Publications by authors named "Klaus Kaczirek"

58 Publications

Lithium preserves peritoneal membrane integrity by suppressing mesothelial cell αB-crystallin.

Sci Transl Med 2021 Aug;13(608)

Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.

Life-saving renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. However, the pathophysiological mechanisms involved are incompletely understood, limiting identification of therapeutic targets. We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGF-β-independent activation of TGF-β-regulated targets. In contrast, αB-crystallin knockdown decreased VEGF expression and early mesothelial-to-mesenchymal transition. LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically up-regulated in response to PDF and increased in peritoneal mesothelial cells from biopsies from pediatric patients undergoing PD, correlating with markers of angiogenesis and fibrosis. LiCl-supplemented PDF promoted morphological preservation of mesothelial cells and the submesothelial zone in a mouse model of chronic PD. Thus, repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy.
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http://dx.doi.org/10.1126/scitranslmed.aaz9705DOI Listing
August 2021

Immune checkpoints and liver resection after neoadjuvant chemotherapy including bevacizumab in patients with microsatellite-stable colorectal liver metastases.

HPB (Oxford) 2021 Jun 7. Epub 2021 Jun 7.

Department of Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Electronic address:

Background: The clinical value of immune checkpoint expression as prognostic biomarker in bevacizumab-pretreated patients with resected microsatellite-stable (MMS) colorectal liver metastases is unclear and was retrospectively investigated in this study.

Methods: Expression analyses of IDO-1, PD-L1, and CTLA-4 were performed by immunohistochemistry in resected bevacizumab-pretreated colorectal liver metastases. Association of immune checkpoint expression in tumor cells and immune cells with response and clinical outcome was investigated. Expression profiles were compared with those of patients with anti-EGFR-targeted therapy and lung metastases, respectively.

Results: One hundred thirty-six patients with MMS disease were investigated (79 (58.1%) male/57 (41.9%) female, median age 62.9 years (range 31.0-80.4)). High expression of IDO-1 in immune cells was associated with longer OS (not reached versus 44.8 months, HR 0.23 (95% CI 0.09, 0.55), P = 0.001). Low expression of CTLA-4 in tumor cells was associated with better histological response (26 major, 19 partial, 18 none versus 14 major, 23 partial, 30 none, P = 0.032). Expression profiles differed compared to patients with anti-EGFR-targeted therapy and patients with lung metastases.

Conclusion: Immune checkpoint expression was associated with response and survival. IDO-1 may serve as a novel prognostic and/or predictive biomarker in patients with MMS colorectal liver metastases.
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http://dx.doi.org/10.1016/j.hpb.2021.05.015DOI Listing
June 2021

Performance of two prognostic scores that incorporate genetic information to predict long-term outcomes following resection of colorectal cancer liver metastases: An external validation of the MD Anderson and JHH-MSK scores.

J Hepatobiliary Pancreat Sci 2021 Jul 24;28(7):581-592. Epub 2021 Apr 24.

Department of General, Visceral and Vascular Surgery, Charite Campus Benjamin Franklin, Berlin, Germany.

Introduction: Two novel clinical risk scores (CRS) that incorporate KRAS mutation status were developed: modified CRS (mCRS) and GAME score. However, they have not been tested in large national and international cohorts. The aim of this study was to validate the prognostic discrimination utility and determine the clinical usefulness of the two novel CRS.

Methods: Patients undergoing hepatectomy for CRLM (2000-2018) in 10 centers were included. The discriminatory abilities of mCRS, GAME, and Fong CRS were evaluated using Harrell's C-index and Akaike's Information Criterion.

Results: In the entire cohort, the C-index of the GAME score (0.61) was significantly higher than those of Fong score (0.57) and mCRS (0.54), while the C-Index of mCRS was significantly lower than that of Fong score. When we compared the models in the various geographical regions, the C-index of GAME score was significantly higher than that of mCRS in North America, Europe, and South America. The AIC of Fong score, mCRS, and GAME score were 14 405, 14 447, and 14 319, respectively.

Conclusion: In conclusion, using the largest and most heterogenous population of CRLM patients with known KRAS status, this independent, external validation demonstrated that the GAME score outperforms both the traditional Fong score and mCRS.
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http://dx.doi.org/10.1002/jhbp.963DOI Listing
July 2021

The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi-institutional study.

J Surg Oncol 2021 Mar 5;123(4):939-948. Epub 2021 Jan 5.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background And Objectives: Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established.

Methods: Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature.

Results: A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs.

Conclusion: The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.
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http://dx.doi.org/10.1002/jso.26361DOI Listing
March 2021

Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

Ann Surg Oncol 2021 Mar 10;28(3):1493-1498. Epub 2020 Sep 10.

North Western Hepatobiliary Unit, Aintree University Hospital, Liverpool, UK.

Background: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear.

Methods: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern.

Results: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05).

Conclusion: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.
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http://dx.doi.org/10.1245/s10434-020-09105-1DOI Listing
March 2021

The Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.

Ann Surg 2021 06;273(6):1165-1172

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status.

Background: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors.

Methods: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status.

Results: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38).

Conclusions: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.
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http://dx.doi.org/10.1097/SLA.0000000000003504DOI Listing
June 2021

The value of indocyanine green clearance assessment to predict postoperative liver dysfunction in patients undergoing liver resection.

Sci Rep 2019 06 10;9(1):8421. Epub 2019 Jun 10.

Department of Surgery, Division of General Surgery, Medical University Vienna, Vienna, Austria.

Postoperative liver dysfunction remains a major concern following hepatic resection. In order to identify patients who are at risk of developing liver dysfunction, indocyanine green (ICG) clearance has been proposed to predict postoperative liver function. All patients who underwent liver resection at the Medical University Vienna, Austria between 2006 and 2015 with preoperative ICG clearance testing (PDR, R15) were analyzed in this study. Postoperative liver dysfunction was analyzed as defined by the International Study Group of Liver Surgery. Overall, 698 patients (male: 394 (56.4%); female: 304 (43.6%)) with a mean age of 61.3 years (SD: 12.9) were included in this study, including 313 minor liver resections (44.8%) and 385 major liver resections (55.2%). One hundred and seven patients developed postoperative liver dysfunction after liver resection (15.3%). Factors associated with liver dysfunction were: male sex (p = 0.043), major liver resection (p < 0.0001), and preoperative ICG clearance (PDR (p = 0.002) and R15 (p < 0.0001)). Notably ICG clearance was significantly associated with liver dysfunction in minor and major liver resections respectively and remained a predictor upon multivariable analysis. An optimal cut-off for preoperative ICG clearance to accurately predict liver dysfunction was PDR < 19.5%/min and R15 > 5.6%. To the best of our knowledge, this is the largest study analyzing the predictive value of preoperative ICG clearance assessment in patients undergoing liver resection. ICG clearance is useful to identify patients at risk of postoperative liver dysfunction.
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http://dx.doi.org/10.1038/s41598-019-44815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557886PMC
June 2019

Prognostic Factors Change Over Time After Hepatectomy for Colorectal Liver Metastases: A Multi-institutional, International Analysis of 1099 Patients.

Ann Surg 2019 06;269(6):1129-1137

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis.

Background: CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery.

Methods: CS analysis was performed in 1099 patients of an international, multi-institutional cohort. Three-year CS (CS3) estimates at the "xth" year after surgery were calculated as follows: CS3 = CS (x + 3)/CS (x). The standardized difference (d) between CS3 rates was used to estimate the changing prognostic power of selected variables over time. A d < 0.1 indicated very small differences between groups, 0.1 ≤ d < 0.3 indicated small differences, 0.3 ≤ d < 0.5 indicated moderate differences, and d ≥ 0.5 indicated strong differences.

Results: According to OS estimates calculated at the time of surgery, the presence of BRAF and KRAS mutations, R1 margin status, resected extrahepatic disease, patient age, primary tumor lymph node metastasis, tumor number, and carcinoembryonic antigen levels independently predicted worse survival. However, when temporal changes in the prognostic impact of these variables were considered using CS3 estimates, BRAF mutation dominated prognosis during the first year (d = 0.48), whereas surgeon-related variables (ie, surgical margin and resected extrahepatic disease) determined prognosis thereafter (d ≥ 0.5). Traditional clinicopathologic factors affected survival constantly, but only to a moderate degree (0.3 ≤ d < 0.5).

Conclusions: The impact of genetic, surgery-related, and clinicopathologic factors on OS and CS3 changed dramatically over time. Specifically, BRAF mutation status dominated prognosis in the first year, whereas positive surgical margins and resected extrahepatic disease determined prognosis thereafter.
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http://dx.doi.org/10.1097/SLA.0000000000002664DOI Listing
June 2019

KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases.

HPB (Oxford) 2019 11 9;21(11):1527-1534. Epub 2019 Apr 9.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address:

Background: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined.

Methods: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response.

Results: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023).

Conclusions: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.
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http://dx.doi.org/10.1016/j.hpb.2019.03.368DOI Listing
November 2019

FDG-PET/MRI imaging for the management of alveolar echinococcosis: initial clinical experience at a reference centre in Austria.

Trop Med Int Health 2019 06 27;24(6):663-670. Epub 2019 Mar 27.

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Background: [ F]-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (FDG-PET/CT) imaging provides important information about the size and metabolic activity of lesions caused by Echinococcus multilocularis and is therefore recommended for the initial assessment and follow-up of human alveolar echinococcosis (AE). The introduction of positron emission tomography/magnetic resonance imaging (PET/MRI) into clinical practice in affluent health care systems provides an alternative dual imaging modality, which has not yet been evaluated for AE.

Objective: Here, we describe the initial clinical experience with comparative PET/CT and PET/MR imaging in four human AE patients at an Austrian reference centre.

Results: PET/MR imaging showed comparable diagnostic capacity for liver lesions attributable to E. multilocularis infection, with a discrepancy only in the assessment of calcifications in one patient. Effective doses of radiation were 30.4-31 mSV for PET/CT, which were reduced in PET/MRI to the exposure of F-FDG only (4.9-5.5 mSv).

Conclusions: PET/MRI provides comparable diagnostic information for AE management. The reduction in radiation exposure compared to PET/CT may be of particular importance for children and young patients not amenable for curative surgery requiring repeated long-term follow-up with dual imaging modalities. Further studies are warranted to prospectively evaluate the potential of PET/MRI in the management of AE.
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http://dx.doi.org/10.1111/tmi.13228DOI Listing
June 2019

Evaluation of direct costs associated with alveolar and cystic echinococcosis in Austria.

PLoS Negl Trop Dis 2019 01 31;13(1):e0007110. Epub 2019 Jan 31.

Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Cystic echinococcosis (CE) is a globally occurring zoonosis, whereas alveolar echinococcosis (AE) is endemic only in certain parts of the Northern Hemisphere. The socioeconomic impact of human echinococcosis has been shown to be considerable in highly endemic regions. However, detailed data on direct healthcare-related costs associated with CE and AE are scarce for high income countries. The aim of this study was to evaluate direct costs of human disease caused by CE and AE in Austria.

Methods: Clinical data from a registry maintained at a national reference center for echinococcosis at the Medical University of Vienna were obtained for the years 2012-2014. These data were used in conjunction with epidemiological data from Austria's national disease reporting system and diagnostic reference laboratory for echinococcosis to assess nationwide costs attributable to CE and AE.

Results: In Austria, total modelled direct costs were 486,598€ (95%CI 341,825€ - 631,372€) per year for CE, and 683,824€ (95%CI 469,161€ - 898,486€) for AE. Median costs per patient with AE from diagnosis until the end of a 10-year follow-up period were 30,832€ (25th- 75th percentile: 23,197€ - 31,220€) and 62,777€ (25th- 75th percentile: 60,806€ - 67,867€) for inoperable and operable patients, respectively. Median costs per patients with CE from diagnosis until end of follow-up after 10 years were 16,253€ (25th- 75th percentile: 8,555€ - 24,832€) and 1,786€ (25th- 75th percentile: 736€ - 2,146€) for patients with active and inactive cyst stages, respectively. The first year after inclusion was the most cost-intense year in the observed period, with hospitalizations and albendazole therapy the main contributors to direct costs.

Conclusions: This study provides detailed information on direct healthcare-related costs associated with CE and AE in Austria, which may reflect trends for other high-income countries. Surgery and albendazole therapy, due to surprisingly high drug prices, were identified as important cost-drivers. These data will be important for cost-effectiveness analyses of possible prevention programs.
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http://dx.doi.org/10.1371/journal.pntd.0007110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354963PMC
January 2019

How radical is total parathyroidectomy in patients with renal hyperparathyroidism?

Langenbecks Arch Surg 2018 Dec 5;403(8):1007-1013. Epub 2018 Dec 5.

Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna, Waehringer Gürtel 18-20, A-1090, Vienna, Austria.

Purpose: Total parathyroidectomy (tPTX) in patients with renal hyperparathyroidism (RHPT) aims at the complete removal of all hyperfunctioning parathyroid tissue. Whenever parathyroidectomy is termed "total," undetectable postoperative parathyroid hormone (PTH) levels within the first postoperative week are expected. The aim of this study was to evaluate if tPTX is technically possible using a radical surgical procedure.

Methods: In 109 consecutive patients with RHPT (on hemodialysis: n = 50; after kidney grafting n = 59), removal of all visible parathyroid tissue, bilateral thymectomy, bilateral central neck dissection (level VI), and immediate autotransplantation (AT) was performed. Intact PTH (iPTH) levels were measured in the first postoperative week. PTX was classified "total" when iPTH dropped below 10 pg/ml, "subtotal" between 10 and 65 pg/ml, and "insufficient" where levels stayed above 65 pg/ml.

Results: According to the postoperative PTH value, tPTX was achieved in 80 of 109 (73.4%) patients (hemodialysis n = 27, normal kidney function: n = 43, restricted: n = 10). PTX was "subtotal" in 25 patients (22.9%), 19 on hemodialysis, 2 had normal, and 4 had restricted kidney graft function. PTX turned out to be insufficient in four patients (3.7%); all of them were on hemodialysis. Insufficient PTX was not observed in kidney-grafted patients. Postoperative temporary laryngeal nerve morbidity was 1.8% (no permanent paresis).

Conclusions: Although applying a very radical concept in patients with RHPT, PTX was "total" in only 73.4%. Persistence of disease was avoided in 91.7%, and low morbidity was documented. In conclusion, it seems difficult to remove all parathyroid tissue from the neck which has to be considered when choosing the surgical procedure.
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http://dx.doi.org/10.1007/s00423-018-1739-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328515PMC
December 2018

von Willebrand Factor Antigen Predicts Outcomes in Patients after Liver Resection of Hepatocellular Carcinoma.

Gut Liver 2020 03;14(2):218-224

Department of General Surgery, Medical University Vienna, Vienna, Austria.

Background/aims: von Willebrand factor antigen (vWF-Ag) is a noninvasive predictor of portal hypertension that serves as a negative prognostic marker in various malignancies. Increased portal hypertension is associated with higher postoperative morbidity and decreased survival after hepatectomy. The purpose of this study was to determine the correlation between vWF-Ag, postoperative morbidity and oncological outcome.

Methods: This analysis includes 55 patients who underwent liver resection for hepatocellular carcinoma (HCC) between 2008 and 2015 with available preoperative vWF-Ag levels. The primary endpoints were postoperative complications and long-term outcome, including overall and disease-free survival.

Results: The median plasma level of vWF-Ag was 191% (range, 162.5% to 277%). There was a significant correlation between vWF-Ag levels and tumor size in the resected specimens (p=0.010, r=0.350). Patients who developed any grade of postoperative complication had significantly higher preoperative vWF-Ag levels (216% [range, 178% to 283.25%] vs 176% [range, 148% to 246%], p=0.041). Median overall survival was 39.8 months in patients with high vWF-Ag levels (≥191%) compared with 73.4 months in patients with low levels (<191%, p=0.007). Of note, there was a remarkable disparity in the number of patients who died of HCC with low versus high vWF-Ag levels (14.8% vs 28.6%, p=0.011).

Conclusions: vWF-Ag may serve as a prognostic marker for the outcome of patients undergoing liver resection for HCC that is closely connected to tumor size, postoperative complication rate and long-term outcome.
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http://dx.doi.org/10.5009/gnl17115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096232PMC
March 2020

The prognosis of colorectal cancer liver metastases associated with inflammatory bowel disease: An exploratory analysis.

J Surg Oncol 2018 Dec 27;118(7):1074-1080. Epub 2018 Sep 27.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background And Objectives: In contrast with sporadic colorectal cancer liver metastases (CRLM), inflammatory bowel disease (IBD)-related CRLM have not been studied to date.

Methods: Patients who underwent resection for IBD-related and sporadic CRLM from 2000 to 2015 were identified from an international registry and matched for pertinent prognostic variables. Overall survival (OS) and recurrence-free survival (RFS) were subsequently assessed.

Results: Twenty-eight patients had IBD-related CRLM. Synchronous extrahepatic disease was more common in IBD-related CRLM patients than patients with sporadic CRLM (28.6% vs 8.3%; P < 0.001), most commonly located in the lungs. In multivariable analysis, IBD did not have a significant influence on OS ( P = 0.835), and had a hazard ratio (HR) close to 1 (HR, 0.95; 95% confidence interval [CI], 0.57-1.57). IBD was also not associated with inferior RFS (HR, 1.07; 95%CI, 0.68-1.68; P = 0.780). Among patients with IBD-related CRLM, 9(50%) had isolated intrahepatic recurrence and 8(44.4%) isolated extrahepatic recurrence, while only 1(5.6%) developed combined recurrence. Of those who experienced recurrence after resection of IBD-related CRLM, 10 had their recurrence treated with curative intent.

Conclusions: Patients with IBD-related CRLM had similar survival compared with patients with sporadic CRLM, even though they more often present with extrahepatic disease. In addition, patients with IBD-related CRLM may experience patterns of recurrence different from patients with sporadic CRLM.
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http://dx.doi.org/10.1002/jso.25251DOI Listing
December 2018

Austrian consensus guidelines on imaging requirements prior to hepatic surgery and during follow-up in patients with malignant hepatic lesions.

Wien Klin Wochenschr 2018 Nov 30;130(21-22):665-672. Epub 2018 Aug 30.

Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases, hepatocellular carcinoma and cholangiocarcinoma. A variety of imaging modalities are available and play a pivotal role in the work-up of patients, particularly as imaging findings determine resectability. Surgery often represents the only measure that can render long-term survival possible. Imaging is also indispensable for the assessment of responses to neoadjuvant treatment and for the detection of recurrence. At a consensus meeting held in June 2017 in Vienna, Austria, Austrian experts in the fields of surgery and radiology discussed imaging requirements prior to and after hepatic surgery for malignant liver lesions. This consensus was refined by online voting on a total of 47 items. Generally, the degree of consensus was high. The recommendations relate to the type of preferred preoperative imaging modalities, technical settings with respect to computed tomography and magnetic resonance imaging, use of contrast agents, reporting, postoperative follow-up, and long-term follow-up. Taking local resources into account, these consensus recommendations can be implemented in daily clinical practice at specialized centers as well as outpatient diagnostic institutes in Austria.
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http://dx.doi.org/10.1007/s00508-018-1387-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244807PMC
November 2018

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

Ann Surg 2018 11;268(5):894-902

Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC.

Patients And Methods: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9.

Results: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response.

Conclusion: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.
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http://dx.doi.org/10.1097/SLA.0000000000002901DOI Listing
November 2018

Liver resection for non-colorectal metastases.

Eur Surg 2018 25;50(3):113-116. Epub 2018 Apr 25.

Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Whereas liver resection for colorectal metastasis has become standard of care, hepatectomy in patients with non-colorectal metastases remains controversial, mainly due to a heterogeneous tumor biology and missing data from prospective trials. This review aims at giving an overview about the indications and limits of liver surgery in patients with an advanced disease of a non-colorectal malignancy. Even though prospective trials are largely missing, results from retrospective studies indicate a survival benefit for liver resection in selected patients. Thus, in metastasized patients, treatment strategies should be developed in a multidisciplinary tumor board including an experienced liver surgeon.
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http://dx.doi.org/10.1007/s10353-018-0528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968069PMC
April 2018

Association of BRAF Mutations With Survival and Recurrence in Surgically Treated Patients With Metastatic Colorectal Liver Cancer.

JAMA Surg 2018 07 18;153(7):e180996. Epub 2018 Jul 18.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: BRAF mutations are reportedly associated with aggressive tumor biology. However, in contrast with primary colorectal cancer, the association of V600E and non-V600E BRAF mutations with survival and recurrence after resection of colorectal liver metastases (CRLM) has not been well studied.

Objective: To investigate the prognostic association of BRAF mutations with survival and recurrence independently and compared with other prognostic determinants, such as KRAS mutations.

Design, Setting, And Participants: In this cohort study, all patients who underwent resection for CRLM with curative intent from January 1, 2000, through December 31, 2016, at the institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had data on BRAF and KRAS mutational status were retrospectively identified. Multivariate Cox proportional hazards regression models were used to assess long-term outcomes.

Interventions: Hepatectomy in patients with CRLM.

Main Outcomes And Measures: The association of V600E and non-V600E BRAF mutations with disease-free survival (DFS) and overall survival (OS).

Results: Of 853 patients who met inclusion criteria (510 men [59.8%] and 343 women [40.2%]; mean [SD] age, 60.2 [12.4] years), 849 were included in the study analyses. Forty-three (5.1%) had a mutated (mut) BRAF/wild-type (wt) KRAS (V600E and non-V600E) genotype; 480 (56.5%), a wtBRAF/wtKRAS genotype; and 326 (38.4%), a wtBRAF/mutKRAS genotype. Compared with the wtBRAF/wtKRAS genotype group, patients with a mutBRAF/wtKRAS genotype more frequently were female (27 [62.8%] vs 169 [35.2%]) and 65 years or older (22 [51.2%] vs 176 [36.9%]), had right-sided primary tumors (27 [62.8%] vs 83 [17.4%]), and presented with a metachronous liver metastasis (28 [64.3%] vs 229 [46.8%]). On multivariable analysis, V600E but not non-V600E BRAF mutation was associated with worse OS (hazard ratio [HR], 2.76; 95% CI, 1.74-4.37; P < .001) and DFS (HR, 2.04; 95% CI, 1.30-3.20; P = .002). The V600E BRAF mutation had a stronger association with OS and DFS than the KRAS mutations (β for OS, 10.15 vs 2.94; β for DFS, 7.14 vs 2.27).

Conclusions And Relevance: The presence of the V600E BRAF mutation was associated with worse prognosis and increased risk of recurrence. The V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort.
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http://dx.doi.org/10.1001/jamasurg.2018.0996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137519PMC
July 2018

Post-hepatectomy liver failure after major hepatic surgery: not only size matters.

Eur Radiol 2018 Nov 16;28(11):4748-4756. Epub 2018 May 16.

Department of Bio-medical Imaging and Image-guided Therapy, Medical University of Vienna - Vienna General Hospital, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

Objectives: To compare the value of functional future liver remnant (functFLR) to established clinical and imaging variables in prediction of post-hepatectomy liver failure (PHLF) after major liver resection.

Methods: This retrospective, cross-sectional study included 62 patients, who underwent gadoxetic acid enhanced MRI and MDCT within 10 weeks prior to resection of ≥ 4 liver segments. Future liver remnant (FLR) was measured in MDCT using semi-automatic software. Relative liver enhancement for each FLR segment was calculated as the ratio of signal intensity of parenchyma before and 20 min after i.v. administration of gadoxetic acid and given as mean (remnantRLE). Established variables included indocyanine green clearance, FLR, proportion of FLR, weight-adapted FLR and remnantRLE. functFLR was calculated as FLR multiplied by remnantRLE and divided by patient's weight. The association of measured variables and PHLF was tested with univariate and multivariate logistic regression analysis and receiver operator characteristics (ROC) curves compared with the DeLong method.

Results: Sixteen patients (25.8%) experienced PHLF. Univariate logistic regression identified FLR (p = 0.015), proportion of FLR (p = 0.004), weight-adapted FLR (p = 0.003), remnantRLE (p = 0.002) and functFLR (p = 0.002) to be significantly related to the probability of PHLF. In multivariate logistic regression analysis, a decreased functFLR was independently associated with the probability of PHLF (0.561; p = 0.002). Comparing ROC curves, functFLR showed a significantly higher area under the curve (0.904; p < 0.001) than established variables.

Conclusions: functFLR seems to be superior to established variables in prediction of PHLF after major liver resection.

Key Points: • functFLR is a parameter combining volumetric and functional imaging information, derived from MDCT and gadoxetic acid enhanced MRI. • In comparison to other established methods, functFLR is superior in prediction of post-hepatectomy liver failure. • functFLR could help to improve patient selection prior major hepatic surgery.
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http://dx.doi.org/10.1007/s00330-018-5487-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182758PMC
November 2018

Double and Mutations in Surgically Treated Colorectal Cancer Liver Metastases: An International, Multi-institutional Case Series.

Anticancer Res 2018 05;38(5):2891-2895

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, U.S.A.

Background: While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described.

Case Series: We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection.

Conclusion: The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.
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http://dx.doi.org/10.21873/anticanres.12535DOI Listing
May 2018

Microscopic biliary and perineural invasion and clinical outcome after neoadjuvant bevacizumab-based chemotherapy and liver resection in patients with colorectal liver metastases.

Eur J Surg Oncol 2018 Jan 26;44(1):139-147. Epub 2017 Nov 26.

Department of General Surgery, Medical University Vienna, Austria.

Background: The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue.

Methods: Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS).

Results: One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis.

Conclusions: In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.
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http://dx.doi.org/10.1016/j.ejso.2017.11.018DOI Listing
January 2018

Inflammatory response and oxidative stress during liver resection.

PLoS One 2017 18;12(10):e0185685. Epub 2017 Oct 18.

Department of Surgery and Center for Perioperative Medicine, Medical University of Vienna, Vienna, Austria.

Background: Postoperative complications are still a major concern after liver resection (LR). Systemic inflammation and deregulated reactive oxygen species during major abdominal surgery may impair outcome after hepatectomy.

Methods: Patients undergoing LR were included in this study (n = 40). Oxidative stress (OS) was measured peri- and post-operatively as static oxidation-reduction potential markers (sORP) and antioxidant capacity ORP (cORP) by using the RedoxSYS Diagnostic system. Furthermore, Th1- and Th2-specific cytokines were assessed.

Results: Whereas there was no significant change in systemic sORP during LR and in the early postoperative course, there was a substantial decrease of cORP immediately post-surgery, and on postoperative days 1 and 3 (p<0.001). OS response was tightly regulated, as there was a significant correlation between sORP and cORP (p<0.0001; R2:0.457). An increase of OS (sORP) after LR of more than 3 mV was predictive for severe postoperative complications (53.8% vs. 12.5; p = 0.017). There was a significantly higher IL-2 (p = 0.006) and IL-5 (p = 0.001) increase during hepatectomy in patients who developed a severe morbidity.

Conclusion: Antioxidant capacity remained stable during LR but dropped during the post-surgical period, suggesting a consumption of antioxidants to maintain OS within healthy range. Severe postoperative complications were associated with a pronounced inflammatory response during surgery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646773PMC
October 2017

FDG-PET/MRI in alveolar echinococcosis.

Int J Infect Dis 2017 11 19;64:67-68. Epub 2017 Sep 19.

Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Institut für Tropenmedizin, University of Tübingen, Tübingen, Germany; Bernhard Nocht Hospital for Tropical Diseases, Bernhard Nocht Institute for Tropical Medicine and University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2017.09.006DOI Listing
November 2017

ASCO 2016 - update colorectal liver metastases.

Authors:
Klaus Kaczirek

Memo 2017 17;10(2):103-105. Epub 2017 Jan 17.

Department of Surgery and Center for Perioperative Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

This short review summarizes the most relevant data on colorectal liver metastases (CLM) presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO). For this update, congress abstracts were grouped into three clinically relevant scenarios: CLM that are deemed upfront resectable, borderline resectable, and primarily unresectable. According to a large registry study, small, upfront resectable, solitary CLM should be resected using a parenchymal sparing technique. A prospective noninterventional study suggested that chemotherapy plus the anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is effective and well tolerated in patients with borderline resectable CLM. In the setting of CLM deemed initially unresectable, a phase 2 study reported superior outcomes in terms of liver metastases resection rates as well as overall survival (OS) in patients receiving a chemotherapy triplet (FOLFIRINOX) plus a targeted agent as compared to FOLFIRI or FOLFOX4 with the same targeted therapy. Finally, a study suggested that tailoring first-line chemotherapy according to and polymorphism status results in higher response rates and longer progression-free survival (PFS) as well as OS.
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http://dx.doi.org/10.1007/s12254-016-0308-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493718PMC
January 2017

Effects of Portal Hypertension on Gadoxetic Acid-Enhanced Liver Magnetic Resonance: Diagnostic and Prognostic Implications.

Invest Radiol 2017 08;52(8):462-469

From the *Departments of Biomedical Imaging and Image-Guided Therapy, †Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, and ‡Department of Surgery, Medical University of Vienna, Vienna; and §Department of Gastroenterology/Hepatology, Endocrinology, and Nephrology, Klinikum Klagenfurt am Woerthersee, Klagenfurt, Austria.

Objective: The aim of this study was to investigate the impact of portal hypertension (PH) on gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) and assess diagnostic and prognostic implications in comparison to established imaging features of PH.

Materials And Methods: Institutional review board-approved retrospective study of 178 patients (142 men; median age, 59.4 years) with chronic liver disease undergoing MRI and hepatic venous pressure gradient (HVPG) measurement between January 2008 and April 2015. Magnetic resonance imaging was assessed for established features of PH (splenic and portal vein diameters, portosystemic collaterals, ascites) and for features on 20 minutes delayed T1-weighted gadoxetic acid-enhanced MRI, that is, relative liver enhancement (RLE), biliary contrast excretion, or portal vein hyperintensity or isointensity (ie, portal vein hyperintensity sign, PVHS). Statistics encompassed linear regression, logistic regression, and survival analysis.

Results: There was an inverse correlation between HVPG and RLE (r = 0.18, P < 0.0001). On univariate analysis, clinically significant PH (ie, HVPG ≥ 10 mm Hg, n = 109) and severe PH (ie, HVPG ≥ 12 mm Hg, n = 99) were associated with delayed biliary contrast excretion (n = 33) and the PVHS (n = 74) (P < 0.01 for all). Multivariate analysis demonstrated significant associations between the PVHS and severe PH (odds ratio [OR], 3.33; P = 0.008), independently of spleen size (OR, 1.26; P = 0.002), portosystemic collaterals (n = 81; OR, 5.46; P = 0.0001), and ascites (n = 88; OR, 3.24; P = 0.006). Lower RLE and the PVHS were associated with lower 3-year, transplantation-free survival (hazards ratios, 0.98 and 3.99, respectively, P = 0.002 for all), independently of the Child-Pugh and Model for End-Stage Liver Disease scores.

Conclusions: The presence of the PVHS on gadoxetic acid-enhanced MRI is an independent indicator of severe PH and may enable more accurate diagnosis. This feature and decreased hepatic contrast uptake may also comprise prognostic information.
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http://dx.doi.org/10.1097/RLI.0000000000000366DOI Listing
August 2017

The value of [C]-acetate PET and [F]-FDG PET in hepatocellular carcinoma before and after treatment with transarterial chemoembolization and bevacizumab.

Eur J Nucl Med Mol Imaging 2017 Sep 29;44(10):1732-1741. Epub 2017 May 29.

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Purpose: This prospective study was to investigate the value of [C]-acetate PET and [F]-FDG PET in the evaluation of hepatocellular carcinoma (HCC) before and after treatment with transarterial chemoembolization (TACE) and vascular endothelial growth factor (VEGF) antibody (bevacizumab).

Methods: Twenty-two patients (three women, 19 men; 62 ± 8 years) with HCC verified by histopathology were treated with TACE and bevacizumab (n = 11) or placebo (n = 11). [C]-acetate PET and [F]-FDG PET were performed before and after TACE with bevacizumab or placebo. Comparisons between groups were performed with t-tests and Chi-squared tests, where appropriate. Overall survival (OS) was defined as the time from start of bevacizumab or placebo until the date of death/last follow-up, respectively.

Results: The patient-related sensitivity of [C]-acetate PET, [F]-FDG PET, and combined [C]-acetate and [F]-FDG PET was 68%, 45%, and 73%, respectively. There was a significantly higher rate of conversion from [C]-acetate positive lesions to negative lesions in patients treated with TACE and bevacizumab as compared with that in patients with TACE and placebo (p < 0.05). In patients with negative acetate PET, the mean OS in patients treated with TACE and bevacizumab was 259 ± 118 days and was markedly shorter as compared with that (668 ± 217 days) in patients treated with TACE and placebo (p < 0.05). In patients treated with TACE and placebo, there was significant difference in mean OS in patients with positive FDG PET as compared with that in patients with negative FDG PET (p < 0.05). The HCC lesions had different tracer avidities showing the heterogeneity of HCC.

Conclusions: Our study suggests that combining [F]-FDG with [C]-acetate PET could be useful for the management of HCC patients and might also provide relevant prognostic and molecular heterogeneity information.
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http://dx.doi.org/10.1007/s00259-017-3724-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537334PMC
September 2017

Impact of Neoadjuvant Chemotherapy on Clinical Risk Scores and Survival in Patients with Colorectal Liver Metastases.

Ann Surg Oncol 2017 Jan 11;24(1):236-243. Epub 2016 Oct 11.

Department of General Surgery, Medical University of Vienna, Vienna, Austria.

Background: Several clinical risk scores for patients with colorectal liver metastases (CLM) were established in cohorts of patients undergoing liver resection (LR) without neoadjuvant chemotherapy (NAC). The purpose of the study was to evaluate the predictive values of four common risk scores in the setting of NAC and the impact of score changes during NAC.

Methods: Risk scores (Fong, Nordlinger, Nagashima, and Konopke) were retrospectively calculated for 336 patients undergoing LR for CLM, including 109 patients without and 227 patients with NAC. In patients with NAC, the scores were calculated before and after NAC.

Results: In patients without NAC (n = 109), all risk scores except the Konopke score showed a significant correlation with disease-free survival (DFS). Only the Nagashima score also was predictive for overall survival (OS). In patients with NAC (n = 227), all scores except the Konopke score were predictive for DFS and OS before and after NAC. Score changes in the Fong and the Nagashima score showed a significant correlation with DFS and OS.

Conclusions: Nagashima score was the most universally applicable score and predicted prognosis in all tested scenarios.
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http://dx.doi.org/10.1245/s10434-016-5615-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179581PMC
January 2017

Intra-cystic concentrations of albendazole-sulphoxide in human cystic echinococcosis: a systematic review and analysis of individual patient data.

Parasitol Res 2016 Aug 16;115(8):2995-3001. Epub 2016 Apr 16.

Division of Infectious Diseases and Tropical Medicine Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)-the first-line anthelminthic drug for medical treatment of CE-is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = -0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 μg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 μg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 μg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts (β = -17.2 μg/L/cm; 95th CI, -35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis.
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http://dx.doi.org/10.1007/s00436-016-5054-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958128PMC
August 2016

Transection Speed and Impact on Perioperative Inflammatory Response - A Randomized Controlled Trial Comparing Stapler Hepatectomy and CUSA Resection.

PLoS One 2015 9;10(10):e0140314. Epub 2015 Oct 9.

Dept. of Surgery, Div. of General Surgery, Medical University of Vienna, Vienna, Austria.

Background: Parenchymal transection represents a crucial step during liver surgery and many different techniques have been described so far. Stapler resection is supposed to be faster than CUSA resection. However, whether speed impacts on the inflammatory response in patients undergoing liver resection (LR) remains unclear.

Materials And Methods: This is a randomized controlled trial including 40 patients undergoing anatomical LR. Primary endpoint was transection speed (cm2/min). Secondary endpoints included the perioperative change of pro- and anti-inflammatory cytokines, overall surgery duration, length of hospital stay, morbidity and mortality.

Results: Mean transection speed was significantly higher in patients undergoing stapler hepatectomy compared to CUSA resection (CUSA: 1 (0.4) cm2/min vs. Stapler: 10.8 (6.1) cm2/min; p<0.0001). Analyzing the impact of surgery duration on inflammatory response revealed a significant correlation between IL-6 levels measured at the end of surgery and the overall length of surgery (p<0.0001, r = 0.6188). Patients undergoing CUSA LR had significantly higher increase of interleukin-6 (IL-6) after parenchymal transection compared to patients with stapler hepatectomy in the portal and hepatic veins, respectively (p = 0.028; p = 0.044). C-reactive protein levels on the first post-operative day were significantly lower in the stapler cohort (p = 0.010). There was a trend towards a reduced overall surgery time in patients with stapler LR, especially in the subgroup of patients undergoing minor hepatectomies (p = 0.020).

Conclusions: Liver resection using staplers is fast, safe and suggests a diminished inflammatory response probably due to a decreased parenchymal transection time.

Trial Registration: ClinicalTrials.gov NCT01785212.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140314PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599945PMC
June 2016

FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study.

Clin Colorectal Cancer 2015 Jun 24;14(2):91-8. Epub 2014 Dec 24.

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab.

Patients And Methods: Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups.

Results: Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.

Conclusion: These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.
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http://dx.doi.org/10.1016/j.clcc.2014.12.003DOI Listing
June 2015
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