E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. METHODS: A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. RESULTS: Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. CONCLUSION: These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.

Liver surgery is an effective treatment for liver tumours. Liver failure is a major problem in patients with a poor liver quality or having large operations. The treatment options for liver failure are limited, with high death rates. To estimate patient risk, assessing liver function before surgery is important. Many methods exist for this purpose, including functional, blood, and imaging tests. This guideline summarizes the available literature and expert opinions, and aids clinicians in planning safe liver surgery.

Incidence and risk factors for anastomotic bile leakage in hepatic resection with bilioenteric reconstruction - A international multicenter study.

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 (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001). CONCLUSION: 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.

Early response evaluation during preoperative chemotherapy for colorectal liver metastases: Combined size and morphology-based criteria predict pathological response and survival after resection.

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 <6-12 weeks) or morphological criteria (MC) may better predict oncological outcome. METHODS: In patients undergoing resection after preopCTX between 2003-2017 pathological and radiological response was reassessed according to Blazer classification, ETS, MC, and RECIST within 90 days and correlated with survival. RESULTS: Seventy-two patients were included, with a median of two (1-10) liver lesions, 53% bilobar involvement, and 7% extrahepatic disease. PreopCTX was applied for 3 months in median (1-6). During restaging after a median of 62 days, presence of ETS was associated with improved median overall survival (OS; 57.1 vs 33.7 months; P = .010) and disease-free survival (16 vs 7.2 months; P = .025). MC significantly correlated with major pathological response (P = .021). When combining ETS with optimal MC, presence of one or both factors was associated with pathological response (61.5% and 92.3%; P = .044) and OS in log-rank (P = .011), and multivariable analysis (hazard ratio [HR] 0.41; 95% confidence interval [CI], 0.19-0.90 and HR 0.32; 95%CI, 0.11-0.97). CONCLUSION: Response-grading by combined ETS/MC criteria less than 90 days after preopCTX initiation predicts pathological response and postoperative survival in CRLM.

Is it safe to drive after oral surgery?

OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL RELEVANCE: 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).

Morphometric MRI profiles of multiple system atrophy variants and implications for differential diagnosis.

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 International Parkinson and Movement Disorder Society.

Optimizing odor identification testing as quick and accurate diagnostic tool for Parkinson's disease.

INTRODUCTION: The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD. METHODS: Odor identification with the 16-item Sniffin' Sticks test (SS-16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1-regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts. RESULTS: Olfactory performance was lower in PD patients compared with controls and non-PD patients in all cohorts (each P < 0.001). Both the full SS-16 and a subscore of the top eight discriminating odors (SS-8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non-PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS-16 and the SS-8 (sensitivity, 100%; positive predictive value, 61.5%). CONCLUSIONS: Odor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Supine hypertension in Parkinson's disease and multiple system atrophy.

OBJECTIVE: Supine hypertension (SH) is a feature of cardiovascular autonomic failure that often accompanies orthostatic hypotension and may represent a negative prognostic factor in parkinsonian syndromes. Here we investigated the frequency rate as well as the clinical and tilt test correlates of SH in Parkinson's disease (PD) and multiple system atrophy (MSA). METHODS: 197 PD (33 demented) and 78 MSA (24 MSA-Cerebellar, 54 MSA-Parkinsonian) patients who had undergone a tilt test examination were retrospectively included. Clinical-demographic characteristics were collected from clinical records at the time of the tilt test examination. RESULTS: SH (>140 mmHg systolic, >90 mmHg diastolic) occurred in 34 % of PD patients (n = 66, mild in 71 % of patients, moderate in 27 %, severe in 2 %) and 37 % of MSA ones (n = 29, mild in 55 % of patients, moderate in 17 %, severe in 28 %). No difference was observed in SH frequency between demented versus gender-, age- and disease duration-matched non-demented PD patients, or between patients with the parkinsonian (MSA-P) versus the cerebellar (MSA-C) variant of MSA. In PD, SH was associated with presence of cardiovascular comorbidities (p = 0.002) and greater systolic (p = 0.007) and diastolic (p = 0.002) orthostatic blood pressure fall. Orthostatic hypotension (p = 0.002), and to a lesser degree, lower daily dopaminergic intake (p = 0.01) and use of anti-hypertensive medications (p = 0.04) were associated with SH in MSA. INTERPRETATION: One-third of PD and MSA patients suffer from mild to severe SH, independently of age, disease duration or stage. In PD, cardiovascular comorbidities significantly contribute to the development of SH, while in MSA, SH appears to reflect cardiovascular autonomic failure.

Nonmotor symptoms in subjects without evidence of dopaminergic deficits.

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.

Multiple sclerosis in the elderly: a retrospective cohort study.

BACKGROUND: There is a lack of knowledge of disease course, prognosis, comorbidities and potential treatments of elderly MS patients. OBJECTIVE: To characterize the disease course including disability progression and relapses, to quantify the use of DMTs and to identify comorbidities and risk factors for progression in elderly multiple sclerosis (MS) patients. METHODS: This is a retrospective study of 1200 Austrian MS patients older than 55 years as of May 1st, 2017 representing roughly one-third of all the MS patients of this age in Austria. Data were collected from 15 MS centers including demographics, first symptom at onset, number of relapses, evolvement of disability, medication, and comorbidities. RESULTS: Median observation time was 17.1 years with 957 (80%) relapsing and 243 (20%) progressive onsets. Average age at diagnosis was 45 years with a female predominance of 71%. Three-hundred and twenty-six (27%) patients were never treated with a DMT, while most treated patients received interferons (496; 41%) at some point. At last follow-up, 420 (35%) patients were still treated with a DMT. No difference was found between treated and never-treated patients in terms of clinical outcome; however, patients with worse disability progression had significantly more DMT switches. Pyramidal onset, number of comorbidities, dementia, epilepsy, and psychiatric conditions as well as a higher number of relapses were associated with worse outcome. The risk of reaching EDSS 6 rose with every additional comorbidity by 22%. In late and very-late-onset MS (LOMS, VLOMS) time to diagnosis took nearly twice the time compared to adult and early onset (AEOMS). The overall annualized relapse rate (ARR) decreased over time and patients with AEOMS had significantly higher ARR compared to LOMS and VLOMS. Four percent of MS patients had five medications or more fulfilling criteria of polypharmacy and 20% of psychiatric drugs were administered without a matching diagnosis. CONCLUSIONS: In this study, we identified number of comorbidities, pyramidal and cerebellar signs, and a higher number of relapses as unfavorable prognostic factors in elderly MS patients filling gaps of knowledge in patients usually underrepresented in clinical trials and may guide future therapeutic studies.

68Ga-DOTA°-Tyr³-octreotide positron emission tomography in head and neck squamous cell carcinoma.

PURPOSE: 68Ga-labelled DOTA°-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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Incidence of arteriovenous fistula closure due to high-output cardiac failure in kidney-transplanted patients.

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.

Poor Mobilizers in Lymphoma but Not Myeloma Patients Had Significantly Poorer Progression-Free Survival after Autologous Stem Cell Transplantation: Results of a Large Retrospective, Single-Center Observational Study.

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.

Pain in Multiple System Atrophy a Systematic Review and Meta-Analysis.

Background: Individuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non-motor feature of MSA. Objectives: Here, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: "pain," "multiple system atrophy," "MSA," "olivopontocerebellar atrophy," "OPCA," "striatonigral degeneration," "SND," "Shy Drager," and "atypical parkinsonism." Results: The search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross-sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%-75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%-87%] vs. 45% [95% CI = 33%-57%], P = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment. Conclusions: We found that pain is a frequent, but still under-recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA.

VIP-expressing interneurons in the anterior insular cortex contribute to sensory processing to regulate adaptive behavior.

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.

Study protocol of "From Science 2 School"-prevalence of sports and physical exercise linked to omnivorous, vegetarian and vegan, diets among Austrian secondary schools.

The increasing prevalence of unhealthy lifestyle choices contribute to almost all chronic conditions negatively affecting individual and public health. As the most beneficial preventative solution, a healthy lifestyle focusing on the dual approach of physical activity (PA) and a healthful diet is highly recommended. Considering the growing number of people interested in sustainable, plant-based diets, it seems crucial to analyze lifestyle behaviors with a special focus on diet type to delve deeper into the unenthusiastic health status among young populations. Therefore, this multidisciplinary study aims to survey and scale health behaviors with a special focus on the prevalence of traditional and vegetarian diets in connection with PA levels among Austrian pupils (10-19 years), teachers and principals in secondary education levels I and II. Following a cross-sectional design, sociodemographic and school-related data along with a complete profile of lifestyle behaviors, including detailed information regarding diet, PA, sports & exercise, and other health-related behaviors, were collected using online-based questionnaires. A total number of 8,845 children/adolescents (~1.2% of the eligible 771,525 Austrian secondary school pupils) and 1,350 adults (~1.5% of total eligible 89,243 Austrian teachers/principals) participated in the study. As this is the first investigation to explore the prevalence of veganism/vegetarianism amongst a large group of pupils, the present study will add an important contribution to overcome the lack of knowledge on PA, sports & exercise linked to healthy alternative diets. With a sustainable healthy lifestyle, a healthy transition from childhood to adulthood occurs, which can result in growing healthier functioning generations at all social levels. As a study protocol, the present article is intended to present comprehensive details of the study design, objectives, and the associated analytical procedures of the "From Science 2 School" study.

Prognostic significance of methylated RASSF1A and PITX2 genes in blood- and bone marrow plasma of breast cancer patients.

Free circulating DNA is increased in the serum/plasma of cancer patients, and methylation of certain genes has been found to be characteristic for malignancy. Therefore, we investigated the prognostic value of two promising genes, PITX2 and RASSF1A, in peripheral blood-plasma (PB-P) and bone marrow plasma (BM-P) of breast cancer patients. Peripheral blood and bone marrow samples from patients with primary breast cancer were prospectively collected during primary surgery at the Department of Obstetrics and Gynecology in Innsbruck (n = 428) from June 2000 to December 2006. The study has been approved by the ethical committee of the Medical University of Innsbruck. Methylation analysis was performed using MethyLight, a methylation-specific quantitative PCR-method. In univariate survival analysis, methylated PITX2 in PB-P was found to be a significant indicator for poor overall survival (OAS) and distant disease-free survival (DDFS) (P = 0.001 and P = 0.023). Methylated RASSF1A in PB-P was also an indicator for poor OAS and DDFS (P = 0.001 and P = 0.004). RASSF1A had also significant prognostic potential when determined in BM-P (P = 0.016). In multivariate survival analysis methylated PITX2 and RASSF1A in PB-P remained as therapy-independent prognostic factors for OAS (P = 0.021, P < 0.001). For DDFS only RASSF1A in PB-P showed prognostic significance (P = 0.002). Methylated RASSF1A and PITX2 in PB-P appear to have promising potential as prognostic markers in clinical use.

Rheumatologic diseases impact the risk of progression of MGUS to overt multiple myeloma.

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.

The FMS like Tyrosine Kinase 3 (FLT3) Is Overexpressed in a Subgroup of Multiple Myeloma Patients with Inferior Prognosis.

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 1-6) revealed that a high FES (>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.

Sex differences in disease presentation, surgical and oncological outcome of liver resection for primary and metastatic liver tumors-A retrospective multicenter study.

BACKGROUND: Sex differences are becoming of rising interest in many fields of medicine. It remains unknown whether sex has a role in postoperative and long-term outcome after hepatic resection (HR). The aim of this study was to investigate sex differences in disease presentation, surgical and oncological outcome after curative HR. METHODS: Retrospective analysis of 1010 patients who underwent HR between 2005 and 2018 at two tertiary hospitals in Austria. Demographics and survival data were obtained from a prospectively maintained database. Univariate analysis was used to identify sex differences for the entire cohort and for sub-cohorts. Disease-free- and overall survival was assessed by the Kaplan-Meier estimate and results were compared by log-rank tests. RESULTS: 436 females and 574 males were analyzed. Women were younger (p<0.001), had less liver cirrhosis (p<0.001), cardiac comorbidities (p<0.001), diabetes (28 (p<0.001) and obesity (p<0.001). Type of HR and surgical management did not vary by sex. Ninety-day morbidity (p = 0.179) and -mortality (p = 0.888) were comparable. In patients with malignant disease, no differences in disease-free- and overall survival was observed, neither for the entire cohort nor for the subgroups according to tumor entity or type of resection. Only in HCC patients, females showed an inferior OS (p = 0.029). CONCLUSION: This study delivers new insights on the impact of sex differences in liver surgery. Despite the fact that male patients have a higher incidence of preoperative morbidities, we did not observe specific disparities in terms of immediate postoperative as well as long term oncological outcome between sexes.

Diagnostic potential of automated tractography in progressive supranuclear palsy variants.

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.