgung des ICT zu integrieren. Diskussion Durch die Befragung von Gesundheitsexpert*innen aus verschiedenen Bereichen und Patient*innen mit unterschiedlichen Entitaten, konnten die Bedurfnisse der Krebspatient*innen uber verschiedene Phasen der Erkrankung und zusatzlich mogliche Unterschiede zwischen den Krebsentitaten erfasst werden. Durch die Implementierung einer LQ-Lotsin im ICT soll mit Hilfe des Screenings eine strukturierte Erhebung der Lebensqualitat und eine Analyse der Patient*innenbedurfnisse stattfinden. Um das Screening in der Routineversorgung zu integrieren, wurde ein Workflow erstellt. Daruber hinaus wurde der Fragebogen so konzipiert, dass er wiederholt zu verschiedenen Zeitpunkten eingesetzt werden kann. Um wichtige Etappen des Therapieverlaufs abzudecken und zu eruieren wie sich die Patient*innenbedurfnisse im Verlauf verandern, sollen die Patient*innen den Fragebogen mehrmals in definierten Abstanden ausfullen. Schlussfolgerung Durch den Fragebogen sollen die Bedurfnisse der ambulanten Krebspatient*innen im ICT strukturiert erhoben werden. Zukunftig gilt es zu untersuchen, wie sich der Einsatz und das Zusammenspiel von Bogen und Workflow in der klinischen Praxis bewahrt und die Lebensqualitat der Patient*innen verbessert. Zudem ist interessant zu analysieren, welche Patient*innen das Beratungsangebot einer Lotsin annehmen und welche Bedurfnisse besonders oft geausert werden.

The macro-metastasis/organ parenchyma interface (MMPI) was previously considered an inert anatomical border which sharply separates the affected organ parenchyma from the macro-metastatic tissue. Recently, infiltrative growth of macro-metastases from various primary tumors was described in the brain, liver and lung, with significant impact on survival. Strikingly, the MMPI patterns differed between entities, so that at least nine different patterns were described. The MMPI patterns could be further classified into three major groups: displacing, epithelial and diffuse infiltrating. Additionally, macro-metastases are a source of further tumor cell dissemination in the affected organ; and these intra-organ metastatic dissemination tracks starting from the MMPI also vary depending on the anatomical structures of the colonized organ and influence disease outcome. In spite of their relevance, MMPIs and organ-specific dissemination tracks are still largely overlooked by many clinicians, pathologists and/or researchers. In this review, we aim to address this important issue and enhance our current understanding of the different MMPI patterns and dissemination tracks in the brain, liver and lung.

B cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in adults, is still essentially incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. A comprehensive proteome analysis of primary human B-CLL cells and B cells from younger as well as elderly healthy donors was performed. For comparison, the chronic B cell leukemia cell line JVM-13 was also included. A principal component analysis comprising 6,945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and B-CLL patients, while identifying JVM-13 as poorly related cells. Mass spectrometric proteomics data have been made fully accessible via ProteomeXchange with identifier PXD006570-PXD006572, PXD006576, PXD006578, and PXD006589-PXD006591. Remarkably, B cells from aged controls displayed significant regulation of proteins related to stress management in mitochondria and ROS stress such as DLAT, FIS1, and NDUFAB1, and DNA repair, including RAD9A, MGMT, and XPA. ROS levels were indeed found significantly increased in B cells but not in T cells or monocytes from aged individuals. These alterations may be relevant for tumorigenesis and were observed similarly in B-CLL cells. In B-CLL cells, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, the stress-related serotonin transporter SLC6A4, and high expression of ZNF207, CCDC88A, PIGR and ID3, otherwise associated with stem cell phenotype, were determined. Alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify a potential proteome signature for immune senescence in addition to previously unrecognized features of B-CLL cells and suggest that aging may be accompanied by cellular reprogramming functionally relevant for predisposing B cells to transform to B-CLL cells.

Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia.

Background The ModuLung trial addresses the medical need for low-toxic therapies in frequently comorbid patients with relapsed or refractory non-small cell lung cancer (NSCLC). We evaluated safety and efficacy of a biomodulatory approach in > =2nd-line, aiming for induction of anakoinosis i.e. communicative reprogramming of dysregulated cellular and intercellular homeostasis. Methods Patients with stage IIIB/IV squamous or non-squamous NSCLC and disease progression during or after at least one platinum-based chemotherapy were stratified according to histology, and randomly assigned 1:1 to treosulfan 250 mg twice daily, pioglitazone 45 mg once daily and clarithromycin 250 mg twice daily (experimental arm) or nivolumab 3 mg/kg every 2 weeks (control arm). The primary endpoint was progression-free survival (PFS). Results Due to the approval of checkpoint inhibitors in first-line, the study was prematurely closed after randomization of 40 of the 86 initially planned patients. The main efficacy and safety results are presented in the table and show no statistically significant difference between groups. The two-year survival rate achieved in the biomodulatory arm was 10% (95% CI, 1.2 to 31.7) and 5.9% (95% CI, 0.1 to 28.7) in the nivolumab arm. 75% and 53% of the patients proceeded to a further line of therapy, respectively. Table . 1570P Results Biomodulatory Arm (n = 20) 35% > 2nd-line Nivolumab Arm (n = 17) 41.2% > 2nd-line HR & 95% CI or p-value PFS, median in months 1.6 2.1 HR = 1.17; 95% CI, 0.59--2.34 OS, median in months 8.2 6.9 HR = 0.86; 95% CI, 0.38-1.96 ORR, n (%) 2 (10%) 0 (0%) P = 0.49 Grade 3-5 AE, n (%) 2 (10%) 6 (35%) P = 0.11 Conclusions Combination of clarithromycin, pioglitazone and metronomic chemotherapy is active in the > =2nd line treatment of NSCLC and warrants further investigations. Nivolumab did not induce any tumor response and was relatively toxic in this population. Novel treatment approaches are urgently needed for patients who previously received platinum-based chemotherapy for advanced squamous and non-squamous NSCLC (Funded by Anticancer Fund, EudraCT number 2014-004095-31). Clinical trial identification EudraCT: 2014-004095-31, Start Date: 2015-07-13. Legal entity responsible for the study Freistaat Bayern respresented by University of Regensburg represented by Kaufmannischer Direktor. Funding Anticancer Fund, Brussels, Belgium. Disclosure All authors have declared no conflicts of interest.

Background Wnt/β-catenin signaling is known to play an important role in colorectal cancer (CRC). Niclosamide, a salicylamide derivative used in the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. The objective of this study was to investigate niclosamide as a therapeutic agent against CRC. Methods The antiproliferative effects of 1, 3, 10, and 50 μM concentrations of niclosamide on human (SW480 and SW620) and rodent (CC531) CRC cell lines were determined by MTS assay and direct cell count. The lymphoid enhancer–binding factor 1/transcription factor (LEF/TCF) reporter assay monitored the activity of Wnt signaling. Immunofluorescence staining demonstrated the expression pattern of active β-catenin. Gene expression of canonical and noncanonical Wnt signaling components was analyzed using qRT-PCR. Western blot analysis was performed with antibodies detecting nuclear localization of β-catenin and c-jun. Results Cell proliferation in CRC cell lines was blocked dose dependently after 12 and 24 h of incubation. The Wnt promoter activity of LEF/TCF significantly decreased with niclosamide concentrations of 10 and 50 μM after 12 h of incubation. Active β-catenin did not shift from the nuclear to the cytosolic pool. However, canonical target genes (met, MMP7, and cyclin D1) as well as the coactivating factor Bcl9 were downregulated, whereas the noncanonical key player c-jun was clearly activated. Conclusions Niclosamide treatment is associated with an inhibitory effect on CRC development and reduced Wnt activity. It may exert its effect by interfering with the nuclear β-catenin-Bcl9-LEF/TCF triple-complex and by upregulation of c-jun representing noncanonical Wnt/JNK signaling. Thus, our findings warrant further research into this substance as a treatment option for patients with advanced CRC.

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

Maintenance of tissue homeostasis and immune surveillance are important functions of the lymphatic vascular system. Lymphatic vessels are lined by lymphatic endothelial cells (LECs). By gene micro-array expression studies we recently compared human lymphangioma-derived LECs with umbilical vein endothelial cells (HUVECs). Here, we followed up on these studies. Besides well-known LEC markers, we observed regulation of molecules involved in immune regulation, acetylcholine degradation and platelet regulation. Moreover we identified differentially expressed WNT pathway components, which play important roles in the morphogenesis of various organs, including the blood vascular system. WNT signaling has not yet been addressed in lymphangiogenesis. We found high expression of FZD3, FZD5 and DKK2 mRNA in HUVECs, and WNT5A in LECs. The latter was verified in normal skin-derived LECs. With immunohistological methods we detected WNT5A in LECs, as well as ROR1, ROR2 and RYK in both LECs and HUVECs. In the human, mutations of WNT5A or its receptor ROR2 cause the Robinow syndrome. These patients show multiple developmental defects including the cardio-vascular system. We studied Wnt5a-knockout (ko) mouse embryos at day 18.5. We show that the number of dermal lymphatic capillaries is significantly lower in Wnt5a-null-mice. However, the mean size of individual lymphatics and the LEC number per vessel are greater. In sum, the total area covered by lymphatics and the total number of LECs are not significantly altered. The reduced number of lymphatic capillaries indicates a sprouting defect rather than a proliferation defect in the dermis of Wnt5a-ko-mice, and identifies Wnt5a as a regulator of lymphangiogenesis.

Burkitt's lymphoma (BL) is a highly malignant, aggressive non-Hodgkin's lymphoma derived from germinal center B cells. Recently, global gene expression profiling of patient samples led to a molecular definition of BL with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Herein, we report the expression of nucleic LEF1 in 15 of 18 patients with BL and the identification of LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression, as were mantle cell lymphoma (0 of 5), marginal zone lymphoma (0 of 6), follicular lymphoma (0 of 12), and diffuse large B-cell lymphoma (1 of 31). Whole-genome gene expression profiling after transient knockdown of LEF1 in BL cell lines identified new LEF1 target genes; these LEF1 targets are enriched with genes associated with cancers. The expression of LEF1 and LEF1-regulated genes in primary BL suggests that LEF1 is not only aberrantly expressed but also transcriptionally active. This study supports a functionally important role for LEF1 and its target genes in BLs.

Convergent extension movements are the main driving force of Xenopus gastrulation. A fine-tuned regulation of cadherin-mediated cell-cell adhesion is thought to be required for this process. Members of the Wnt family of extracellular glycoproteins have been shown to modulate cadherin-mediated cell-cell adhesion, convergent extension movements, and cell differentiation. Here we show that endogenous Wnt/beta-catenin signaling activity is essential for convergent extension movements due to its effect on gene expression rather than on cadherins. Our data also suggest that XLEF-1 rather than XTCF-3 is required for convergent extension movements and that XLEF-1 functions in this context in the Wnt/beta-catenin pathway to regulate Xnr-3. In contrast, activation of the Wnt/Ca2+ pathway blocks convergent extension movements, with potential regulation of the Wnt/beta-catenin pathway at two different levels. PKC, activated by the Wnt/Ca2+ pathway, blocks the Wnt/beta-catenin pathway upstream of beta-catenin and phosphorylates Dishevelled. CamKII, also activated by the Wnt/Ca2+ pathway, inhibits the Wnt/beta-catenin signaling cascade downstream of beta-catenin. Thus, an opposing cross-talk of two distinct Wnt signaling cascades regulates convergent extension movements in Xenopus.