Biostructural, biochemical and biophysical studies of mutant IDH1.

We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.

Fracture sonography-review of literature and current recommendations.

Over a span of more than two years, a collaborative expert group consisting of 9 professional societies has meticulously crafted the S2e guideline on fracture sonography. This publication encapsulates the essential insights pertaining to specific indications. A thorough and systematic literature search, covering the period from 2000 to March 2021, was conducted across PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews, complemented by an evaluation of bibliographies. Inclusion criteria encompassed randomized controlled clinical trials, observational clinical trials, meta-analyses, and systematic reviews, while guidelines, conferences, reviews, case reports, and expert opinions were excluded. The SIGN grading system (1999-2012) was applied to assess evidence, and resultant SIGN tables were presented to the expert group. Specific recommendations for the application of fracture sonography were then derived through unanimous consensus after detailed discussions. Out of the initial pool of 520 literature sources, a meticulous screening and content assessment process yielded 182 sources (146 clinical studies and 36 meta-analyses and systematic reviews) for evaluation. The comprehensive analysis identified twenty-one indications that substantiate the judicious use of fracture sonography. Ultrasound emerges as a pragmatic and user-friendly diagnostic method, showcasing feasibility across a diverse range of indications.

Placental growth factor promotes neural invasion and predicts disease prognosis in resectable pancreatic cancer.

BACKGROUND: Surgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of curative-intent tumor resection. Neural invasion (NI), particularly the spread of tumor cells along nerves into extratumoral regions of the pancreas, constitutes a well-recognized risk factor for recurrence. Hence, monitoring and therapeutic targeting of NI offer the potential to stratify recurrence risk and improve recurrence-free survival. Based on the evolutionary conserved dual function of axon and vessel guidance molecules, we hypothesize that the proangiogenic vessel guidance factor placental growth factor (PlGF) fosters NI. To test this hypothesis, we correlated PlGF with NI in PDAC patient samples and functionally assessed its role for the interaction of tumor cells with nerves. METHODS: Serum levels of PlGF and its soluble receptor sFlt1, and expression of PlGF mRNA transcripts in tumor tissues were determined by ELISA or qPCR in a retrospective discovery and a prospective validation cohort. Free circulating PlGF was calculated from the ratio PlGF/sFlt1. Incidence and extent of NI were quantified based on histomorphometric measurements and separately assessed for intratumoral and extratumoral nerves. PlGF function on reciprocal chemoattraction and directed neurite outgrowth was evaluated in co-cultures of PDAC cells with primary dorsal-root-ganglia neurons or Schwann cells using blocking anti-PlGF antibodies. RESULTS: Elevated circulating levels of free PlGF correlated with NI and shorter overall survival in patients with PDAC qualifying for curative-intent surgery. Furthermore, high tissue PlGF mRNA transcript levels in patients undergoing curative-intent surgery correlated with a higher incidence and greater extent of NI spreading to tumor-distant extratumoral nerves. In turn, more abundant extratumoral NI predicted shorter disease-free and overall survival. Experimentally, PlGF facilitated directional and dynamic changes in neurite outgrowth of primary dorsal-root-ganglia neurons upon exposure to PDAC derived guidance and growth factors and supported mutual chemoattraction of tumor cells with neurons and Schwann cells. CONCLUSION: Our translational results highlight PlGF as an axon guidance factor, which fosters neurite outgrowth and attracts tumor cells towards nerves. Hence, PlGF represents a promising circulating biomarker of NI and potential therapeutic target to improve the clinical outcome for patients with resectable PDAC.

Neuroborreliosis Presenting as Encephalitis: A Case Report.

Infection with Borrelia burgdorferi spirochetes can cause Lyme neuroborreliosis (LNB). Neuroborreliosis presenting as encephalitis is a rare manifestation. We present a 72-year-old male patient hospitalized after three days of confusion and altered mental status. Initial computerized tomography (CT) and magnetic resonance imaging (MRI) of the brain were both unremarkable. Lumbar puncture showed an elevated number of white blood cells, elevated protein, and normal glucose levels in the cerebrospinal fluid (CSF), normal electroencephalogram (EEG), and negative tests for common microorganisms in the CSF. The patient received treatment with acyclovir and ceftriaxone. Lumbar puncture repeated on day 16 showed a decreasing number of white blood cells. A repeated MRI showed white matter edema, interpreted as encephalitis, while a repeated EEG showed signs of a non-specific cerebral lesion. The first lumbar puncture revealed intrathecal immunoglobulin M (IgM) antibodies against Borrelia and was positive for Borrelia DNA using real-time PCR, and the following lumbar puncture showed both IgM and IgG intrathecal antibody production. These results thus confirmed the diagnosis of Lyme Borrelia encephalitis. The patient improved clinically and was discharged after treatment with ceftriaxone for three weeks. Encephalitis due to LNB should be considered as a differential diagnosis in cases with unexplained neurological symptoms. Changes in MRI and/or EEG might occur late in the course of the disease, underlining the need for repeated tests in unresolved cases.

The Modified Ultrasound-Assisted Method: A Study of the Correlation between Magnetic Resonance Imaging and the Ultrasound-Assisted Evaluation of the Critical Shoulder Angle.

BACKGROUND: An increased or decreased critical shoulder angle (CSA) is a known risk factor for osteoarthritis, lesions, and re-ruptures in the rotator cuff. A CSA greater than 35° correlates with degenerative rotator cuff tears, while a CSA of less than 30° correlates with osteoarthritis in the glenohumeral joint. The diagnostic gold standard for its determination is X-ray or MRI. OBJECTIVES: The primary objective of this research was to assess the viability of utilizing sonography imaging as a diagnostic tool to determine the modified critical shoulder angle (mCSA). This study aimed to investigate the feasibility and effectiveness of sonographic techniques in accurately diagnosing CSA compared to MRI. STUDY DESIGN AND METHODS: A cohort study was carried out (level of evidence 3). The CSA (MRI) and the mCSA (ultrasound) were assessed retrospectively by two independent board-certified investigators in 109 patients with shoulder pain by MRI and musculoskeletal sonography. The CSA in the MRI dataset was determined using routine protocols and then compared to the values assessed using the modified sonography-assisted method (mCSA). Both results were analyzed with linear regression to determine a possible correlation. All investigations were performed by a DEGUM (German Society for Medical Ultrasound)-certified specialist in musculoskeletal sonography. RESULTS: A total of 112 patients were included in this study, namely 40 female patients and 72 male patients with a mean age of 54.7 years at the time of the investigation. The mean CSA in MRI was 31.5° ± 3.899, and the mCSA in sonography was 30.1° ± 4.753. The inter- and intraobserver reliability for the CSA was factual with values of 0.993 and 0.967. The inter- and intraobserver reliability for mCSA was factual as well, with values of 0.989 and 0.948. The ANOVA analysis did not reveal a significant difference between the CSA and the mCSA values, and linear regression determined the R2 value to be 0.358 with p < 0.05. CONCLUSIONS: Diagnosing the mCSA using sonography is a safe and valid method. No statistically significant differences between the results in MRI and sonography could be seen. Although this is a retrospective, single-center study including only Caucasian mid-Europeans, and with the known limitations of ultrasound imaging, it nevertheless shows that sonography can be used as a simple, cheap, and fast technique to assess a modified CSA, which shows very good correlation with the standard CSA without losing the diagnostic quality.

Anaerobic digestion of wastewater from hydrothermal liquefaction of sewage sludge and combined wheat straw-manure.

Hydrothermal liquefaction (HTL) shows promise for converting wet biomass waste into biofuel, but the resulting high-strength process water (PW) requires treatment. This study explored enhancing energy recovery by anaerobic digestion using semi-batch reactors. Co-digesting manure with HTL-PW from wheat straw-manure co-HTL yielded methane (43-49% of the chemical oxygen demand, COD) at concentrations up to 17.8 gCOD·L-1, whereas HTL-PW from sewage sludge yielded methane (43% of the COD) up to only 12.8 gCOD·L-1 and complete inhibition occurred at 17 gCOD·L-1. Microbial community shifts confirmed inhibition of methanogenic archaea, while hydrolytic-fermentative bacteria were resilient. Differences in chemical composition, particularly higher levels of N-containing heterocyclic compounds in PW of sewage sludge, likely caused the microbial inhibition. The considerable potential of combining HTL with anaerobic digestion for enhanced energy recovery from straw-manure in an agricultural context is demonstrated, yet sewage sludge HTL-PW requires more advanced approaches to deal with methanogenesis inhibitors.

Fracture sonography - Literature review and current recommendations.

PURPOSE: Over the course of more than two years, an expert group of 9 professional societies has created the S2e guidelines for fracture sonography. This publication summarizes the key points regarding the individual indications. MATERIALS AND METHODS: A systematic literature search was performed in PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews from 2000 to March 2021 with evaluation of the literature lists. Randomized controlled clinical trials, observational clinical trials, meta-analyses, and systematic reviews were included. Guidelines, conferences, reviews, case reports, and expert opinions were excluded. Evidence was graded using the SIGN grading system 1999-2012, and the SIGN tables were then presented to the expert group. These were used to develop specific recommendations for the use of fracture sonography. All recommendations were discussed in detail and finally unanimously agreed upon. RESULTS: Of the 520 primary literature sources found, 182 sources (146 clinical studies and 36 meta-analyses and systematic reviews) were evaluated after screening and content assessment. 21 indications that allow reasonable application of fracture sonography were identified. CONCLUSION: Ultrasound is a sensible, easy-to-use diagnostic method that is feasible for a large number of indications.

Dynamics and Coordination of a P2N2 Ligand - from Twisted Conformation to Chelation.

Based on their general spacial flexibility, their Lewis and Brønsted basicity, and ability to mimic second sphere effects the 1,5-diaza-3,7-diphosphacyclooctane ligand family and their complexes have regained substantial scientific interest. It was now possible to structurally analyze a recently reported member of this family with p-tolyl and t-butyl substituents on P and N, respectively, (P2 p-tolN2 tBu). Notably, the ligand crystallizes with a 'twisted' backbone. This compound is the very first of its kind to have been unambiguously characterized with regard to its chemical and molecular structure as being in this conformation. A temperature-dependent NMR study provides insight into the molecular dynamics of two isomers in solution, which are most likely also both twisted, as judged by the observed limited reactivity. Despite the in principle unfavorable conformation of the free ligand, it was successfully chelated to tungsten and molybdenum centers in mononuclear carbonyl complexes. The ligand, a derivative thereof and four new complexes were comprehensively characterized and analyzed in comparison. This includes single crystal XRD molecular structures of P2 p-tolN2 tBu and all four complexes. P2 p-tolN2 tBu, regardless of its twisted conformation, is able to coordinate to metal centers given that enough energy (heat) for a conformational change is provided.

Gold Nanoparticles Bioproduced in Cyanobacteria in the Initial Phase Opened an Avenue for the Discovery of Corresponding Cerium Nanoparticles.

The production of isolated metallic nanoparticles with multifunctionalized properties, such as size and shape, is crucial for biomedical, photocatalytic, and energy storage or remediation applications. This study investigates the initial particle formations of gold nanoparticles (AuNPs) bioproduced in the cyanobacteria Anabaena sp. using high-resolution transmission electron microscopy images for digital image analysis. The developed method enabled the discovery of cerium nanoparticles (CeNPs), which were biosynthesized in the cyanobacteria Calothrix desertica. The particle size distributions for AuNPs and CeNPs were analyzed. After 10 h, the average equivalent circular diameter for AuNPs was 4.8 nm, while for CeNPs, it was approximately 5.2 nm after 25 h. The initial shape of AuNPs was sub-round to round, while the shape of CeNPs was more roundish due to their amorphous structure and formation restricted to heterocysts. The local PSDs indicate that the maturation of AuNPs begins in the middle of vegetative cells and near the cell membrane, compared to the other regions of the cell.

Determination of Material and Fracture Properties of a Case-Hardened Planet Gear and Its Homogenisation Method to Obtain the Damage Mechanism Caused by Fragment Ingestion.

Before a new type of engine is introduced into civil aviation, it must comply with various safety regulations. These regulations include the analysis of secondary damage caused by the re-ingestion of a tooth fragment. The purpose is to prevent crack propagation through the gear rim, which would lead to catastrophic failure. In this context, identification of the initial crack location is crucial to determine the crack propagation path. Therefore, this paper presents a technique to determine and validate a constitutive material model and fracture locus for case-hardened spur gears. As the modelling of the surface-hardened layer is computationally intensive, it is necessary to homogenise the model. This paper comprehensively reviews and discusses the associated effects and errors. To determine the plastic behaviour of the case-hardened external gear (30CrNiMo8) and the nitrided internal gear (35CrAlNi7-10), the widely acknowledged Johnson-Cook material model is implemented using compression and Vickers indenter tests to define the necessary parameters. The fracture locus implementation is also based on the Johnson-Cook method and an axial shift of the fracture locus based on the hardness profile of the spur gears is determined by quasi-static pulsator tests. For validation, a project-specific gearbox test rig is used, enabling consistent ingestion of defined fragments. In addition, to check the likelihood of a tooth flank crack and to validate the results, a simplified ingestion experiment is performed.

Earlier consolidation and improved knee function of medial open wedge high tibial osteotomy with autologous bone graft.

PURPOSE: Medial knee osteoarthritis can be treated with medial open wedge high tibial osteotomy (OWHTO). We sought to investigate osseous consolidation of the osteotomy with and without autologous bone grafts (ABG) to detect possible benefits of ABG in osseous healing and functional outcome. METHODS: In this prospective study, patients without graft transplantation were compared to those receiving ABG after medial OWHTO. They were followed up 6 weeks, 12 weeks, 6 months and 12 months postoperatively. Radiographic progress of consolidation, clinical scores, contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were assessed at each appointment. RESULTS: A total of 35 patients were enrolled, 20 without and 15 with graft transplantation. Radiologic evaluation showed a significantly earlier consolidation of the osteotomy gaps (p = 0.012) in patients with ABG, resulting in a significantly higher rate of consolidation 12 months after surgery (60% without bone graft vs. 100% with bone graft, p = 0.006). At 6 weeks as well as 6-month follow-up, a tendency of earlier consolidation with ABG was apparent, but not statistically significant (6 weeks: 50% vs. 80%, p = 0.089; 6 months: 30% vs. 60%, p = 0.097). CEUS and DCE-MRI showed physiological perfusion of the osteotomy gaps in both groups. A tendency to better function and less pain in patients with ABG was recognizable. CONCLUSION: In our study, autologous bone grafting evocated earlier osseous consolidation after medial OWHTO and showed a tendency to a better functional outcome.

Contrast-enhanced ultrasound reveals perfusion differences between benign lipoma and semi-malignant atypical lipomatous tumors: A prospective clinical study.

PURPOSE: Soft tissue tumors (STT) are difficult to diagnose accurately, and distinguishing between benign and malignant tumors is challenging. Lipoma is the most common STT, while atypical lipomatous tumors (ALT) can dedifferentiate into malignant lipomatous tumors like grade 1 liposarcoma and require more radical therapy. This study aims to investigate the potential of contrast-enhanced ultrasound (CEUS) to differentiate between lipoma and ALT based on tumor perfusion. MATERIALS AND METHODS: We prospectively examined 52 patients who were scheduled for biopsy for suspected lipoma or ALT. The CEUS examination was performed using SonoVue as a contrast agent to quantify tumor perfusion using VueBox V7.1 software. Peak enhancement (PE), rise time (RT), wash-in perfusion index (WiPI), and wash-out rate (WoR) were used to assess contrast enhancement inside the STT. RESULTS: Among 50 tumors examined, 30 were lipomas, and 20 were ALTs. We found significant differences in perfusion between lipomas and ALTs (PE: 49.22 ± 45.75 a.u. vs. 165.67 ± 174.80; RT: 23.86 ± 20.47s vs. 10.72 ± 5.34 s; WiPI: 33.06 ± 29.94 dB vs. 107.21 ± 112.43 dB; WoR: 2.44 ± 3.70 dB/s vs. 12.75 ± 15.80 dB/s; p<.001). ROC analysis of PE resulted in a diagnostic accuracy of 74% for the detection of an ALT, and 77% for the detection of a lipoma. CONCLUSION: CEUS may enhance the differential diagnosis of benign lipomas and ALTs, with ALTs showing higher levels of perfusion. If larger prospective studies confirm these findings, CEUS could enhance diagnostic accuracy, guide surgical planning, and potentially reduce unnecessary treatments for patients presenting with ambiguous lipomatous tumors like lipoma or ALT.

ChatGPT in education: global reactions to AI innovations.

The release and rapid diffusion of ChatGPT have caught the attention of educators worldwide. Some educators are enthusiastic about its potential to support learning. Others are concerned about how it might circumvent learning opportunities or contribute to misinformation. To better understand reactions about ChatGPT concerning education, we analyzed Twitter data (16,830,997 tweets from 5,541,457 users). Based on topic modeling and sentiment analysis, we provide an overview of global perceptions and reactions to ChatGPT regarding education. ChatGPT triggered a massive response on Twitter, with education being the most tweeted content topic. Topics ranged from specific (e.g., cheating) to broad (e.g., opportunities), which were discussed with mixed sentiment. We traced that authority decisions may influence public opinions. We discussed that the average reaction on Twitter (e.g., using ChatGPT to cheat in exams) differs from discussions in which education and teaching-learning researchers are likely to be more interested (e.g., ChatGPT as an intelligent learning partner). This study provides insights into people's reactions when new groundbreaking technology is released and implications for scientific and policy communication in rapidly changing circumstances.

Delayed Treatment of Bloodstream Infection at Admission is Associated With Initial Low Early Warning Score and Increased Mortality.

OBJECTIVES: To identify factors associated with antibiotic treatment delay in patients admitted with bloodstream infections (BSIs). DESIGN: Retrospective cohort study. SETTING: North Zealand Hospital, Denmark. PATIENTS: Adult patients with positive blood cultures obtained within the first 48 hours of admission between January 1, 2015, and December 31, 2015 (n = 926). MEASUREMENTS AND MAIN RESULTS: First recorded Early Warning Score (EWS), patient characteristics, time to antibiotic treatment, and survival at day 60 after admission were obtained from electronic health records and medicine module. Presence of contaminants and the match between the antibiotic treatment and susceptibility of the cultured microorganism were included in the analysis. Data were stratified according to EWS quartiles. Overall, time from admission to prescription of antibiotic treatment was 3.7 (3.4-4.0) hours, whereas time from admission to antibiotic treatment was 5.7 (5.4-6.1) hours. A gap between prescription and administration of antibiotic treatment was present across all EWS quartiles. Importantly, 23.4% of patients admitted with BSI presented with an initial EWS 0-1. Within this group of patients, time to antibiotic treatment was markedly higher among nonsurvivors at day 60 compared with survivors. Furthermore, time to antibiotic treatment later than 6 hours was associated with increased mortality at day 60. Among patients with an initial EWS of 0-1, 51.3% of survivors received antibiotic treatment within 6 hours, whereas only 19.0% of nonsurvivors received antibiotic treatment within 6 hours. CONCLUSIONS: Among patients with initial low EWS, delay in antibiotic treatment of BSIs was associated with increased mortality at day 60. Lag from prescription to administration may contribute to delayed antibiotic treatment. A more frequent reevaluation of patients with infections with a low initial EWS and reduction of time from prescription to administration may reduce the time to antibiotic treatment, thus potentially improving survival.

Contrast-Enhanced Ultrasound-Assessed Supraspinatus Muscle Perfusion Indicates Better Tissue Vitality and Outcome After Supraspinatus Tendon Repair and Subacromial Decompression.

OBJECTIVE: Supraspinatus tendon (SSP) tears are a frequent indication for shoulder surgery. Therapy options include physiotherapy, tendon repair and less invasive surgical options like subacromial decompression (SAD). The selection of the most appropriate treatment depends on the specific characteristics and needs of each patient subgroup. Typically, physically active patients are candidates for tendon repair, while a conservative approach is preferred for individuals with severe muscle degeneration or low physical demands. The goal of this study was to assess the impact of contrast-enhanced ultrasound (CEUS)-assessed SSP muscle perfusion on post-operative shoulder function and tendon healing in patients undergoing SSP repair or SAD, thereby enhancing personalized therapy for SSP tendon tears. METHODS: Two cohorts of patients with SSP tendon tears were treated either by SAD or tendon repair. Pre-operative and 6-month post-operative SSP muscle perfusion was quantified using CEUS and investigated as a surrogate for tissue vitality. The magnetic resonance imaging-derived parameters fatty infiltration and tendon retraction and established shoulder function scores were assessed pre- and post-operatively. RESULTS: Thirty-five SSP repair patients were compared with 20 SAD patients. Pre-operative perfusion was comparable in the SAD and SSP repair cohorts when a re-tear occurred (wash-in perfusion index = 103.8 ± 124.0 vs. 114.6 ± 155.0, p = 0.83), while being significantly higher among patients with an intact repair (103.8 ± 124 vs. 325.4 ± 388.6, p = 0.006). Below-median pre-operative muscle perfusion was associated with lower post-operative shoulder function (Constant score: 59 ± 28 vs. 78 ± 19, p = 0.012). CONCLUSION: CEUS can visualize SSP muscle perfusion as a surrogate for tissue vitality and tendon healing, which is associated with better post-operative shoulder function.

Traumatized German soldiers with moral injury - value-based cognitive-behavioral group therapy to treat war-related shame.

Introduction: During deployment, soldiers are confronted with potentially morally injurious events. In many cases, these events violate their personal values and belief systems, resulting in feelings of anger, alienation, guilt, and shame. The psychological distress caused by such transgressions is defined as moral injury. It remains unclear to date, which therapeutic interventions are most appropriate for addressing this specific psychological condition. This study examines the effectiveness of value-based cognitive-behavioral group therapy combining elements of cognitive-behavioral therapy, acceptance and commitment therapy, spiritual care, and adaptive disclosure therapy. Materials and methods: This controlled study uses the Compass of Shame Scale to assess symptom severity among participants both before and after a three-week inpatient group therapy regimen for moral injury. An intervention group (n = 45) was compared to a waiting-list control group (n = 40). A one-way between subjects ANOVA was conducted to determine the differences between the two measurement points in the intervention group compared to the control group. A positive ethics vote from the Humboldt University Berlin (Charité) was available (No.EA1/092/15). Results: A significant difference was found on the shame-associated maladaptive strategies subscales of attack self (F (1, 83) = 5.942, p = 0.017, Cohen's f = 0,27), withdrawal (F (1, 83) = 8.263, p = 0.005, Cohen's f = 0,32), and attack others (F (1, 83) = 10.552, p = 0.002, Cohen's f = 0,36) of the Compass of Shame Scale between the intervention group and the control group at the p < 0.05 level in the pre- and post-treatment (t1-t2) comparison. Conclusion: This study suggests that the special therapeutic focus in cognitive-behavioral group therapy can alter shame-based maladaptive coping behaviors in response to war-related moral injury. This study provides further evidence that therapeutic approaches - through fostering a reconciliatory, compassionate, and forgiving approach toward oneself and others - target the underlying mechanisms of moral injury. Therefore, value-based cognitive-behavioral interventions should be considered as a standard element of trauma care in a military setting. Future studies should further examine such interventions in randomized control trials. It would also be particularly valuable for future studies to include a follow-up time point.

Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms.

PURPOSE: Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker. METHODS: OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed. RESULTS: OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors. CONCLUSION: Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.