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Figure S1. Cells isolated from bone marrow aspirates of ML-DS and AMKL patients as well HDs fulfilled the minimal ISCT criteria of MSCs. Figure S2. Unsupervised hierarchical clustering of MSCs without grouping according to their entities. Figure S3. Gene set enrichment analysis plots for overexpressed hallmark gene sets associated with proliferation in the disease-derived MSCs compared to HD-MSCs. Table S1: Clinical data of patients and HDs. Table S2: Results of immunphenotypic characterisation. Table S3: Overview of all generated ossicle-like structures. Table S4: TaqMan probes used in RT-PCR assays. Table S5: Anti-human primary antibodies used for immunohistochemical staining.

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients—adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2. We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT–related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.

Supplemental Methods; Supplemental Figure S1: Cancer-related mutations in the DKTK-Master patient cohort; Supplemental Figure S2: T1-PTEN cells were treated with increasing concentrations of approved KIT-inhibitors for 72h and analyzed by SRB assay; Supplemental Figure S3: Dose-combination studies with sapanisertib

Background Orbital aspergillosis is a rare sight- and life-threatening fungal infection affecting immunocompromised or otherwise healthy patients. It is often misdiagnosed due to its unspecific clinical and radiologic appearance. Therapeutic delay can have dramatic consequences. However, progress in microbiological diagnostic techniques and therapeutic experience from case series help improve the management of this disease. Case presentation A 78-year-old immunocompetent woman presented at an eye clinic for subacute swelling, reddening, and ptosis of her left upper eyelid. Based on radiologic and histologic considerations, she was treated for idiopathic orbital inflammation, but her condition worsened. After a second biopsy of the orbital mass, aspergillosis was diagnosed. Her condition improved promptly after initiation of an oral voriconazole treatment. Additionally, using a polymerase chain reaction (PCR) assay, A. fumigatus was identified on tissue of both biopsies and its azole susceptibility was examined simultaneously. Conclusions In the case described here, oral antifungal treatment was sufficient for the therapy of invasive orbital aspergillosis. Performing fungal PCR on orbital tissue can accelerate the diagnostic process and should be performed in ambiguous cases of slowly growing orbital mass. Finally, interdisciplinary management is the key to optimal treatment of orbital tumours and infections.

Mesenchymale Tumoren, insbesondere High-grade-Sarkome, weisen oft einen chaotischen Genotyp auf. Wenige Sarkome entstehen auf dem Boden eines erblichen Tumorsyndroms mit Keimbahnmutation in einem Tumorsuppressorgen. Eine wachsende Zahl von Weichgewebstumoren und Knochentumoren ist jedoch durch eine spezifische, rekurrente genomische Alteration charakterisiert, die fur diagnostische Zwecke herangezogen werden kann. Darunter sind insbesondere spezifische Translokationen und Amplifikationen, in selteneren Fallen auch Deletionen. Diese Veranderungen konnen unter anderem auch mit In-situ-Hybridisierung detektiert werden. Die steigende Zahl von genomweiten Sequenzierungen von Weichgewebs- und Knochentumoren fuhrt zu einem besseren Verstandnis der Genetik von mesenchymale Tumoren und bietet damit auch die Basis fur eine steigende diagnostische Relevanz der In-situ-Hybridisierung als diagnostische Technik. In diesem Ubersichtsartikel werden klinisch relevante, mittels In-situ-Hybridisierung detektierbare Alterationen bei Fettgewebstumoren, Sarkomen mit spindelzelliger und epitheloider Morphologie, Gefastumoren, klein-, blau- und rundzelligen Sarkomen und Knochentumoren dargestellt.

Purpose: To evaluate and compare the clinical utility of simultaneously obtained quantitative 18F-fluorodeoxyglucose positron-emission-tomography (18F-FDG PET) and diffusion-weighted imaging (DWI) datasets for the prediction of histopathological therapy response of soft tissue sarcomas (STS) under neoadjuvant isolated limb perfusion (ILP). Methods: A total of 37 patients with confirmation of a STS of the extremities underwent an 18F-FDG PET/magnetic resonance imaging (MRI) examination before (1st scan) and after (2nd scan) ILP with melphalan and TNF-α. For each patient, the maximum tumor size, metabolic activity (standardized uptake values, SUV) and diffusion-restriction (apparent diffusion restriction values, ADC) were determined in pre- and posttherapeutic examinations and percentage changes during treatment were calculated. A Mann-Whitney U test was used and receiver operating characteristic (ROC) analysis was performed to compare the results of the different quantitative parameters to predict histopathological therapy response. Results from histopathological analysis after subsequent tumor resection served as reference standard and patients were defined as responders/non-responders based on the grading scale by Salzer-Kuntschik. Results: Histopathological analysis categorized 22 (59%) patients as therapy responders (Grade I-III) and 15 (41%) patients as non-responders (Grade IV-VI). Tumors in the responder group showed a mean reduction in size of -9.7% and metabolic activity (SUVpeak: -51.9%; SUVmean: -43.8%) as well as an increase of the ADC values (ADCmin: +29.4% and ADCmean: +32.8%) under treatment. Percentage changes in the non-responder group amounted to: tumor size -6.2%; SUVpeak: -17.3%; SUVmean: -13.9%; ADCmin: +15.3% and ADCmean: +14.6%. Changes of the SUVs and ADCmean values between responders and non-responders were significantly different ( 0.05). The corresponding AUCs were 0.63 (tumor size), 0.87 (SUVpeak), 0.82 (SUVmean), 0.63 (ADCmin), 0.84 (ADCmean) and 0.89 (ratio: ADCmean/SUVpeak), respectively. Conclusion:18F-FDG PET and MR-derived quantitative imaging parameters (SUVs and ADCmean) and their combination reveal a good performance for the prediction of histopathological therapy response of STS under neoadjuvant ILP. Therefore, integrated PET/MRI could serve as a valuable tool for pretherapeutic assessment as well as monitoring of neoadjuvant treatment strategies of STS.

COVID-19 is a potential life-threatening viral disease caused by SARS-CoV-2 and was declared a pandemic by the WHO in March 2020. mRNA-based SARS-CoV-2 vaccines are routinely recommended in immune-compromised patients, including patients with AA, as these patients are at increased risk of contracting COVID-19 and developing a more severe course of disease. Between March 2021 and November 2021 relapse of AA occurred in four (age [median]: 53 years, range 30-84 years) out of 135 patients currently registered at our department and two de novo cases of AA in temporal context to vaccination against SARS-CoV-2, were documented. Median time after first COVID-19 vaccination and relapse of AA was 77 days. All relapsed patients were vaccinated with the mRNA-based vaccine Comirnaty (R). Relapse in two out of the four patients was refractory to CsA/eltrombopag, favoring IST with hATG/CsA or BMT, respectively. Our observations should prompt clinicians to take vaccine-induced relapse of AA or de novo AA after SARS-CoV-2 vaccination into account. Furthermore, careful clinical monitoring and vigilance for signs or symptoms that may indicate relapse of AA (e.g., bleeding complications) are indicated

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients—adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2. We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT–related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.

Our purpose was to assess the diagnostic potential of simultaneously acquired 18F-FDG PET and MRI data sets for therapy response assessment of isolated limb perfusion (ILP) in patients with soft-tissue sarcomas (STS). Methods: In total, 45 patients with histopathologically verified STS were prospectively enrolled for an integrated 18F-FDG PET/MRI examination before and after ILP. Therapy response was assessed based on different MRI- and PET-derived morphologic (RECIST and the MR-adapted Choi criteria) and metabolic (PERCIST) criteria. In addition, a regression model was used combining relative changes in quantitative variables to predict treatment response under ILP. Histopathologic results after subsequent tumor resection served as the reference standard, and patients were categorized as responders or nonresponders on the basis of the 6-stage regression scale by Salzer-Kuntschik. Results: Histopathologic analysis categorized 27 patients as responders (grades I-III) and 18 patients as nonresponders (grades IV-VI). Calculated sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 22%, 89%, 75%, 43%, and 49% for RECIST; 70%, 44%, 66%, 50%, and 60% for the Choi criteria; and 85%, 78%, 85%, 78%, and 82% for PERCIST. Receiver-operating-characteristic analysis revealed an area under the curve (AUC) of 0.56 for RECIST, 0.57 for the Choi criteria, and 0.82 for PERCIST. The combined regression model revealed higher values (AUC, 0.90) than for the stand-alone analysis, however, differences to metabolic parameters did not reach significance (P value: 0.067). Conclusion: Our study demonstrates the superiority of 18F-FDG PET over MRI data sets for response assessment of STS under neoadjuvant ILP. In a clinical setting, MRI delivers valuable information for presurgical assessment. Therefore, combining 18F-FDG PET and MRI data may enable more reliable treatment planning and therapy monitoring of STS.

Simple Summary In this study, we assessed the potential of simultaneously acquired 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and magnetic resonance imaging-derived quantitative imaging parameters to predict the tumor grade, metastatic status, and response to neoadjuvant therapy of primary soft-tissue sarcomas of the extremities. Based on the results of the present study, quantifications of the 18F-FDG PET uptake provide useful prognostic data for the evaluation of histopathological response to neoadjuvant treatment as well as the aggressiveness of high-risk sarcomas, whereas no correlation between the different outcome variables and the results for tumor size and diffusion-weighted imaging-derived apparent diffusion coefficient values was found. Accordingly, measurements of the metabolic activity of primary and untreated soft-tissue sarcomas could non-invasively deliver relevant information, that may be used for treatment planning and risk-stratification of sarcoma patients in a pretherapeutic setting. Abstract Background: To evaluate the potential of simultaneously acquired 18F-FDG PET- and MR-derived quantitative imaging data sets of primary soft-tissue sarcomas for the prediction of neoadjuvant treatment response, the metastatic status and tumor grade. Methods: A total of 52 patients with a high-risk soft-tissue sarcoma underwent a 18F-FDG PET/MR examination within one week before the start of neoadjuvant treatment. For each patient, the maximum tumor size, metabolic activity (SUVs), and diffusion-restriction (ADC values) of the tumor manifestations were determined. A Mann–Whitney-U test was used, and ROC analysis was performed to evaluate the potential to predict histopathological treatment response, the metastatic status or tumor grade. The results from the histopathological analysis served as reference standard. Results: Soft-tissue sarcomas with a histopathological treatment response revealed a significantly higher metabolic activity than tumors in the non-responder group. In addition, grade 3 tumors showed a significant higher 18F-FDG uptake than grade 2 tumors. Furthermore, no significant correlation between the different outcome variables and tumor size or calculated ADC-values could be identified. Conclusion: Measurements of the metabolic activity of primary and untreated soft-tissue sarcomas could non-invasively deliver relevant information that may be used for treatment planning and risk-stratification of high-risk sarcoma patients in a pretherapeutic setting.

Konventionelle Chondrosarkome treten als zweithaufigster, primar maligner Knochentumor vornehmlich im hoheren Erwachsenenalter auf. Im Kindes- und Jugendalter sind sie eine Raritat. In diesem Fallbericht wird der Diagnose- und Behandlungsverlauf eines 13-jahrigen Jungen mit symptomatischem, chondrogenem Tumor des rechten distalen Femurs vorgestellt, der histopathologisch einem epiphysaren, mittelgradig differenzierten Chondrosarkom (G2) zugeordnet werden konnte. Mogliche radiologische und histopathologische Differenzialdiagnosen, wie das Chondroblastom oder das chondroblastische Osteosarkom, werden erortert und die diagnostischen Behandlungsschritte sowie die Therapie des konventionellen Chondrosarkoms vor dem Hintergrund tumororthopadisch etablierter Behandlungsstandards diskutiert.

Mesenchymal tumors, especially high-grade sarcomas, frequently harbor chaotic genotypes. Few tumors arise in association with genetic tumor predisposition syndromes with germline mutations in tumor suppressor genes. An increasing number of soft-tissue and bone tumors are characterized by recurrent genomic alterations, which can be utilized for diagnostic purposes. These include translocations and amplifications and less frequently deletions. These alterations can be detected by fluorescence in situ hybridization among other techniques. The rising number of whole genome sequencing of soft-tissue and bone tumors leads to an improved understanding of tumor genetics. On this basis, fluorescence in situ hybridization has gained relevance as a diagnostic tool. This review covers relevant genetic alterations in lipomatous tumors, soft-tissue tumors with spindle-cell and epithelioid morphology, vascular tumors, small-blue-round-cell tumors, and bone tumors that are detectable by fluorescence in situ hybridization.

Our purpose was to evaluate and compare the clinical utility of simultaneously obtained quantitative

Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.

Secondary Angiosarcoma (Stewart-Treves Syndrome) is a rare malignant cutaneous lesion, which arises in chronic lymphedema of the extremity, often observed after breast cancer treatment. We reviewed the history and the oncological outcome of two patients with this disease. Multimodal therapy including hyperthermic isolated limb perfusion with TNF-alpha and Melphalan, combined with radical resection of the affected skin and subcutaneous tissue including the fascia, with large safety margins may probably lead to better survival. © 2019 Wiley Periodicals, Inc.

Murine models of myeloid neoplasia show how leukemia infiltration alters the hematopoietic stem cell (HSC) niche to reinforce malignancy at the expense of healthy hematopoiesis. However, little is known about the bone marrow architecture in humans and its impact on clinical outcome. Here, we dissect the bone marrow niche in patients with acute myeloid leukemia (AML) at first diagnosis. We combined immunohistochemical stainings with global gene expression analyses from these AML patients and correlated them with clinical features. Mesenchymal stem and progenitor cells (MSPCs) lost quiescence and significantly expanded in the bone marrow of AML patients. Strikingly, their HSC- and niche-regulating capacities were impaired with significant inhibition of osteogenesis and bone formation in a cell contact–dependent manner through inhibition of cytoplasmic β-catenin. Assessment of bone metabolism by quantifying peripheral blood osteocalcin levels revealed 30% lower expression in AML patients at first diagnosis than in non-leukemic donors. Furthermore, patients with osteocalcin levels ≤11 ng/mL showed inferior overall survival with a 1-year survival rate of 38.7% whereas patients with higher osteocalcin levels reached a survival rate of 66.8%. These novel insights into the human AML bone marrow microenvironment help translate findings from preclinical models and detect new targets which might pave the way for niche-targeted therapies in AML patients.

Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSC) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche (BMN). To model the BMN of pediatric patients with AMKL in mice, we first established MSCs from pediatric patients with AMKL (n = 5) and ML-DS (n = 9). Healthy donor control MSCs (n = 6) were generated from unaffected children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential and enrichment of proliferation-associated genes. Importantly, TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN subcutaneously in immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice, using a mixture of MSCs, human umbilical vein endothelial cell, and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this BMN after 8 weeks induced fibrosis grade I/II in a dose-dependent fashion over a time period of 4 weeks. Thus, our study developed a humanized mouse model that will be instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL blasts in future. Implications: TGFB1 supports fibrosis induction in a pediatric AMKL model generated with patient-derived MSCs. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg.

18F-FDG PET/MR versus MR Alone in Whole-Body Primary Staging and Restaging of Patients with Rectal Cancer: What Is the Benefit of PET? by Yan Li 1,* [OrcID] , Laura Isabel Mueller 1 [OrcID] , Jan Peter Neuhaus 2, Stefanie Bertram 3, Benedikt Michael Schaarschmidt 1, Aydin Demircioglu 1, Johannes Maximilian Ludwig 1, Julian Kirchner 4, Christoph Rischpler 5 [OrcID] , Ken Herrmann 5 [OrcID] , Onofrio Antonio Catalano 6 [OrcID] and Lale Umutlu 1 1 Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany 2 Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany 3 Institute of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany 4 Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, 40225 Dusseldorf, Germany 5 Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany 6 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA 02114, USA * Author to whom correspondence should be addressed. J. Clin. Med. 2020, 9(10), 3163; https://doi.org/10.3390/jcm9103163 Received: 22 August 2020 / Revised: 24 September 2020 / Accepted: 28 September 2020 / Published: 29 September 2020 (This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers) Download PDF Browse Figures Abstract Background: To investigate and compare the diagnostic performance of 18F-Fluorodeoxyglucose (18F-FDG) PET/MR and MR alone in whole-body primary staging and restaging of patients with rectal cancer. Methods: A retrospective analysis was performed to evaluate diagnostic accuracies of combined reading of PET/MR and MR alone in T, N and M staging against the reference standard. Inter-observer agreement regarding TNM staging was calculated separately for PET/MR and MR alone. Results: A total of 39 studies of 34 patients could be evaluated. Diagnostic accuracies of PET/MR and MR alone were the same in locoregional T staging. For predicting N+ stage, the specificity of combined reading of PET and MR (0.917 and 0.833 for reader 1 and 2, respectively) was slightly higher than MR alone (0.833 and 0.75) without significantly increasing the overall accuracy (0.783 vs. 0.783 and 0.783 vs. 0.739). For detecting distant metastasis, the sensitivities of PET/MR and MR alone were shown equal (1.0 vs. 1.0 and 0.938 vs. 0.938), while the specificity of PET/MR was marginally lower (0.87 vs. 0.913 and 0.826 vs. 0.87). The inter-observer agreements were good to excellent in M (κ = 0.64 and 0.637 for PET/MR and MR alone, p < 0.001) and N staging (0.819 and 0.738, p < 0.001).Conclusion: PET did not yield a significant improvement in diagnostic accuracy of PET/MR in TNM staging of rectal cancer, since MR alone facilitated accurate classification of disease stage with good to excellent inter-observer agreement. OA Förderung 2020

Background: An increasing knowledge about the bone marrow niche demonstrates the high complexity of leukemogenesis. Mesenchymal stromal cells (MSC) are important members of the bone marrow niche and source of fibrosis. Further, the microenvironment seems to be regulated by megakaryocytes and platelets via cytokines, such as transforming growth factor beta 1 (TGFB1). Despite extensive research, the pathogenesis of the bone marrow niche in childhood leukemia and the therapeutic potential is still unclear. We focus on acute childhood megakaryoblastic leukemia (AMKL) as a disease model and include patients with (ML-DS) and without Down syndrome. Based on similar clinical progressions - myelofibrosis occurs as a side-effect of both leukemia subtypes; these two diseases suit to characterize the leukemic bone marrow niche. Methods: We performed a comprehensive characterisation of MSC from ML-DS (n=9), AMKL patients (n=5) and healthy donors (HD; n=6) via e.g. differentiation assays (adipogenic, osteogenic), gene expression profiles and western blot analysis. In addition, we established an in vivo model with humanized ossicles, representing a human bone marrow microenvironment (as described by Chen et al. 2012; Reinisch et al. 2015): We injected MSC mixed with pooled human umbilical vein endothelial cells (HUVEC) and Matrigel subcutaneously into NOD scid gamma (NSG) mice. After 8 weeks, the engrafted ossicles were injected with megakaryoblastic cells (CMK cell line); injected ossicles (n=16); uninjected ossicle (n=27), MSC from ML-DS (n=19 ossicles), AML M1 (n=15 ossicles) and HD (n=9 ossicles). After 4 more weeks, histopathology evaluation of fibrosis in the ossicles was performed in accordance with the European Consensus on Grading Bone Marrow criteria from an independent pathologist. Results: The detailed characterisation of MSC with ML-DS and AMKL demonstrated a high similarity to MSC of HD: morphology, osteogenic differentiation potential, colony forming unit-fibroblast assay, proliferation and gene expression profiles. However, two differences emerged in our analysis: MSC showed a decreased adipogenic differentiation potential in ML-DS and AMKL compared to HD (ML-DS vs. HD=0.26-fold, p TGFB1 - known to be secreted by leukemic megakaryoblasts - induced a fibrotic state in MSC regardless of their origin indicated by decreased adipogenic differentiation potential (treated vs. untreated: ML-DS 0.22-fold; AMKL 0.08-fold; HD 0.06-fold, p The humanized bone marrow niche in our mouse model demonstrated a development of myelofibrosis after injection of the megakaryoblastic cell line (CMK): Grade 1 or 2 in 81% of the ossicles. The induction was independent of the MSC entity (HD/ML-DS). Of note, a monocytic subpopulation, which engrafted unexpectedly in ossicle from HD-MSC (n=3 ossicle), did not induce fibrotic fibers. Conclusion: Our data impressively illustrate the mutual influence between MSC and leukemic blasts that leads to a fibrotic microenvironment. This correlation has been observed in vitro but also in a unique mouse model. The interaction of MSC and leukemic blasts seems to be the key factor for the development of the leukemic niche in AMKL mediated inter alia by the TGFB pathway. However, we could identify several disease specific characteristics of MSC. Our model offers a unique opportunity to fundamentally examine of the leukemic niche in order to subsequently evaluate the potential therapeutic use in further studies. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; CSL Behring: Research Funding; Jazz: Other: Participation in Advisory Boards, Research Funding; Roche: Research Funding.

Aim: To assess the diagnostic accuracy of liver maximum capacity (LiMAx®) test compared to transient elastography (TE) and serum biomarkers for the noninvasive detection of different stages of liver fibrosis and cirrhosis. Patients and Methods: We retrospectively correlated LiMAx®, TE, aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) score with histological specimens in 102 patients with chronic liver disease (CLD) who underwent liver biopsy (either percutaneously or via mini-laparoscopy) at the University Clinic of Essen between 10/2016 and 12/2017. Results: Median LiMAx® values showed a tendency to decrease in accordance with increasing histological degree of fibrosis based on the Desmet scoring system (F0: 446.5 [381.0–592.5] µg/h/kg, F1: 405.0 [343.0–547.0] µg/h/kg, F2: 337.0 [250.0–394.0] µg/h/kg, F3: 281.0 [262.0–364.0] µg/h/kg, and F4: 181.5 [130.0–256.5] µg/h/kg. Furthermore, ­LiMAx® was superior to TE, FIB-4, AAR, and APRI in detecting different stages of fibrosis, while Spearman’s rank correlation test showed a statistically significant association of –0.68, 0.62, 0.61, 0.46, and 0.42, respectively. However, the combination of TE and LiMAx® had the highest diagnostic accuracy in detecting liver cirrhosis (sensitivity 88.9%, specificity 84.6%, Youden index 0.735). Conclusion: Enzymatic liver function measured by LiMAx® showed strong correlation with histology in patients with CLD irrespective of its underlying etiology and was superior to TE and serum biomarkers, possibly making it useful as a novel and noninvasive tool for the determination of hepatic disease severity.

The exact discrimination of lesions with true hepatocellular differentiation from secondary tumours and neoplasms with hepatocellular histomorphology like hepatoid adenocarcinomas (HAC) is crucial. Therefore, we aimed to identify ancillary protein biomarkers by using complementary proteomic techniques (2D-DIGE, label-free MS). The identified candidates were immunohistochemically validated in 14 paired samples of hepatocellular carcinoma (HCC) and non-tumourous liver tissue (NT). The candidates and HepPar1/Arginase1 were afterwards tested for consistency in a large cohort of hepatocellular lesions and NT (n = 290), non-hepatocellular malignancies (n = 383) and HAC (n = 13). Eight non-redundant, differentially expressed proteins were suitable for further immunohistochemical validation and four (ABAT, BHMT, FABP1, HAOX1) for further evaluation. Sensitivity and specificity rates for HCC/HAC were as follows: HepPar1 80.2%, 94.3% / 80.2%, 46.2%; Arginase1 82%, 99.4% / 82%, 69.2%; BHMT 61.4%, 93.8% / 61.4%, 100%; ABAT 84.4%, 33.7% / 84.4%, 30.8%; FABP1 87.2%, 95% / 87.2%, 69.2%; HAOX1 95.5%, 36.3% / 95.5%, 46.2%. The best 2×/3× biomarker panels for the diagnosis of HCC consisted of Arginase1/HAOX1 and BHMT/Arginase1/HAOX1 and for HAC consisted of Arginase1/FABP1 and BHMT/Arginase1/FABP1. In summary, we successfully identified, validated and benchmarked protein biomarker candidates of hepatocellular differentiation. BHMT in particular exhibited superior diagnostic characteristics in hepatocellular lesions and specifically in HAC. BHMT is therefore a promising (panel based) biomarker candidate in the differential diagnostic process of lesions with hepatocellular aspect.

Arteriosklerose fuhrt durch langsame Entwicklung von Stenosen oder durch plotzliche Okklusion des Gefaslumens durch einen Thrombus zu klinischer Symptomatik. Diese entsteht durch verminderte Perfusion im Myokard (koronare Herzerkrankung, KHK), im zentralen Nervensystem (Apoplexie) oder in den Extremitaten (periphere arterielle Verschlusskrankheit, pAVK). Die KHK stellt die haufigste Manifestation arteriosklerotischer Gefaslasionen dar und umfasst sowohl die stabile Angina pectoris wie auch die akuten Koronarsyndrome. Arteriosklerose ist eine im Wesentlichen durch Lipoproteinakkumulation in der Arterienwand ausgeloste Erkrankung, welche mit der Formation von Plaques an bestimmten Stellen des arteriellen Systems einhergeht. Die entscheidenden Pathomechanismen umfassen Entzundung, Nekrose, Fibrose und Kalzifizierung. Nach jahrzehntelangem indolenten Verlauf kann es plotzlich zu lebensbedrohlichen akuten Koronarsyndromen kommen. In den allermeisten Fallen ist die zugrunde liegende Lasion eine rupturierte Plaque, deren nekrotisches Material ihres „Kerns“ eine hohe Thrombogenitat aufweist. Die arteriosklerotischen Lasionen, die zu einer plotzlichen Thrombosierung mit kompletter oder inkompletter Okklusion fuhren konnen, sind das sog. „thin-cap fibroatheroma“, die Plaque-Erosion und das sog. kalzifizierte Knotchen bei stark verkalkten Arterien alterer Individuen, wobei der jeweilige Pathomechanismus bis dato nicht vollstandig geklart ist. Die vorliegende Ubersichtsarbeit soll einen Uberblick uber die Entstehung der wichtigsten arteriosklerotischen Veranderungen und deren Progression zur Plaque-Ruptur bzw. Thrombusformation geben.

e23517Background: Clinical staging systems are an important daily tool for risk assessment and patient counseling. For gastrointestinal stromal tumors (GIST) the AFIP classification is most widely ...

The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis.

Discriminating intrahepatic cholangiocarcinoma (ICC) from hepatic metastases of pancreatic ductal adenocarcinoma (mPDAC) can be challenging. While pathologists might depend on clinical information regarding a primary tumor, their diagnosis will lead the patient either to potentially curative surgery (for ICC) or to palliation (for mPDAC). Beyond the validation of recently published potential biomarkers for PDAC (primary or metastatic) in a large cohort, we assessed diagnostic performance of the most promising candidates in the challenging task of discriminating metastatic PDAC (mPDAC) from ICC. In a training set of 87 ICC and 88 pPDAC, our previously identified biomarkers Annexin A1 (ANXA1), ANXA10, and ANXA13 were tested and compared with 11 published biomarkers or panels (MUCIN 1, Agrin, S100P, MUC5 AC, Laminin, VHL, CK 17, N-Cadherin, ELAC2, PODXL and HSPG2). Biomarkers with best results were further tested in an independent series of biopsies of 27 ICC and 36 mPDAC. Highest AUC values (between 0.72 and 0.84) for the discrimination between ICC and pPDAC were found in the training set for Annexin A1, Annexin A10, MUC5 AC, CK17, and N-Cadherin. These markers were further tested on an independent series of liver biopsies containing ICC or mPDAC. Diagnostic characteristics were evaluated for individual markers as well as for 3× panels. ANXA 10 showed the highest diagnostic potential of all single markers, correctly classifying 75% of mPDAC and 85% of ICC. Our results suggest that ANXA10 may be useful to differentiate between ICC and mPDAC, when only a tissue specimen is available.

Donor livers marginally acceptable or acceptable according to extended criteria are more frequently transplanted due to the growing discrepancy between demand and availability of donor organs. One type of marginally acceptable graft is a steatotic donor liver, because it is more sensitive to ischemia-reperfusion injury. Thus, quantitative assessment of steatosis is crucial prior to liver transplantation. Extent of steatosis of 49 pre-reperfusion liver biopsies from patients who received orthotopic liver transplantation was assessed by three techniques: semi-quantitative histological evaluation, computerized histomorphometry, and NMR-based estimation of fat content. The findings were correlated to clinical data and to histological examination of corresponding post-reperfusion biopsies for quantification of ischemia-reperfusion injury. We found that values obtained through all three assessment methods were positively correlated. None of the values obtained by the three applied methods correlated with clinical outcome or extent of ischemia-reperfusion injury. Quantitative evaluation of steatosis by NMR yields results comparable to histological and morphometrical assessment. This technique is rapid (

Hepatocellular Carcinoma (HCC) is a lethal cancer worldwide. Recently, the hippo signaling pathway has been implicated in tumorigenesis of HCC and other malignant tumors. Aim of the study was therefore to evaluate the hippo signaling pathway activity and its clinico-pathological associations and crosstalk in different tumor forming hepatocellular lesions (HCC, hepatocellular adenoma (HCA), focal nodular hyperplasia (FNH) and cirrhosis). A tissue micro array (TMA) from paired human tumorous and non-tumorous (NT) tissue samples of HCC (n = 92), HCA (n = 25), FNH (n = 28) and cirrhosis (n = 28; no NT) was constructed. The hippo-pathway related proteins of MST1/2, (nuclear(n)/cytoplasmic(c)) YAP and (phospho(p)) TAZ and interactors as Glypican3, RASSF1a, pAKT, pERK and pP70S6K were evaluated by immunohistochemistry (IHC). Proliferation was assessed by Ki67-IHC and apoptosis by TUNEL-technique. MST1/2- and nYAP-immunoreactivity was associated with lymph node status (p = 0.048, p = 0.001), higher grading (p = 0.012, p = 0.24) and unfavorable relapse-free survival (p = 0.004, p = 0.003). MST1/2, c/nYAP and pTAZ were significantly different between HCC/NT (p

Cholangiocellular carcinoma (CCC) and pancreatic ductal adenocarcinoma (PDAC) are two highly aggressive cancer types that arise from epithelial cells of the pancreatobiliary system. Owing to their histological and morphological similarity, differential diagnosis between CCC and metastasis of PDAC located in the liver frequently proves an unsolvable issue for pathologists. The detection of biomarkers with high specificity and sensitivity for the differentiation of these tumor types would therefore be a valuable tool. Here, we address this problem by comparing microdissected CCC and PDAC tumor cells from nine and eleven cancer patients, respectively, in a label-free proteomics approach. The novel biomarker candidates were subsequently verified by immunohistochemical staining of 73 CCC, 78 primary, and 18 metastatic PDAC tissue sections. In the proteome analysis, we found 180 proteins with a significantly differential expression between CCC and PDAC cells (p value < 0.05, absolute fold change > 2). Nine candidate proteins were chosen for an immunohistochemical verification out of which three showed very promising results. These were the annexins ANXA1, ANXA10, and ANXA13. For the correct classification of PDAC, ANXA1 showed a sensitivity of 84% and a specificity of 85% and ANXA10 a sensitivity of 90% at a specificity of 66%. ANXA13 was higher abundant in CCC. It presented a sensitivity of 84% at a specificity of 55%. In metastatic PDAC tissue ANXA1 and ANXA10 showed similar staining behavior as in the primary PDAC tumors (13/18 and 17/18 positive, respectively). ANXA13, however, presented positive staining in eight out of eighteen secondary PDAC tumors and was therefore not suitable for the differentiation of these from CCC. We conclude that ANXA1 and ANXA10 are promising biomarker candidates with high diagnostic values for the differential diagnosis of intrahepatic CCC and metastatic liver tumors deriving from PDAC.

BackgroundFor the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours.MethodsIn order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16).ResultsConcerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, pConclusionmiRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential.

Cirrhotic cardiomyopathy may appear following liver transplantation. Brain-natriuretic peptide (BNP) values exceeding 391 pg/ml or 567 pg/ml may partially reflect ventricular stress because of cardiac dysfunction or indicate cirrhotic cardiomyopathy, respectively. The aim of the study was to assess cardiac dysfunction in liver transplant patients and its correlation with BNP as a biomarker. From 1/2008 to 7/2009, 157 adult liver transplant recipients with proven cirrhosis were recruited for the study. BNP and liver enzymes were recorded upon admission, on the first postoperative day (POD) and 1 week after transplantation. Patients with ischemic heart attacks were excluded from the study. We identified two groups of patients. Group 1 was characterized by a BNP 391 pg/ml. Group 2 had a significantly higher model of end-stage liver disease score than Group 1 (median 30, range 10-40 versus median 22, range 10-40, respectively; P = 0.003), required significantly more dialysis treatments and had a significantly higher mortality rate. Postoperative echocardiography in patients with a BNP >391 pg/ml indicated diastolic dysfunction in all of the patients and systolic dysfunction in 10 of the patients. Increased serum-BNP was associated with an overall higher mortality rate.

This paper discusses a chemistry lesson plan on potato crisps for 10th grade (age range 15-16) chemistry classes in Germany. The lesson plan focuses on the discussion about low-fat and low-carb diets as they are presented in everyday media such as TV or newspapers in Germany. The discussion follows a socio-critical and problem-oriented approach to chemistry teaching, and is used to promote learning about carbohydrates and fats in chemistry. The goal is to foster the students' competency in reflecting upon the use of science-related information in their daily lives. The lesson plan was developed within a Participatory Action Research project. From the accompanying evaluation based on teachers' feedback, written student questionnaires, and a study based on students' group discussions, the lesson plan was found to be highly workable, motivating, and an initiator of intense discussions among pupils. These group discussions indicated that the socio-critical teaching approach has the potential to promote a more balanced and well-thought out view among some students when dealing with the aspects of healthy nutrition and various diet reports in the media. This case study indicates that the overall approach seems promising for promoting higher-order cognitive skills in the areas of reflection, and evaluating topics within the framework of science, technology and society.

AimsThe distinction between intrahepatic cholangiocarcinoma (ICC) and benign bile duct lesions can be challenging. Using our previously identified potential biomarkers for ICC, we examined whether these are useful for the differential diagnosis of ICC, bile duct adenoma and reactive bile duct proliferations in an immunohistochemical approach and identified a diagnostic marker panel including known biomarkers.MethodsSubjects included samples from 77 patients with ICC, 33 patients with bile duct adenoma and 47 patients with ductular reactions in liver cirrhosis. Our previously identified biomarkers (stress-induced phosphoprotein 1 (STIP1), SerpinH1, 14-3-3Sigma) were tested immunohistochemically following comparison with candidates from the literature (cluster of differentiation 56, heat shock protein (HSP)27, HSP70, B-cell-lymphoma2, p53, ki67).ResultsThe expression of SerpinH1 and 14-3-3Sigma was significantly higher in ICC than in bile duct adenomas and ductular reactions (pConclusionsThis suggests that 14-3-3Sigma and SerpinH1 may be useful in the differential diagnosis of malignant, benign and reactive bile duct lesions in addition to ki67 where a cut-off of >5% might be used for the distinction of malignant and non-malignant lesions.

Background Tumor biopsy is not essential for the diagnosis of hepatocellular carcinoma (HCC); however, grading remains important for the prognosis. Purpose To investigate whether combined Gd-EOB-DTPA and gadobutrol liver magnetic resonance imaging (MRI) can predict HCC grading. Material and Methods Thirty patients (66.6 ± 7.3 years) with histologically confirmed HCC (grade 1, n = 5; grade 1–2, n = 6; grade 2, n = 13; grade 2–3, n = 2; grade 3, n = 4) underwent two liver MRIs, one with gadobutrol and one with Gd-EOB-DTPA, on consecutive days. Blinded to grading, two radiologists reviewed the gadobutrol and Gd-EOB-DTPA images in consensus with respect to: (i) HCC hyper-/iso-/hypointensity in the arterial, portal-venous/delayed, and Gd-EOB-DTPA hepatocellular phase; and (ii) morphologic tumor features (encapsulated growth, vessel invasion, heterogeneity, liver capsule infiltration, satellite metastases). Results A significant correlation with grading was not found for either the combined dynamic information of all gadobutrol phases (r = −0.187, P = 0.331) or all the Gd-EOB-DTPA phases (r = 0.052, P = 0.802). No correlation with grading was found for a combination of arterial and hepatocellular phase in Gd-EOB-DTPA MRI (r = 0.209, P = 0.305), a combination of both arterial phases (gadobutrol and Gd-EOB-DTPA) with the Gd-EOB-DTPA hepatocellular phase (r = 0.240, P = 0.248), or a combination of all available gadobutrol and Gd-EOB-DTPA phases (r = 0.086, P = 0.691). For all gadobutrol information (dynamic phases and morphology; r = 0.049, P = 0.801) and for all Gd-EOB-DTPA information (r = 0.040, P = 0.845), no correlation with grading was found. Hepatocellular Gd-EOB-DTPA phase iso-/hyperintensity never occurred in grade 3 HCCs. Conclusion Histological HCC grading cannot be predicted by combined Gd-EOB-DTPA/gadobutrol MRI. However, Gd-EOB-DTPA hepatocellular phase iso-/hyperintensity was never detected in grade 3 HCCs.

Hepatocellular carcinoma (HCC) is a major lethal cancer worldwide. Despite sophisticated diagnostic algorithms, the differential diagnosis of small liver nodules still is difficult. While imaging techniques have advanced, adjuvant protein-biomarkers as glypican3 (GPC3), glutamine-synthetase (GS) and heat-shock protein 70 (HSP70) have enhanced diagnostic accuracy. The aim was to further detect useful protein-biomarkers of HCC with a structured systematic approach using differential proteome techniques, bring the results to practical application and compare the diagnostic accuracy of the candidates with the established biomarkers. After label-free and gel-based proteomics (n=18 HCC/corresponding non-tumorous liver tissue (NTLT)) biomarker candidates were tested for diagnostic accuracy in immunohistochemical analyses (n=14 HCC/NTLT). Suitable candidates were further tested for consistency in comparison to known protein-biomarkers in HCC (n=78), hepatocellular adenoma (n=25; HCA), focal nodular hyperplasia (n=28; FNH) and cirrhosis (n=28). Of all protein-biomarkers, 14-3-3Sigma (14-3-3S) exhibited the most pronounced up-regulation (58.8×) in proteomics and superior diagnostic accuracy (73.0%) in the differentiation of HCC from non-tumorous hepatocytes also compared to established biomarkers as GPC3 (64.7%) and GS (45.4%). 14-3-3S was part of the best diagnostic three-biomarker panel (GPC3, HSP70, 14-3-3S) for the differentiation of HCC and HCA which is of most important significance. Exclusion of GS and inclusion of 14-3-3S in the panel (>1 marker positive) resulted in a profound increase in specificity (+44.0%) and accuracy (+11.0%) while sensitivity remained stable (96.0%). 14-3-3S is an interesting protein biomarker with the potential to further improve the accuracy of differential diagnostic process of hepatocellular tumors. This article is part of a Special Issue entitled: Medical Proteomics.

Cirrhotic cardiomyopathy may appear following liver transplantation. Brain-natriuretic peptide (BNP) values exceeding 391 pg/ml or 567 pg/ml may partially reflect ventricular stress because of cardiac dysfunction or indicate cirrhotic cardiomyopathy, respectively. The aim of the study was to assess cardiac dysfunction in liver transplant patients and its correlation with BNP as a biomarker. From 1/2008 to 7/2009, 157 adult liver transplant recipients with proven cirrhosis were recruited for the study. BNP and liver enzymes were recorded upon admission, on the first postoperative day (POD) and 1 week after transplantation. Patients with ischemic heart attacks were excluded from the study. We identified two groups of patients. Group 1 was characterized by a BNP391 pg/ml and Group 2 by a BNP391 pg/ml. Group 2 had a significantly higher model of end-stage liver disease score than Group 1 (median 30, range 10-40 versus median 22, range 10-40, respectively; P = 0.003), required significantly more dialysis treatments and had a significantly higher mortality rate. Postoperative echocardiography in patients with a BNP391 pg/ml indicated diastolic dysfunction in all of the patients and systolic dysfunction in 10 of the patients. Increased serum-BNP was associated with an overall higher mortality rate.

Background Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation. Autophagy is involved in both tumorigenesis and tumour suppression. Here we investigated the potential prognostic value of the autophagy-related proteins Beclin-1, p62, LC3 and uncoordinated (UNC) 51-like kinase 1 (ULK1) in a cohort of colorectal cancer (CRC) specimens. Methods In this study, we analysed the immunoexpression of the autophagy-related proteins p62, LC3, Beclin-1 and ULK1 in 127 CRC patients with known KRAS mutational status and detailed clinical follow-up. Results Survival analysis of p62 staining showed a significant correlation of cytoplasmic (not nuclear) p62 expression with a favourable tumour-specific overall survival (OS). The prognostic power of cytoplasmic p62 was found in the KRAS-mutated subgroup but was lost in the KRAS wildtype subgroup. Survival analysis of Beclin-1 staining did not show an association with OS in the complete cohort. LC3 overexpression demonstrated a slight, though not significant, association with decreased OS. Upon stratifying cases by KRAS mutational status, nuclear (not cytoplasmic) Beclin-1 staining was associated with a significantly decreased OS in the KRAS-mutated subgroup but not in the KRAS wildtype CRCs. In addition, LC3 overexpression was significantly associated with decreased OS in the KRAS-mutated CRC subgroup. ULK1 expression was not correlated to survival. Conclusions Immunohistochemical analyses of LC3, p62 and Beclin-1 may constitute promising novel prognostic markers in CRC, especially in KRAS-mutated CRCs. This strategy might help in identifying high-risk patients who would benefit from autophagy-related anticancer drugs. Electronic supplementary material The online version of this article (doi:10.1186/s12957-016-0946-x) contains supplementary material, which is available to authorized users.