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In our single-center study, 357 myeloma and lymphoma patients between 2009 and 2019 were mobilized with granulocyte colony-stimulating factor (G-CSF 7.5 µg/kg bid for four days) plus a fixed dose of 24 mg Plerixafor when indicated (Plerixafor Group, n = 187) or G-CSF alone (G-CSF Group, n = 170). The target CD34 cell yields were ≥2.0 × 106 CD34+ cells/kg in lymphoma and ≥4.0 × 106 CD34+ cells/kg in myeloma patients to enable putative second transplants in the latter. There were no significant differences in engraftment kinetics or transfusion requirements between the Plerixafor Group and the control group in the myeloma cohort, with lymphoma patients not requiring Plerixafor showing significantly faster neutrophil recovery, a trend to faster platelet recovery, and a significantly lower need for platelet transfusions, probably due to the significantly lower number of CD34-positive cells re-transfused. While in myeloma patients the outcome (overall survival, progression-free survival) following autologous stem cell transplantation (ASCT) was similar between the Plerixafor Group and the control group, hard to mobilize lymphoma patients had significantly poorer progression-free survival (47% vs. 74% at 36 months after ASCT, p = 0.003) with a trend also to poorer overall survival (71% vs. 84%). In conclusion, while there seem to be no differences in stemness capacity and long-term engraftment efficiency between the Plerixafor and the G-CSF Group in lymphoma as well as myeloma patients, poor mobilizing lymphoma patients per se constitute a high-risk population with a poorer outcome after ASCT. Whether disease characteristics and/or a more intense or stem cell-toxic pre-mobilization chemo-/radiotherapy burden in this cohort are responsible for this observation remains to be shown in future studies.

Monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition, is associated with various chronic inflammatory rheumatic diseases (RDs) and is frequently observed as an incidental finding during routine work-up. The association of MGUS and chronic RDs is well established, but the impact of RDs on the risk of transformation into overt multiple myeloma (MM) has not been evaluated so far. MGUS patients diagnosed between January 2000 and August 2016 were identified and screened for concomitant RDs. RDs were grouped into antibody (Ab)-mediated RDs and non-Ab–mediated RDs (polymyalgia rheumatica, large-vessel giant cell arteritis, spondyloarthritis, and gout). Progression to MM was defined as a categorical (yes/no) or continuous time-dependent (time to progression) variable. Of 2935 MGUS patients, 255 (9%) had a concomitant RD. MGUS patients diagnosed with non-Ab–mediated RDs had a doubled risk of progression compared with those without a concomitant RD (hazard ratio, 2.1; 95% CI, 1.1-3.9; P = .02). These data translate into a 5-year risk of progression of 4% in MGUS patients without rheumatologic comorbidity, 10% in those with concomitant non-Ab–mediated RDS, and 2% in those with Ab-mediated RDs. By using the complex risk stratification model that includes myeloma protein (M-protein) concentration, immunoglobulin type, and level of free light chain ratio as variables, patients with non-Ab–mediated RDs (n = 57) had the highest risk for progression (hazard ratio, 6.8; 95% CI, 1.5-30.7; P = .01) compared with patients with Ab-mediated RDs (n = 77). Chronic inflammatory diseases have an impact on the risk of MGUS progressing into overt MM, with a doubled risk of transformation observed in patients with non-Ab–mediated RDs. Future research can elucidate whether comorbidities such as RDs should be included in currently applied prognostic MGUS scores.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Background Post-operative pancreatic fistula (POPF) remains a critical complication after pancreatic resection. This prospective pilot study evaluates perioperative markers of pancreatitis and systemic inflammation to predict clinically relevant grade B/C-POPF (CR-POPF). Methods All patients undergoing pancreatic resection from December 2017 to April 2019 were prospectively enrolled. Surgical procedures and outcomes were correlated with perioperative blood markers. ROC analysis was performed to assess their predictive value for CR-POPF. Cut-offs were calculated with the Youden index. Results In total, 70 patients were analysed (43 pancreatoduodenectomies and 27 distal pancreatectomies). In-hospital/90-d mortality and morbidity were 5.7/7.1% (n = 4/n = 5) and 75.7% (n = 53). Major complications (Clavien–Dindo ≥ 3a) occurred in 28 (40.0%) patients, CR-POPF in 20 (28.6%) patients. Serum lipase (cut-off > 51U/L) and IL-6 (> 56.5 ng/l) on POD3 were significant predictors for CR-POPF (AUC = 0.799, 95%-CI 0.686–0.912 and AUC = 0.784, 95%-CI 0.668–0.900; combined AUC = 0.858, 95%-CI 0.758–0.958; all p p p = 0.013 and p = 0.009). Conclusions Post-operative pancreatitis and inflammatory response are major determinants for development of POPF. A combination of serum lipase and IL-6 on POD3 is a highly significant early predictor of CR-POPF and overall complications, potentially guiding patient management. Clinical trial registration The study protocol was registered at clinicaltrials.gov (NCT04294797)

Background: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions.Methods: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases.Results: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (pConclusion: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients’ postoperative course negatively.

Background Short treatment‐duration with early restaging is crucial to avoid liver injury after preoperative chemotherapy (preopCTX) for colorectal liver metastases (CRLM). Response evaluation according to response evaluation criteria in solid tumors (RECIST) criteria implies several limitations. Early tumor shrinkage (ETS; ≥20% size reduction

Driving ability largely depends on the total brake response time (TBRT) corresponding to the time a subject needs to react to a stimulus and apply a well-defined force on the brake pedal. As yet, the English literature completely lacks clinical studies evaluating the TBRT following oral surgery. In this case-control study, a driving simulator was used to evaluate the TBRT in patients scheduled for oral surgery in local anesthesia. Measurements were taken shortly before (t1) and after (t2) surgery as well as 7–10 days later (t3) when sutures were removed. Results were compared to data of a group of healthy volunteers. Seventy-three patients (37 women, 36 men) underwent evaluation at t1, t2, and t3. In 13 patients who did not return for removal of sutures, only measurements at t1 and t2 could be performed. The median TBRT was 583 milliseconds (ms), 634 ms, and 520 ms at t1, t2, and t3, respectively. Statistical analysis revealed significant differences between readings at t1 versus t2 (t = − 4.944, p < 0.001), t1 versus t3 (t = 7.454, p < 0.001), and t2 versus t3 (t = 11.971, p < 0.001). There was no significant difference between TBRT at t3 in study subjects compared to normal reference values of 67 healthy volunteers. TBRT was significantly increased immediately after oral surgery (t2) compared to measurements 7–10 days postoperatively (t3). Since readings at t3 did not differ from TBRT values in the comparison group, they were considered normal. Due to significantly elevated total brake response time, driving ability is assumed to be considerably affected following oral surgery, and patients should be advised to abstain from driving immediately after such operations. Our study results put into question patients’ driving ability following dentoalveolar procedures which should be considered regarding informed consent and could potentially have consequences on health issues (road traffic accidents) as well as legal and financial matters (court charges, insurance claims).

Background Manual width measurements of the middle cerebellar peduncle on MRI were shown to improve the accuracy of an imaging‐guided diagnosis of multiple system atrophy (MSA). Recently, automated volume segmentation algorithms were able to reliably differentiate patients with Parkinson's disease (PD) and the parkinsonian variant of MSA. The objective of the current study was to integrate probabilistic information of the middle cerebellar peduncle into an existing MRI atlas for automated subcortical segmentation and to evaluate the diagnostic properties of the novel atlas for the differential diagnosis of MSA (parkinsonian and cerebellar variant) versus PD. Methods Three Tesla MRI scans of 48 healthy individuals were used to establish an automated whole‐brain segmentation procedure that includes the volumes of the putamen, cerebellar gray and white matter, and the middle cerebellar peduncles. Classification accuracy of segmented volumes were tested in early‐stage MSA patients (18 MSA‐parkinsonism, 13 MSA‐cerebellar) and 19 PD patients using a C4.5 classifier. Results Putaminal and infratentorial atrophy were present in 77.8% and 61.1% of MSA‐parkinsonian patients, respectively. Four of 18 MSA‐parkinsonian patients (22.2%) had infratentorial atrophy without evidence of putaminal atrophy. Infratentorial atrophy was present in all MSA‐cerebellar patients, with concomitant putaminal atrophy in 46.2% of these cases. The diagnostic algorithm using putaminal and infratentorial volumetric information correctly classified all PD patients and 96.8% of MSA patients. Conclusions The middle cerebellar peduncle was successfully integrated into a subcortical segmentation atlas, and its excellent diagnostic accuracy outperformed existing volumetric MRI processing strategies in differentiating MSA patients with variable atrophy patterns from PD patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Adaptive behavior critically depends on the detection of behaviorally relevant stimuli. The anterior insular cortex (aIC) has long been proposed as a key player in the representation and integration of sensory stimuli, and implicated in a wide variety of cognitive and emotional functions. However, to date, little is known about the contribution of aIC interneurons to sensory processing. By using a combination of whole-brain connectivity tracing, imaging of neural calcium dynamics, and optogenetic modulation in freely moving mice across different experimental paradigms, such as fear conditioning and social preference, we describe here a role for aIC vasoactive intestinal polypeptide-expressing (VIP+) interneurons in mediating adaptive behaviors. Our findings enlighten the contribution of aIC VIP+ interneurons to sensory processing, showing that they are anatomically connected to a wide range of sensory-related brain areas and critically respond to behaviorally relevant stimuli independent of task and modality.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients &gt, 60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off &ge, 0.2mg/dL, hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size &ge, 3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p &lt, 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Introduction. The prognosis of multiple myeloma is still unfavorable due to inherent characteristics of the disease and the often-delayed diagnosis due to widespread and unspecific symptoms such as back pain and fatigue. Therefore, a simple diagnostic blood test would be helpful to speed up the diagnostic procedure in such patients (pts.). Here, we evaluated the diagnostic value of plasma levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in the peripheral blood and bone marrow of pts. with plasma cell disorders and in healthy controls. Materials and Methods. Immunoreactive CEACAM6 was determined in the peripheral blood and bone marrow (n=95/100) of pts. with monoclonal gammopathy of unknown significance (MGUS: 28/37), newly diagnosed multiple myeloma (NDMM: 42/40), and relapsed/refractory multiple myeloma (RRMM: 25/23) by sandwich ELISA. Results. Median CEACAM6 levels in the peripheral blood of pts. with plasma cell disorders were significantly higher than those of healthy controls (healthy controls: 15.2 pg/ml (12.1-17.1); MGUS: 19.0 pg/ml (16.4-22.5); NDMM: 18.0 pg/ml (13.4-21.2); and RRMM: 18.9 pg/ml (15.2-21.5); p<0.001). Plasma levels of CEACAM6 discriminated healthy subjects from MGUS/NDMM pts. (AUC=0.71, 95% CI: 0.6-0.8); i.e., a CEACAM6 level>17.3 pg/ml has an 82% (95% CI: 70-90) predictive probability for the identification of MGUS or NDMM. Moreover, CEACAM6 levels in the bone marrow were significantly higher in RRMM pts. than in NDMM pts. (p=0.04), suggesting a role of this molecule in disease progression. Conclusion. CEACAM6 plasma levels can noninvasively identify pts. with a plasma cell disorder and should be evaluated prospectively as a potential diagnostic marker. Moreover, due to high CEACAM6 levels in the bone marrow in RRMM pts., this adhesion molecule might be a therapeutic target in multiple myeloma pts.

Background Pancreas retransplantation is still a controversial option after loss of a pancreatic graft. This article describes the experience of pancreas retransplantation at a high‐volume centre. Methods This was a retrospective observational study of all pancreas retransplantations performed in a single centre between 1997 and 2013. Pancreatic graft loss was defined by the return to insulin dependence. Risk factors for graft loss as well as patient and graft survival were analysed using logistic and time‐to‐event regression models. Results Of 409 pancreas transplantations undertaken, 52 (12·7 per cent) were identified as pancreas retransplantations. After a median follow‐up of 65·0 (range 0·8–174·3) months, 1‐ and 5‐year graft survival rates were 79 and 69 per cent respectively, and 1‐ and 5‐year patient survival rates were 96 and 89 per cent. During the entire follow‐up, 22 grafts (42 per cent) were lost. Patient survival was not associated with any of the donor‐ or recipient‐related factors investigated. Five‐year graft survival was better after simultaneous kidney–pancreas retransplantation than pancreas retransplantation alone: 80 per cent (16 of 20) versus 63 per cent (20 of 32) (P = 0·226). Acute rejection (odds ratio 4·49, 95 per cent c.i. 1·59 to 12·68; P = 0·005) and early surgical complications (OR 3·29, 1·09 to 9·99, P = 0·035) were identified as factors with an independent negative effect on graft survival. Conclusion Pancreas retransplantation may be considered for patients whose previous graft has failed., Good outcome in selected patients

// Normann Steiner 1, 2, * , Bojana Borjan 2, 3, * , Roman Hajek 5, 6 , Karin Johrer 3 , Georg Gobel 4 , Wolfgang Willenbacher 1 , Johann Kern 3 , Eberhard Gunsilius 1, 2, * and Gerold Untergasser 1, 3, * 1 Department of Internal Medicine V, Hematology and Medical Oncology, Innsbruck Medical University, Innsbruck, Austria 2 Laboratory for Tumor Biology and Angiogenesis, Innsbruck Medical University, Innsbruck, Austria 3 Tyrolean Cancer Research Institute, Innsbruck, Austria 4 Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria 5 Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic 6 Department of Hemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic * These authors have contributed equally to this work Correspondence to: Normann Steiner, email: normann.steiner@i-med.ac.at Keywords: multiple myeloma, MGUS, GRP78, ELISA, prognostic marker Received: January 17, 2017 Accepted: April 11, 2017 Published: April 21, 2017 ABSTRACT Introduction: Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses. Results: GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM. In bone marrow plasma, the amount of released GRP78 protein was not significantly increased between MGUS-, NDMM- and RRMM patients. MM cells of the three cell lines release GRP78 as full-length protein under apoptotic, but not under acidotic or ER-stress conditions. In necrosis, only proteolytic fragments of GRP78 were detected in supernatants of MM cells. Materials and Methods: GRP78 protein expression and plasma levels were quantified in bone marrow aspirates of patients with monoclonal gammopathy of undetermined significance (MGUS, n = 29), newly diagnosed MM (NDMM, n = 29) and with relapsed/refractory MM (RRMM, n = 15) by immunohistochemistry and sandwich ELISA. The human MM cell lines U266, NCI-H929 and OPM-2 were used for functional GRP78 release- and processing studies after induction of acidosis, ER stress, apoptosis and necrosis. Conclusions: Ectopic expression of GRP78 on cell membrane or its release in the microenvironment is not a suitable marker to distinguish MGUS from NDMM and RRMM.

Background Microstructural white matter integrity captured by diffusion-tensor imaging (DTI) is significantly more affected in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) compared to PSP-parkinsonism (PSP–P). Objectives To characterize the microstructural integrity of large fascicular bundles using standardized probabilistic tractography and combine it with previously established DTI- and volumetric measures of subcortical brain structures in order to evaluate its diagnostic properties for the differentiation of PSP- RS, PSP-P and Parkinson's disease (PD). Methods DTI metrics as well as volumes of subcortical brain regions, acquired by 3T MRI of patients with PSP-RS (n = 15), PSP-P (n = 13), and a mean disease duration of 2.7 ± 1.8 years, were quantified by probabilistic tractography as well as a validated infratentorial atlas and compared to PD (n = 18) and healthy controls (n = 20). Classification accuracy of MRI measures was tested by consecutive linear discriminant analyses. Results DTI metrics of the anterior thalamic radiation, the corticospinal tract, the superior longitudinal fasciculus, the bundles of the corpus callosum and cingulate, the dentatorubrothalamic tract as well as volumes of the dorsal midbrain, globus pallidus and thalamus were significantly altered in PSP-RS and to a lesser extent in PSP-P compared to PD and healthy controls. Linear discriminant analysis identified DTI metrics of the dentatorubrothalamic tract and the anterior thalamic radiation as well as the volume of the dorsal midbrain to classify correctly 91.3% of PSP-RS, PSP-P and PD patients. Conclusions Observer-independent investigations of microstructural integrity of major fiber bundles improved existing MRI processing strategies to differentiate PSP-P from PSP-RS and PD, in their early disease stages.

Associative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.

// Normann Steiner 1 , Angelika Schwarzler 1 , Georg Gobel 3 , Wolfgang Loscher 2 , Julia Wanschitz 2, * , Eberhard Gunsilius 1, * 1 Department of Internal Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, A-6020 Innsbruck, Austria 2 Department of Neurology, Medical University of Innsbruck, A-6020 Innsbruck, Austria 3 Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, A-6020 Innsbruck, Austria * These authors have contributed equally to this work Correspondence to: Eberhard Gunsilius, email: eberhard.gunsilius@i-med.ac.at Keywords: monoclonal gammopathy of undetermined significance, MGUS, MGUS associated neuropathy, multiple myeloma Received: June 21, 2016 Accepted: November 21, 2016 Published: December 10, 2016 ABSTRACT Objectives: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. Neurological symptoms caused by the monoclonal immunoglobulins or free light-chains are often associated with a high morbidity. We analyzed the prevalence of neuropathy, clinical features and the long-term outcome in 223 patients (pts.) with MGUS. Patients and Methods: Between 1/2005 and 3/2015, 223 adult pts. with MGUS were identified in our database. Results: In36/223 pts. (16%) a neuropathy was diagnosed (MGUS associated neuropathy, MGUS-N). 20 pts. (55%) had a distal symmetric axonal neuropathy, 10 pts. (28%) had a chronic inflammatory demyelinating polyneuropathy and 6 pts (17%) a distal acquired demyelinating symmetric polyneuropathy. In MGUS-NN (without neuropathy) and in MGUS-N, progression to smoldering MM, MM or Waldenstrom’s macroglobulinemia (WM) occurred in 17% of the pts. The Immunoglobulin subtype was predominantly IgG in MGUS-NN and IgM in MGUS-N and ≥5.5% plasma cells in the bone-marrow predicted progression to MM and AL-amyloidosis in MGUS-NN and to WM in MGUS-N (p

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). FLT3 gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by 3H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1&ndash, 6) revealed that a high FES (&gt, 3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (p = 0.04). RNAseq and real-time PCR confirmed the expression of FLT3 in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling.

Background/aim Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma often precede multiple myeloma (MM). The identification of biomarkers predicting progression to MM might facilitate an earlier diagnosis of MM. Our study assessed the diagnostic value of plasma levels of endocan, a 50-kDa soluble dermatan sulfate proteoglycan produced and secreted by endothelial cells, hitherto unknown in MM, in patients with plasma cell dyscrasia. Materials and methods Endocan levels were determined in 96 peripheral blood plasma samples by sandwich enzyme-linked immunosorbent assay (ELISA) in healthy controls (n=12), in patients with MGUS (n=17), and in patients newly diagnosed with (n=42) or relapsed/refractory (n=25) MM. Results Median endocan concentration increased from MGUS (315.00 pg/ml) and healthy controls (316.19 pg/ml) to newly-diagnosed MM (371.82 pg/ml; p=0.027). The low endocan levels (median=246.20 pg/ml) in patients with relapsed/refractory MM were similar to those in healthy controls and patients with MGUS. A cut-off value of >220 pg/ml endocan in peripheral blood discriminated patients newly diagnosed with MM from those with MGUS (area under the curve(AUC)=0.66, 95% confidence interval(CI)=0.55-0.81). Conclusion The plasma levels of endocan can non-invasively differentiate patients newly diagnosed with MM from those with MGUS and should therefore be evaluated prospectively as a potential diagnostic marker.

Aims The left ventricular global function index (LVGFI) is a novel indicator of left ventricular performance. Its prognostic value in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. We sought to evaluate the prognostic significance of LVGFI measured by cardiovascular magnetic resonance (CMR) imaging after STEMI. Methods and results Two hundred eligible STEMI patients (56 ± 11 years, 16% female) revascularized by primary percutaneous coronary intervention were followed-up for 3.1 [2–4.1] years for major adverse cardiac events (MACE). MACE was defined as a composite of death, non-fatal myocardial re-infarction, and new congestive heart failure. All patients underwent CMR imaging within 2 [2–4] days after STEMI. Late enhancement and cine images were acquired to assess myocardial injury as well as myocardial function, including LVGFI. Patients suffering a MACE event ( n = 20, 10%) had a significantly lower LVGFI ( P = 0.001). In Kaplan–Meier analysis, a decreased LVGFI was associated with a reduced MACE-free survival ( P < 0.001). Multivariate Cox regression analysis revealed a decreased LVGFI as a predictor for MACE [hazard ratio = 4.79, 95% confidence interval (CI) 1.46–15.67, P = 0.010] after adjusting for microvascular obstruction, left ventricular mass, and multivessel disease. In receiver operating characteristic analysis, LVGFI was a strong predictor for MACE (area under the curve = 0.73, CI 0.61–0.85). However, c -statistics revealed that LVGFI does not provide incremental prognostic information over left ventricular ejection fraction (LVEF) ( P = 0.38). Conclusion LVGFI assessed by CMR is a strong predictor of MACE within 3 years after first STEMI. A superior predictive value as compared with LVEF was not found in this study.

Background A subgroup of patients initially diagnosed with Parkinson's disease (PD) turn out to have normal dopamine transporter single-photon emission computed tomography imaging and have been labeled as subjects without evidence of dopaminergic deficit (SWEDDs). In this study, we sought to further characterize these patients and have analyzed the frequency of nonmotor symptoms (NMS) in SWEDDs, PD patients, and healthy controls. Methods We analyzed the baseline clinical data of 412 PD patients, 184 controls, and 62 SWEDDs included in the Parkinson's Progression Marker Initiative study on a variety of different NMS questionnaires. Results Both PD patients and SWEDDs had greater frequency of NMS than healthy controls. Furthermore, some NMS, such as orthostatic hypotension as well as cardiovascular and thermoregulatory dysfunction were even more commonly reported in SWEDDs than in PD patients, whereas hyposmia was more common in PD, compared to SWEDDs. Conclusion NMS are more frequent in SWEDDs than in controls, and autonomic dysfunction and orthostatic hypotension were even more common than in PD patients. These findings support the notion that SWEDDS represent a group of patients with still poorly understood pathophysiology. © 2015 International Parkinson and Movement Disorder Society

Introduction Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. Materials & methods Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. Results Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). Conclusion High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.

Background Bile leakage (BL) is a frequent and severe complication following liver surgery. The aim of this study was to evaluate risk factors for BL, related other complications and association with long-term survival. Methods This study included all patients undergoing hepatectomy in a single centre from 2005 to 2016. Perioperative risk factors related to BL were identified using univariable and multivariable analysis. Kaplan-Meier method was used for survival analysis. Results BL occurred in 48 of 458 patients (11%). BLs were more frequent in patients after major hepatectomy (p = 0.001). Portal vein embolization, bilioenteric-anastomosis, lymphadenectomy, vascular reconstruction and operative time were significant factors for developing BL. Comparing patients with or without BL, BL was more commonly associated with other postoperative complications (p = 0.001), especially acute kidney failure and surgical-site-infections. There was no difference in 90-day-mortality (p = 0.124). The median disease-free survival was comparable (17 vs. 15 months, p = 0.976), also no difference was observed when stratifying for different tumour entities. There was no difference in median overall survival (OS) among malignant disease (35 vs. 47 months, p = 0.200) and in 3-year OS (46% vs. 59%). Multivariate analysis confirmed that postoperative liver failure and major hepatectomy were risk factors for reduced OS (p = 0.010). Conclusions Many concerns have been raised regarding tumour progression after major complications. In this study, we only found a relevant influence of BL on OS in pCC, whereas no association was seen in other cancer types, indicating that tumour progression might be triggered by BL in cancer types arising from the bile ducts itself.

Background Some hemodialysis patients develop arteriovenous (AV) fistulas with high flows. This volume overload can result in high-output cardiac failure. To date, predisposing access flow rates are unknown. Methods A retrospective study of all kidney-transplant recipients at the Medical University of Innsbruck (MUI) from 2005 to 2010 included 797 patients with the following criteria: previous hemodialysis with a native AV fistula or a graft, sufficient function of the kidney transplant up to the time of the data analysis, and follow-up care at the MUI. Results Twenty-nine of the 113 patients (25.7%) needed an AV fistula closure, mostly because of symptoms of cardiac failure. The mean shunt flow in the intervention group was 2197.2 mL/min, whereas the mean shunt flow in the non-intervention group was only 850.9 mL/min. Shunt closures were most frequently made in patients with upper-arm shunts (41.7%). Conclusion The necessity of shunt closure is not a rarity. Patients who underwent an AV fistula ligature had high access flows with about 2200 mL/min. As the symptoms of cardiac failure greatly improved after shunt closure, patients with high access flow may benefit from such an intervention.

68Ga-labelled DOTA0-Tyr3-octreotide positron emission tomography (PET)/CT (68Ga-DOTATOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTRs). Recent studies have shown that SSTRs are also expressed in head and neck squamous cell carcinoma (HNSCC). This is the first prospective clinical trial investigating SSTR expression in patients with HNSCC using 68Ga-DOTATOC. Patients with previously untreated HNSCC underwent 68Ga-DOTATOC PET/CT (120 MBq, range 81–150 MBq). Tumour tracer uptake was scored, the maximum standardized uptake value (SUVmax) was measured and the tumour to background uptake ratio was calculated. For each patient, PET/CT findings were correlated with immunohistochemical SSTR expression in tumour specimens. Fifteen HNSCC patients were included in the study from May 2011 to May 2012. Tumour-specific 68Ga-DOTATOC uptake was detected in all patients with an median SUVmax of 4.0 (range 2.2–6.5). Uptake was weak in seven (47 %), moderate in five (33 %) and strong in three (20 %) patients. All tumour specimens were SSTR positive on immunohistochemistry. Of the 15 patients, 14 were positive for SSTR subtype 2, characterized by the highest affinity to octreotide. SSTR expression in HNSCC can be visualized clinically using 68Ga-DOTATOC PET/CT. SSTR expression in HNSCC could provide a potential target for SSTR-based therapy in patients not amenable to standard treatment modalities, but this cannot be predicted by SSTR immunohistochemistry.

The quality of samples stored within a biobank relies on the specimen collection, the transportation, the pre-analytical processing and the long-term storage. Standard Operating Procedures (SOPs) are essential tools to guarantee the quality of samples.The aim of this paper is to present an IT-supported tool (Pre-An Evaluation Tool) that allows assessing the compliance of current pre-analytical procedures (defined in SOPs) of a biobank with international guidelines. The Pre-An Evaluation Tool was implemented based on CEN technical specifications for pre-analytical procedures using REDCap.The data collection instrument of the Pre-An Evaluation tool consists of more than 250 items related to the CEN technical specifications. In order to create a dynamic questionnaire, items following a branching logic were implemented.The Pre-An Evaluation tool is a user-friendly tool that facilitates the assessment of the coverage of the CEN technical specifications by specific SOPs. This tool can help to identify gaps within SOPs and therefore contribute to the overall quality of biological samples stored within a biobank.