Publications by authors named "Philipp Mayer"

202 Publications

Combining Headspace Solid-Phase Microextraction with Internal Benchmarking to Determine the Elimination Kinetics of Hydrophobic UVCBs.

Environ Sci Technol 2021 Jul 29. Epub 2021 Jul 29.

Department for Environmental Science, Stockholm University, 114 19 Stockholm, Sweden.

Substances classified as unknown or variable composition, complex reaction products or biological origin (UVCB) present a challenge for environmental hazard and risk assessment. Here, we present a novel approach for whole-substance bioconcentration testing applied to cedarwood oil-an essential oil composed of volatile, hydrophobic organic chemicals. The method yields whole-body elimination rate constants for a mixture of constituents. Our approach combines in vivo dietary fish exposure with internal benchmarking and headspace solid-phase microextraction (HS-SPME) equilibrium sampling followed by suspect-screening analysis. We quantified depuration rate constants of 13 individual cedarwood oil constituents based on relative peak areas using gas chromatography (GC) coupled with Orbitrap-mass spectrometry (MS) and GC triple-quadrupole (QqQ)-MS. For seven constituents with available analytical standards, we compared the rate constants to the results obtained from solvent extraction, clean-up, and targeted GC-MS analysis. The HS-SPME sampling approach allowed for automated sample extraction and analyte enrichment while minimizing evaporative losses of the volatile target analytes and reducing matrix interferences from low-volatility organics. The suspect-screening analysis enabled the quantification of constituents without available analytical standards, while the internal benchmarking significantly reduced variability from differences in delivered dose and analytical variability between the samples.
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http://dx.doi.org/10.1021/acs.est.1c00179DOI Listing
July 2021

Sublethal Effect Concentrations for Non-Polar Narcosis in the Zebrafish Embryo.

Environ Toxicol Chem 2021 Jul 20. Epub 2021 Jul 20.

Zebrafishlab, Veterinary, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Non-polar narcosis, also known as baseline toxicity, has been described as the minimal toxicity that an organic chemical may elicit based on its lipophilicity. While lethal effects of narcosis-inducing chemicals (NICs) have been thoroughly investigated, knowledge of sublethal effects is still very limited. We investigated the effects of three well-known NICs (phenanthrene, 1,3,5-trichlorobenzene and pentachlorobenzene) on a variety of organismal endpoints (malformations, swim bladder inflation, respiration, heart rate, swimming activity and turning angles), which can be plausibly linked to narcosis in zebrafish embryos. Baseline toxicity recorded as mortality is typically observed in similar exposure ranges in a wide variety of species including fish, corresponding to a chemical activity range between 0.01 and 0.1. In the present study we found that sublethal effects occurred at concentrations around 5 times below lethal concentrations. Altered swimming activity and impaired swim bladder inflation were the most sensitive endpoints occurring at exposure levels below the generally accepted threshold for baseline toxicity for two out of three compounds. Overall, most effective exposure levels across the sublethal endpoints and compounds did fall within the range typically associated with baseline toxicity, and deviations were generally limited to a factor 10. While there could be benefit in adding sublethal endpoints to toxicity tests, such as the Fish Embryo Acute Toxicity (FET) test, based on the present sublethal endpoints and available evidence from our and other studies, the underestimation of toxicity due to the sole assessment of mortality as an endpoint in a FET test may be limited for narcosis. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/etc.5170DOI Listing
July 2021

Biodegradation of an essential oil UVCB - Whole substance testing and constituent specific analytics yield biodegradation kinetics of mixture constituents.

Chemosphere 2021 Sep 1;278:130409. Epub 2021 Apr 1.

Technical University of Denmark, Department of Environmental Engineering, Building 115, 2800 Kgs, Lyngby, Denmark. Electronic address:

Testing and assessing the persistency, bioaccumulative and toxic properties of UVCBs (substances of Unknown or Variable composition, Complex reaction products or Biological materials) pose major technical and analytical challenges. The main aim of this study was to combine whole substance biodegradation testing with constituent specific analytics for determining primary biodegradation kinetics of the main UVCB constituents. An additional aim was to link the primary biodegradation kinetics of the main constituents to the bioaccumulation potential and baseline toxicity potential of the UVCB. Two closed biodegradation experiments were conducted using similar test systems but different analyses. The model substance, cedarwood Virginia oil, was tested at a low concentration and wastewater treatment plant effluent served as inoculum. We used microvolume solvent spiking for a quantitative mass transfer of the UVCB, while avoiding that co-solvent degradation would lead to anaerobic conditions. The biodegradation of UVCB constituents was determined with automated solid-phase microextraction coupled to GC-MS/MS using targeted analysis for main constituents and non-targeted analysis for minor constituents and non-polar degradation products. Primary biodegradation kinetics of main constituents, accounting for 73% w/w of the mixture, were successfully determined with degradation rate constants ranging from 0.09 to 0.25 d. Minor constituents were also degraded and non-polar degradation products were not observed. Finally, the bioaccumulation potential and baseline toxicity potential of the mixture at test start were calculated and both parameters decreased then substantially. The strength of the new approach is the possibility of biodegradation testing of a whole UVCB at low concentration while generating constituent specific biodegradation kinetics.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130409DOI Listing
September 2021

Risk of the Watch-and-Wait Concept in Surgical Treatment of Intraductal Papillary Mucinous Neoplasm.

JAMA Surg 2021 May 19. Epub 2021 May 19.

Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Importance: The natural history of intraductal papillary mucinous neoplasms (IPMNs) remains uncertain. The inconsistencies among published guidelines preclude accurate decision-making. The outcomes and potential risks of a conservative watch-and-wait approach vs a surgical approach must be compared.

Objective: To provide an overview of the surgical management of IPMNs, focusing on the time of resection.

Design, Setting, And Participants: This cohort study was conducted in a single referral center; all patients with pathologically proven IPMN who received a pancreatic resection at the institution between October 2001 and December 2019 were analyzed. Preoperatively obtained images and the medical history were scrutinized for signs of progression and/or malignant features. The timeliness of resection was stratified into too early (adenoma and low-grade dysplasia), timely (intermediate-grade dysplasia and in situ carcinoma), and too late (invasive cancer). The perioperative characteristics and outcomes were compared between these groups.

Exposures: Timeliness of resection according to the final pathological findings.

Main Outcomes And Measures: The risk of malignant transformation at the final pathology.

Results: Of 1439 patients, 438 (30.4%) were assigned to the too early group, 504 (35.1%) to the timely group, and 497 (34.5%) to the too late group. Radiological criteria for malignant conditions were detected in 53 of 382 patients (13.9%), 149 of 432 patients (34.5%), and 341 of 385 patients (88.6%) in the too early, timely, and too late groups, respectively (P < .001). Patients in the too early group underwent more parenchyma-sparing resections (too early group, 123 of 438 [28.1%]; timely group, 40 of 504 [7.9%]; too late group, 5 of 497 [1.0%]; P < .001), while morbidity (too early group, 112 of 438 [25.6%]; timely group, 117 of 504 [23.2%]; too late group, 158 of 497 [31.8%]; P = .002) and mortality (too early group, 4 patients [0.9%]; timely, 4 [0.8%]; too late, 13 [2.6%]; P = .03) were highest in the too late group. Of the 497 patients in the too late group, 124 (24.9%) had a previous history of watch-and-wait care.

Conclusions And Relevance: Until the biology and progression patterns of IPMN are clarified and accurate guidelines established, a watch-and-wait policy should be applied with caution, especially in IPMN bearing a main-duct component. One-third of IPMNs reach the cancer stage before resection. At specialized referral centers, the risks of surgical morbidity and mortality are justifiable.
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http://dx.doi.org/10.1001/jamasurg.2021.0950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135052PMC
May 2021

[The microarchitecture of pancreatic cancer from the point of view of the pathologist and the radiologist].

Pathologe 2021 May 6. Epub 2021 May 6.

Institut für Pathologie, Universitätsmedizin, JGU Mainz, 55131, Mainz, Deutschland.

Diagnostic radiology and diagnostic pathology are medical disciplines that use a variety of morphological analyses with different macroscopic and microscopic resolutions for diagnosis and staging of cancers. In the clinical setting, radiology and pathology departments are often spatially separated. However, there are examples of increasingly tight cooperation and convergence, for example in the setting of multidisciplinary tumor boards. This article focuses exemplarily on the correlations of radiological and histopathological diagnostics in pancreatic cancer.
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http://dx.doi.org/10.1007/s00292-021-00949-2DOI Listing
May 2021

Gastric Venous Congestion After Total Pancreatectomy Is Frequent and Dangerous.

Ann Surg 2021 Mar 4. Epub 2021 Mar 4.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany ‡Department of Radiology, Heidelberg University Hospital, Heidelberg, Germany §Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany ||Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Objective: The aim of this study was to determine the role of gastric venous congestion (GVC) in mortality after total pancreatectomy (TP).

Background: Data from a nationwide administrative database revealed that TP is associated with a 23% mortality rate in Germany.

Methods: A total of 585 consecutive patients who had undergone TP (n = 514) or elective completion pancreatectomy (n = 71) between January 2015 and December 2019 were analyzed. Univariable and multivariable analyses were performed to identify risk factors for GVC and 90-day mortality.

Results: GVC was observed in 163 patients (27.9%) requiring partial or total gastrectomy. Splenectomy (OR 2.14, 95% CI 1.25-3.80, p = 0.007) and coronary vein resection (OR 5.49, 95% CI 3.19-9.64, p < 0.001) were independently associated with GVC. The overall 90-day mortality after TP was 4.1% (24 of 585 patients), 7.4% in patients with GVC and 2.8% in those without GVC (p = 0.014). Of the 24 patients who died after TP, 12 (50%) had GVC.

Conclusion: GVC is a frequent albeit not well-known finding after TP, especially when splenectomy and resection of the coronary vein are performed. Adequate decision making for partial gastrectomy during TP is crucial. Insufficient gastric venous drainage after TP is life-threatening.
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http://dx.doi.org/10.1097/SLA.0000000000004847DOI Listing
March 2021

Passive Dosing of Petroleum and Essential Oil UVCBs-Whole Mixture Toxicity Testing at Controlled Exposure.

Environ Sci Technol 2021 05 8;55(9):6150-6159. Epub 2021 Apr 8.

Department of Environmental Engineering, Technical University of Denmark, Lyngby DK-2800 Kgs, Denmark.

Petroleum products and essential oils are produced and used in large amounts and are categorized as "Substances of Unknown or Variable composition, Complex reaction products or Biological materials (UVCBs)." These UVCBs are notorious difficult-to-test substances, since they are complex mixtures of hydrophobic and volatile compounds. This study introduces two passive dosing (PD) approaches for whole UVCB toxicity testing: (1) headspace PD applies the UVCB and purified lipid oil as a donor to control exposure via the headspace and (2) silicone rod PD applies UVCB-loaded silicone rods to control exposure via an aqueous test medium and headspace. Headspace gas chromatography-mass spectrometry measurements were used to cross-validate the approaches at the saturation level and to confirm exposure and maintain mixture composition at varying donor concentration levels. Both approaches were applied to whole-mixture toxicity tests of petroleum and essential oil UVCBs with daphnia and algae. Finally, the observed toxicity was linked to concentrations in the donor and in lipid membranes at equilibrium with the donors. Dose-response curves were similar across the dosing approaches and tested species for petroleum products but differed by an order of magnitude between essential oils and PD systems. All observed toxic effects were consistent with baseline toxicity, and no excess mixture toxicity was observed.
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http://dx.doi.org/10.1021/acs.est.1c00343DOI Listing
May 2021

Computed Tomography Perfusion Analysis of Pancreatic Adenocarcinoma using Deconvolution, Maximum Slope, and Patlak Methods - Evaluation of Diagnostic Accuracy and Interchangeability of Cut-Off Values.

Rofo 2021 Mar 26. Epub 2021 Mar 26.

Imaging and Prevention Center, Conradia Radiology Munich, Germany.

Purpose:  The goal of this study was to evaluate the diagnostic accuracy of perfusion computed tomography (CT) parameters obtained by different mathematical-kinetic methods for distinguishing pancreatic adenocarcinoma from normal tissue. To determine cut-off values and to assess the interchangeability of cut-off values, which were determined by different methods.

Materials And Methods:  Perfusion CT imaging of the pancreas was prospectively performed in 23 patients. 19 patients with histopathologically confirmed pancreatic adenocarcinoma were included in the study. Blood flow (BF), blood volume (BV) and permeability-surface area product (PS) were measured in pancreatic adenocarcinoma and normal tissue with the deconvolution (BF, BV, PS), maximum slope (BF), and Patlak methods (BV, PS). The interchangeability of cut-off values was examined by assessing agreement between BF, BV, and PS measured with different mathematical-kinetic methods.

Results:  Bland-Altman analysis demonstrated poor agreement between perfusion parameters, measured with different mathematical-kinetic methods. According to receiver operating characteristic (ROC) analysis, PS measured with the Patlak method had the significantly lowest diagnostic accuracy (area under ROC curve = 0.748). All other parameters were of high diagnostic accuracy (area under ROC curve = 0.940-0.997), although differences in diagnostic accuracy were not statistically different. Cut-off values for BF of ≤ 91.83 ml/100 ml/min and for BV of ≤ 5.36 ml/100 ml, both measured with the deconvolution method, appear to be the most appropriate cut-off values to distinguish pancreatic adenocarcinoma from normal tissue.

Conclusion:  Perfusion parameters obtained by different methods are not interchangeable. Therefore, cut-off values, which were determined using different methods, are not interchangeable either. Perfusion parameters can help to distinguish pancreatic adenocarcinoma from normal tissue with high diagnostic accuracy, except for PS measured with the Patlak method.

Key Points:   · Perfusion CT parameters showed high diagnostic accuracy in differentiating between pancreatic adenocarcinoma and normal tissue.. · Only PS measured with the Patlak method showed a significantly lower diagnostic accuracy.. · Perfusion parameters measured with different mathematical-kinetic methods are not interchangeable.. · A specific cut-off value must be determined for each method and each perfusion parameter..

Citation Format: · Koell M, Klauss M, Skornitzke S et al. Computed Tomography Perfusion Analysis of Pancreatic Adenocarcinoma with the Deconvolution, Maximum Slope, and Patlak Methods - Evaluation of Diagnostic Accuracy and Interchangeability of Cut-Off Values. Fortschr Röntgenstr 2021; DOI: 10.1055/a-1401-0333.
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http://dx.doi.org/10.1055/a-1401-0333DOI Listing
March 2021

Clinical presentation and prognosis of adenosquamous carcinoma of the pancreas - Matched-pair analysis with pancreatic ductal adenocarcinoma.

Eur J Surg Oncol 2021 Jul 16;47(7):1734-1741. Epub 2021 Feb 16.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Introduction: Adenosquamous carcinoma of the pancreas (ASCP) is a rare subtype of pancreatic adenocarcinoma. The aim of this study was to investigate the characteristics and outcomes of ASCP in comparison to pancreatic ductal adenocarcinoma (PDAC).

Materials And Methods: All patients with ASCP treated between December 2001 and December 2017 were identified from a prospective database. Clinicopathological and follow-up data were analyzed. A nested case-control-study with matched-pair analysis was performed to compare overall survival of ASCP and PDAC.

Results: Of 4009 patients undergoing surgery for pancreatic adenocarcinoma 91 patients had ASCP. Compared to PDAC ASCP were larger (4.0 vs. 3.2 cm; p < 0.0001), more frequently involved lymph nodes (88% vs. 78%; p = 0.0216), more frequently showed poor differentiation (G3: 79% vs. 36%; p < 0.0001) and more frequently were located in the pancreatic tail (19% vs. 10%; p = 0.0179). Overall median post-resection-survival was shorter in ASCP (10.8 vs. 20.5 months in PDAC; p = 0.0085), but 5-year survival rates were comparable (18.2% vs. 17.5%). After matching for the unevenly distributed prognostic factors survival after resection of ASCP and PDAC was comparable (p = 0.8301). Localization in the head or several parts of the pancreas, high CA 19-9 levels, and M1 disease were independent predictors of survival in patients with ASCP.

Conclusion: ASCP is more aggressive with poorer differentiation and higher rates of lymph node metastases compared to PDAC. In spite of a shorter median survival, 5-year survival rates after surgical resection of about 18% can be expected in ASCP and support resection as part of a multimodal therapy as the treatment of choice in this rare cancer.
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http://dx.doi.org/10.1016/j.ejso.2021.02.011DOI Listing
July 2021

Postoperative acute pancreatitis is a serious but rare complication after distal pancreatectomy.

HPB (Oxford) 2021 Jan 13. Epub 2021 Jan 13.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: The clinical relevance of hyperamylasemia after distal pancreatectomy (DP) remains unclear and no internationally accepted definition of postoperative acute pancreatitis (POAP) exists. The aim of this study was to characterize POAP after DP and to assess the role of serum amylase (SA) in POAP.

Methods: Outcomes of 641 patients who had undergone DP between 2015 and 2019 were analyzed. Postoperative SA was determined in all patients. POAP was defined based on contrast-enhanced computed tomography (CT) or intraoperative findings during relaparotomy.

Results: An elevation of SA on postoperative day 1 (hyperamylasemia) was found in 398 patients (62.1%). Twelve patients (1.87%) were identified with POAP. Ten patients demonstrated radiologic criteria for POAP and in two patients POAP was diagnosed during relaparotomy. Outcome of POAP patients was worse than that of patients with hyperamylasemia alone and that with normal SA without POAP evidence (postoperative pancreatic fistula 50% vs 30.6% vs 18.5%; length of hospital stay 26 days vs 12 vs 11, respectively). The overall 90-day mortality of all 641 patients was 0.6%.

Conclusion: POAP is a serious but rare complication after DP. Hyperamylasemia is of prognostic relevance after DP, but it seems not sufficient as a single parameter to diagnose POAP.
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http://dx.doi.org/10.1016/j.hpb.2021.01.004DOI Listing
January 2021

Assessment of tissue perfusion of pancreatic cancer as potential imaging biomarker by means of Intravoxel incoherent motion MRI and CT perfusion: correlation with histological microvessel density as ground truth.

Cancer Imaging 2021 Jan 19;21(1):13. Epub 2021 Jan 19.

Clinic for Diagnostic and Interventional Radiology (DIR), Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany.

Background/objectives: The aim of this study was to compare intravoxel incoherent motion (IVIM) diffusion weighted (DW) MRI and CT perfusion to assess tumor perfusion of pancreatic ductal adenocarcinoma (PDAC).

Methods: In this prospective study, DW-MRI and CT perfusion were conducted in nineteen patients with PDAC on the day before surgery. IVIM analysis of DW-MRI was performed and the parameters perfusion fraction f, pseudodiffusion coefficient D*, and diffusion coefficient D were extracted for tumors, upstream, and downstream parenchyma. With a deconvolution-based analysis, the CT perfusion parameters blood flow (BF) and blood volume (BV) were estimated for tumors, upstream, and downstream parenchyma. In ten patients, intratumoral microvessel density (MVD) and microvessel area (MVA) were analyzed microscopically in resection specimens. Correlation coefficients between IVIM parameters, CT perfusion parameters, and histological microvessel parameters in tumors were calculated. Receiver operating characteristic (ROC) analysis was performed for differentiation of tumors and upstream parenchyma.

Results: f significantly positively correlated with BF (r = 0.668, p = 0.002) and BV (r = 0.672, p = 0.002). There were significant positive correlations between f and MVD/ MVA (r ≥ 0.770, p ≤ 0.009) as well as between BF and MVD/ MVA (r ≥ 0.697, p ≤ 0.025). Correlation coefficients between f and MVD/ MVA were not significantly different from correlation coefficients between BF and MVD/ MVA (p ≥ 0.400). Moreover, f, BF, BV, and permeability values (PEM) showed excellent performance in distinguishing tumors from upstream parenchyma (area under the ROC curve ≥0.874).

Conclusions: The study shows that IVIM derived f and CT perfusion derived BF similarly reflect vascularity of PDAC and seem to be comparably applicable for the evaluation of tumor perfusion for tumor characterization and as potential quantitative imaging biomarker.

Trial Registration: DRKS, DRKS00022227, Registered 26 June 2020, retrospectively registered. https://www.drks.de/drks_web/navigate.do?navigationId=trial . HTML&TRIAL_ID=DRKS00022227.
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http://dx.doi.org/10.1186/s40644-021-00382-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816417PMC
January 2021

Balanced steady-state free precession MRCP is a robust alternative to respiration-navigated 3D turbo-spin-echo MRCP.

BMC Med Imaging 2021 01 11;21(1):10. Epub 2021 Jan 11.

Diagnostic and Interventional Radiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Despite synchronization to respiration, respiration-navigated (RN) 3D turbo-spin-echo MRCP is limited by susceptibility to motion artifacts. The aim of this study was to assess the quality of pancreaticobiliary duct visualization of a non-RN MRCP alternative based on balanced steady-state free precession imaging (BSSFP) with overlapping slices compared with RN-MRCP.

Methods: This is a retrospective study on 50 patients without pancreaticobiliary duct disease receiving MRCP at 1.5 T. We performed an intraindividual comparison of coronal RN-MRCP with combined coronal and transverse BSSFP-MRCP. Image quality was scored by 3 readers for 6 pancreaticobiliary duct segments (3 pancreatic, 3 biliary) using a 6-point scale. A segment score of 3 or lower as assessed by at least 2 of 3 readers was defined as insufficient segment visualization. Nonparametric tests and interrater reliability testing were used for statistical analysis.

Results: Overall duct visualization averaged over all readers was scored with 4.5 ± 1.1 for RN-MRCP (pancreatic, 4.1 ± 0.5; biliary, 5.0 ± 0.4) and 4.9 ± 0.9 for combined coronal and transverse BSSFP-MRCP (pancreatic, 4.6 ± 0.6; biliary, 5.1 ± 0.6), respectively (p < 0.001). The number of segments visualized insufficiently was 81/300 for RN-MRCP and 43/300 for BSSFP-MRCP (p < 0.001). Segments visualized insufficiently only in RN-MRCP had a mean score of 4.4 ± 0.8 in BSSFP-MRCP. Overall interrater agreement on superiority of BSSFP-MRCP segment scores over corresponding RN-MRCP was 0.70. Mean acquisition time was 98% longer for RN-MRCP (198.0 ± 98.7 s) than for combined coronal and transverse BSSFP-MRCP (100.2 ± 0.4 s).

Conclusions: Non-RN BSSFP-MRCP with overlapping slices is a fast alternative to RN-MRCP, frequently providing sufficient duct visualization when RN-MRCP fails.
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http://dx.doi.org/10.1186/s12880-020-00532-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802244PMC
January 2021

Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany.

Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia could be helpful for treatment decisions, for monitoring, especially in non-resectable tumors, or to optimize personalized therapy. In the present study, we investigated whether tumor hypoxia in PDAC is reflected by diffusion-weighted magnetic resonance imaging (DW-MRI), a functional imaging technique, frequently used in clinical practice for identification and characterization of pancreatic lesions. DW-MRI assesses the tissue microarchitecture by measuring the diffusion of water molecules, which is more restricted in highly compact tissues. As reliable surrogate markers for hypoxia, we determined Blimp-1 (B-lymphocyte induced maturation protein), a transcription factor, as well as vascular endothelial growth factor (VEGF), which are up-regulated in response to hypoxia. In 42 PDAC patients, we observed a close association between restricted water diffusion in DW-MRI and tumor hypoxia in matched samples, as expressed by high levels of Blimp-1 and VEGF in tissue samples of the respective patients. In summary, our data show that DW-MRI is well suited for the evaluation of tumor hypoxia in PDAC and could potentially be used for the identification of lesions with a high hypoxic fraction, which are at high risk for failure of radiochemotherapy.
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http://dx.doi.org/10.3390/cancers13010089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801953PMC
December 2020

Assessing toxicity of hydrophobic aliphatic and monoaromatic hydrocarbons at the solubility limit using novel dosing methods.

Chemosphere 2021 Feb 2;265:129174. Epub 2020 Dec 2.

Concawe, Environmental Management Group, Brussels, Belgium. Electronic address:

Reliable delineation of aquatic toxicity cut-offs for poorly soluble hydrocarbons is lacking. In this study, vapor and passive dosing methods were applied in limit tests with algae and daphnids to evaluate the presence or absence of chronic effects at exposures corresponding to the water solubility for representative hydrocarbons from five structural classes: branched alkanes, mono, di, and polynaphthenic (cyclic) alkanes and monoaromatic naphthenic hydrocarbons (MANHs). Algal growth rate and daphnid immobilization, growth and reproduction served as the chronic endpoints investigated. Results indicated that the dosing methods applied were effective for maintaining mean measured exposure concentrations within a factor of two or higher of the measured water solubility of the substances investigated. Chronic effects were not observed for hydrocarbons with an aqueous solubility below approximately 5 μg/L. This solubility cut-off corresponds to structures consisting of 13-14 carbons for branched and cyclic alkanes and 16-18 carbons for MANHs. These data support reliable hazard and risk evaluation of hydrocarbon classes that comprise petroleum substances and the methods described have broad applicability for establishing empirical solubility cut-offs for other classes of hydrophobic substances. Future work is needed to understand the role of biotransformation on the observed presence or absence of toxicity in chronic tests.
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http://dx.doi.org/10.1016/j.chemosphere.2020.129174DOI Listing
February 2021

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas.

Pancreatology 2021 Jan 3;21(1):224-235. Epub 2020 Dec 3.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background/objectives: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management.

Methods: Patients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed.

Results: Of 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients.

Conclusions: MiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.
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http://dx.doi.org/10.1016/j.pan.2020.11.020DOI Listing
January 2021

Joint Imaging Platform for Federated Clinical Data Analytics.

JCO Clin Cancer Inform 2020 11;4:1027-1038

German Cancer Consortium, Heidelberg, Germany.

Purpose: Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles.

Methods: The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions.

Results: The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform.

Conclusion: The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.
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http://dx.doi.org/10.1200/CCI.20.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713526PMC
November 2020

Effects of a Multicomponent Herbal Extract on the Course of Subclinical Ketosis in Dairy Cows - a Blinded Placebo-controlled Field-study.

Planta Med 2020 Dec 1;86(18):1375-1388. Epub 2020 Oct 1.

Department of Livestock Science, Research Institute of Organic Agriculture (FiBL), Frick, Switzerland.

A blinded placebo-controlled multi-center on-farm trial was conducted in dairy cows with subclinical ketosis to investigate effects of a multicomponent herbal extract. Blood ketone levels were measured weekly in early lactating cows from 16 Swiss herds. Cows were subclassified based on their initial blood--hydroxybutyrate levels (≥ 1.0 [KET-low, 84 cows] and > 1.2 mmol/L [KET-high, 39 cows]) and randomly distributed to 3 groups treated orally with herbal extract containing , and , sodium propionate, or placebo twice a day for 5 days. Milk yield, milk acetone, blood--hydroxybutyrate, glucose, nonesterified fatty acids, gamma-glutamyl transferase, and glutamate dehydrogenase were analyzed over 2 wk. Linear mixed effect models were used for data analysis. No effects were found for nonesterifed fatty acids, gamma-glutamyl transferase, and glucose. Significantly higher glutamate dehydrogenase (29.71 U/L) values were found in herbal extract-treated animals compared to sodium propionate on day 7 (22.33 U/L). By trend, higher blood--hydroxybutyrate levels (1.36 mmol/L) were found in the placebo group of KET-high-cows on day 14 compared to the sodium propionate group (0.91 mmol/L). Milk yields of all treatment groups increased. Milking time and treatment showed a significant interaction for milk acetone: sodium propionate led to an immediate decrease, whereas herbal extracts resulted in a milk acetone decrease from day 7 on, reaching significantly lower milk acetone on day 14 (3.17 mg/L) when compared to placebo (4.89 mg/L). In conclusion, herbal extracts and sodium propionate are both likely to improve subclinical ketosis in dairy cows, however, by different modes of action.
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http://dx.doi.org/10.1055/a-1260-3148DOI Listing
December 2020

Biodegradation kinetics testing of two hydrophobic UVCBs - potential for substrate toxicity supports testing at low concentrations.

Environ Sci Process Impacts 2020 Nov 1;22(11):2172-2180. Epub 2020 Oct 1.

Technical University of Denmark, Department of Environmental Engineering, Bygningstorvet, Building 115, 2800 Kgs. Lyngby, Denmark.

The biodegradation kinetics of UVCB substances (unknown or variable composition, complex reaction products or biological materials) should be determined below the solubility limit to avoid experimental artefacts by the non-dissolved mixture. Recently, we reported delayed biodegradation kinetics of single petroleum hydrocarbons even at concentrations just below the solubility limit and attributed this to toxicity. The present study aimed to determine the concentration effect on biodegradation kinetics for constituents in two UVCBs, using surface water from a rural stream as the inoculum. Parallel biodegradation tests of diesel and lavender oil were conducted at concentrations just below the solubility limit and two orders of magnitude lower. The biodegradation kinetics of diesel oil constituents were generally similar at the two concentrations, which coincided with the stimulation of bacterial productivity (growth) at both concentrations, determined by [H]leucine incorporation. By contrast, the biodegradation of lavender oil constituents was significantly delayed or even halted at the high test concentration. This was consistent with lavender oil stimulating bacterial growth at low concentration but inhibiting it at high concentration. The delayed biodegradation kinetics of lavender oil constituents at high concentration was best explained by mixture toxicity near the solubility limit. Consequently, biodegradation testing of hydrophobic UVCBs should be conducted at low, environmentally relevant concentrations ensuring that mixture toxicity does not affect the biodegradation kinetics.
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http://dx.doi.org/10.1039/d0em00288gDOI Listing
November 2020

Hyperamylasemia and acute pancreatitis after pancreatoduodenectomy: Two different entities.

Surgery 2021 02 25;169(2):369-376. Epub 2020 Sep 25.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Background: Serum amylase activity greater than the institutional upper limit of normal (hyperamylasemia) on postoperative day 0-2 has been suggested as a criterion to define postoperative acute pancreatitis after pancreatoduodenectomy, but robust evidence supporting this definition is lacking.

Background: To assess the clinical impact of hyperamylasemia after pancreatoduodenectomy and to define postoperative acute pancreatitis.

Methods: Data of 1,235 consecutive patients who had undergone pancreatoduodenectomy between January 2010 and December 2014 were extracted from a prospective database and analyzed. Postoperative acute pancreatitis was defined based on the computed tomography severity index. Logistic regression modeling was used to calculate the postoperative acute pancreatitis rate of the entire study population.

Results: Hyperamylasemia on postoperative day 1 was found in 52% of patients after pancreatoduodenectomy. Patients with hyperamylasemia on postoperative day 1 had statistically significantly greater morbidity and mortality than patients with a normal serum amylase activity on postoperative day 1 with the rates of postoperative pancreatic fistula of 14.5% vs 2.1%, and 90-day mortality of 6.6% vs 2.2%, respectively. Of the 364 patients who underwent postoperative computed tomography, 103 (28%) had radiologic signs of acute pancreatitis, thus defining them as having postoperative acute pancreatitis by our definition. Logistic regression modeling showed a 14.7% rate of postoperative acute pancreatitis for the entire patient cohort and 29.2% for patients with hyperamylasemia on postoperative day 1. Outcomes of patients with postoperative acute pancreatitis defined based on the computed tomography severity index showed a rate of postoperative pancreatic fistula of 32.4% and a 90-day mortality rate of 11.8%, which were worse than those of patients with hyperamylasemia on postoperative day 1 alone.

Conclusion: Hyperamylasemia on postoperative day 1 is a frequent finding after pancreatoduodenectomy, but hyperamylasemia on postoperative day 1 alone is not synonymous with postoperative acute pancreatitis because only 29.2% of such patients have acute pancreatitis based on computed tomography findings. Postoperative acute pancreatitis is a dangerous complication after pancreatoduodenectomy, but its prevalence, according to the gold standard of CT, is not as high as reported previously. Our data suggest that hyperamylasemia on postoperative day 1 and postoperative acute pancreatitis are 2 different entities.
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http://dx.doi.org/10.1016/j.surg.2020.07.050DOI Listing
February 2021

Wireless, Artefact Aware Impedance Sensor Node for Continuous Bio-Impedance Monitoring.

IEEE Trans Biomed Circuits Syst 2020 10 2;14(5):1122-1134. Epub 2020 Sep 2.

Body bio-impedance is a unique parameter to monitor changes in body composition non-invasively. Continuous measurement of bio-impedance can track changes in body fluid content and cell mass and has widespread applications for physiological monitoring. State-of-the-art implementation of bio-impedance sensor devices is still limited for continuous use, in part, due to artefacts arising at the skin-electrode (SE) interface. Artefacts at the SE interface may arise due to various factors such as motion, applied pressure on the electrode surface, changes in ambient conditions or gradual drying of electrodes. This paper presents a novel bio-impedance sensor node that includes an artefact aware method for bio-impedance measurement. The sensor node enables autonomous and continuous measurement of bio-impedance and SE contact impedance at ten frequencies between 10 kHz to 100 kHz to detect artefacts at the SE interface. Experimental evaluation with SE contact impedance models using passive 2R1C electronic circuits and also with non-invasive in vivo measurements of SE contact impedance demonstrated high accuracy (with maximum error less than 1.5%) and precision of 0.6 Ω. The ability to detect artefacts caused by motion, vertically applied pressure and skin temperature changes was analysed in proof of concept experiments. Low power sensor node design achieved with 50mW in active mode and only 143 μW in sleep mode estimated a battery life of 90 days with a 250 mAh battery and duty-cycling impedance measurements every 60 seconds. Our method for artefact aware bio-impedance sensing is a step towards autonomous and unobtrusive continuous bio-impedance measurement for health monitoring at-home or in clinical environments.
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http://dx.doi.org/10.1109/TBCAS.2020.3021186DOI Listing
October 2020

Successful BRAF/MEK inhibition in a patient with -mutated extrapancreatic acinar cell carcinoma.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany.

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic mutation and a germline stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
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http://dx.doi.org/10.1101/mcs.a005553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476408PMC
August 2020

Improving the Environmental Risk Assessment of Substances of Unknown or Variable Composition, Complex Reaction Products, or Biological Materials.

Environ Toxicol Chem 2020 11 16;39(11):2097-2108. Epub 2020 Sep 16.

Health and Environmental Sciences Institute, Washington, DC, USA.

Substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs) pose unique risk assessment challenges to regulators and to product registrants. These substances can contain many constituents, sometimes partially unknown and/or variable, depending on fluctuations in their source material and/or manufacturing process. International regulatory agencies have highlighted the difficulties in characterizing UVCBs and assessing their toxicity and environmental fate. Several industrial sectors have attempted to address these issues by developing frameworks and characterization methods. Based on the output of a 2016 workshop, this critical review examines current practices for UVCB risk assessment and reveals a need for a multipronged and transparent approach integrating whole-substance and constituent-based information. In silico tools or empirical measurements can provide information on discrete and/or blocks of UVCB constituents with similar hazard properties. Read-across and/or whole-substance toxicity and fate testing using adapted emerging methods can provide whole-substance information. Continued collaboration of stakeholders representing government, industry, and academia will facilitate the development of practical testing strategies and guidelines for addressing regulatory requirements for UVCBs. Environ Toxicol Chem 2020;39:2097-2108. © 2020 Health and Environmental Sciences Institute. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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http://dx.doi.org/10.1002/etc.4846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693076PMC
November 2020

Salzburg Database of Polygonal Data: Polygons and Their Generators.

Data Brief 2020 Aug 8;31:105984. Epub 2020 Jul 8.

Universität Salzburg, FB Computerwissenschaften, Salzburg, Austria.

The Salzburg Database is a repository of polygonal areas of various classes and sizes, with and without holes. Positive weights are assigned to all edges of all polygons. We introduce this collection and describe the generators that produced its polygons. The source codes for all generators as well as the polygons generated are publicly available.
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http://dx.doi.org/10.1016/j.dib.2020.105984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387775PMC
August 2020

Expression and localization of the aryl hydrocarbon receptors and cytochrome P450 1A during early development of Atlantic cod (Gadus morhua).

Aquat Toxicol 2020 Sep 3;226:105558. Epub 2020 Jul 3.

Department of Biological Sciences, University of Bergen, Bergen, Norway. Electronic address:

The aryl hydrocarbon receptor (Ahr) is a ligand-activated transcription factor that mediates the toxicity of dioxins and dioxin-like compounds (DLCs) in vertebrates. Two clades of the Ahr family exist in teleosts (Ahr1 and Ahr2), and it has been demonstrated that Ahr2 is the main protein involved in mediating the toxicity of dioxins and DLCs in most teleost species. Recently, we characterized the Atlantic cod (Gadus morhua) Ahr1a and Ahr2a receptors. To further explore a possible subfunction partitioning of Ahr1a and Ahr2a in Atlantic cod we have mapped the expression and localization of ahr1a and ahr2a in early developmental stages. Atlantic cod embryos were continuously exposed in a passive-dosing exposure system to the Ahr agonist, benzo[a]pyrene (B[a]P), from five days post fertilization (dpf) until three days post hatching (dph). Expression of ahr1a, ahr2a, and the Ahr-target genes, cyp1a and ahrrb, was assessed in embryos (8 dpf and 10 dpf) and larvae (3 dph) with quantitative real-time PCR analyses (qPCR), while in situ hybridization was used to assess the localization of expression of ahr1a, ahr2a and cyp1a. Quantitative measurements showed an increased cyp1a expression in B[a]P-exposed samples at all sampling points, and for ahr2a at 10 dpf, confirming the activation of the Ahr-signalling pathway. Furthermore, B[a]P strongly induced ahr2a and cyp1a expression in the cardiovascular system and skin, respectively, of embryos and larvae. Induced expression of both ahr2a and cyp1a was also revealed in the liver of B[a]P-exposed larvae. Our results suggest that Ahr2a is the major subtype involved in mediating responses to B[a]P in early developmental stages of Atlantic cod, which involves transcriptional regulation of biotransformation genes, such as cyp1a. The focused expression of ahr1a in the eye of embryos and larvae, and the presence of ahr2a transcripts in the jaws and fin nodes, further indicate evolved specialized roles of the two Ahrs in ontogenesis.
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http://dx.doi.org/10.1016/j.aquatox.2020.105558DOI Listing
September 2020

Diffusion Kurtosis Imaging-A Superior Approach to Assess Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2020 Jun 22;12(6). Epub 2020 Jun 22.

Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany.

Extensive desmoplastic stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression and to the relative resistance of tumor cells towards (radio) chemotherapy. Thus, therapies that target the stroma are under intense investigation. To allow the stratification of patients who would profit from such therapies, non-invasive methods assessing the stroma content in relation to tumor mass are required. In the current prospective study, we investigated the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI), a radiologic method that measures the random motion of water molecules in tissue, in the assessment of PDAC lesions, and more specifically in the desmoplastic tumor stroma. We made use of a sophisticated DW-MRI approach, the so-called diffusion kurtosis imaging (DKI), which possesses potential advantages over conventional and widely used monoexponential diffusion-weighted imaging analysis (cDWI). We found that the diffusion constant D from DKI is highly negatively correlated with the percentage of tumor stroma, the latter determined by histology. D performed significantly better than the widely used apparent diffusion coefficient (ADC) from cDWI in distinguishing stroma-rich (>50% stroma percentage) from stroma-poor tumors (≤50% stroma percentage). Moreover, we could prove the potential of the diffusion constant D as a clinically useful imaging parameter for the differentiation of PDAC-lesions from non-neoplastic pancreatic parenchyma. Therefore, the diffusion constant D from DKI could represent a valuable non-invasive imaging biomarker for assessment of stroma content in PDAC, which is applicable for the clinical diagnostic of PDAC.
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http://dx.doi.org/10.3390/cancers12061656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352692PMC
June 2020

Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience.

World J Surg Oncol 2020 May 12;18(1):93. Epub 2020 May 12.

Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons.

Methods: Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018.

Results: Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection.

Conclusion: FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.
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http://dx.doi.org/10.1186/s12957-020-01855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218513PMC
May 2020

Intraoperative evaluation of hepatic artery blood flow during pancreatoduodenectomy (HEPARFLOW): Protocol of an exploratory study.

Int J Surg Protoc 2020 4;21:21-26. Epub 2020 Apr 4.

Department of General, Visceral and Transplant Surgery, University of Heidelberg, Germany.

Introduction: Pancreatoduodenectomy is the treatment of choice for a range of benign and malignant diseases. The pancreatic head must be separated from its supplying vessels, especially the gastroduodenal artery, during this operation. However, dissection of the gastroduodenal artery can disturb blood supply to the liver and result in liver ischemia. There is currently no well-established algorithm to evaluate and ensure sufficient blood flow in patients with altered hepatic artery blood flow. To address this important issue, this study aims to establish a basis for assessing liver blood supply during pancreatoduodenectomy. Furthermore, factors influencing arterial blood flow and related postoperative complications will be evaluated.

Methods And Analysis: The HEPARFLOW study is a single institutional single-arm prospective exploratory observational clinical trial. All consecutive patients undergoing elective partial or total pancreatoduodenectomy will be screened for inclusion until 100 patients are enrolled. Blood flow in the proper hepatic artery, gastroduodenal artery, portal vein, and additional vessels supplying the liver will be measured during pancreatoduodenectomy using Doppler flowmetry. All patients will be followed up for 90 days after surgery. At each visit, standard clinical data, postoperative complications and mortality will be recorded.

Discussion: This will be the first study to prospectively assess intraoperative flow rates of the hepatic artery and portal vein to evaluate liver blood supply during pancreatoduodenectomy. The preoperative and intraoperative factors influencing blood flow in the hepatic arteries will be identified. This study may also reveal the hemodynamic and clinical relevance of a compression of the celiac axis during pancreatoduodenectomy.

Ethics And Dissemination: This study was approved by the Ethics Committee of the University of Heidelberg (S-073/2018). The results will be published in a peer-reviewed journal and will be presented at medical meetings.
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http://dx.doi.org/10.1016/j.isjp.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182758PMC
April 2020

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors.

Cancers (Basel) 2020 Apr 23;12(4). Epub 2020 Apr 23.

Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany.

Oligoprogression (OPD) of non-small-cell lung cancer (NSCLC) occurs in approximately half of patients under targeted compounds (TKI) and facilitates use of regional therapies that can prolong survival. In order to characterize OPD in immunotherapy (IO)-treated NSCLC, we analyzed the failure pattern under PD-1/PD-L1 inhibitors ( = 297) or chemoimmunotherapy ( = 75). Under IO monotherapy, OPD was more frequent (20% vs. 10%, < 0.05), occurred later (median 11 vs. 5 months, < 0.01), affected fewer sites (mean 1.1 vs. 1.5, < 0.05), and involved fewer lesions (1.4 vs. 2.3, < 0.05) in the first compared to later lines. Lymph nodes (42%, mainly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, OPD occurred later (11 vs. 4 months, < 0.001) and was associated with longer survival (26 vs. 13 months, < 0.001) and higher tumor PD-L1 expression ( < 0.001). Chemoimmunotherapy showed a similar incidence of OPD as IO monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. Thus, NSCLC oligoprogression is less common under IO than under TKI, but also favorable. Since its frequency drops later in the disease, regular restaging and multidisciplinary evaluation are essential in order to exploit the full therapeutic potential.
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http://dx.doi.org/10.3390/cancers12041046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226015PMC
April 2020

Toxicity of dodecylbenzene to algae, crustacean, and fish - Passive dosing of highly hydrophobic liquids at the solubility limit.

Chemosphere 2020 Jul 2;251:126396. Epub 2020 Mar 2.

Institute for Environmental Research (Biology V), RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.

In the current study, improved exposure control and measurements were applied for the aquatic toxicity testing of a highly hydrophobic organic compound. The aim was to reliably determine the ecotoxicity of the model compound dodecylbenzene (DDB, Log K = 8.65) by applying passive dosing for aquatic toxicity testing exactly at the solubility limit. Methodologically, silicone O-rings were saturated by immersion in pure liquid DDB (i.e., "loading by swelling") and then used as passive dosing donors. Daphnia immobilization and fish embryo toxicity tests were successfully conducted and provide, together with recently reported algal growth inhibition data, a full base-set of ecotoxicological data according to REACH. All tests were conducted in closed test systems to avoid evaporative losses, and exposure concentrations were measured throughout test durations. The Daphnia test was optimized by placing the O-rings in cages to prevent direct contact between daphnids and the passive dosing donor. Toxicologically, Daphnia magna immobilization was 19.3 ± 8% (mean ± 95% CI; 6 tests) within 72 h, whereas Danio rerio fish embryos did not show any significant lethal or sublethal toxic responses within 96 h. Growth rate inhibition for the algae Raphidocelis subcapitata was previously reported to be 13 ± 5% in a first and 8 ± 3% in a repeated test. These results for aquatic organisms, spanning three trophic levels, demonstrate toxicity of a highly hydrophobic compound and suggest that improvements of the current ecotoxicological standard tests are needed for these "difficult-to-test" chemicals. Furthermore, the obtained toxicity results significantly question the existence of a generic Log K cut-off in baseline toxicity.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126396DOI Listing
July 2020

Posterior cruciate ligament lesions are mainly present as combined lesions even in sports injuries.

Knee Surg Sports Traumatol Arthrosc 2020 Jul 10;28(7):2091-2098. Epub 2020 Mar 10.

Centre for Sports Orthopedics and Special Joint Surgery, Orthopedic Hospital Markgroeningen, Kurt-Lindemann-Weg 10, 71706, Markgroeningen, Germany.

Purpose: To analyse 1000 consecutive patients, treated with isolated or combined posterior cruciate ligament (PCL) reconstruction in a single centre according to the epidemiological factors and differences in injury patterns depending on the activity during trauma.

Methods: Between 2004 and 2019, one thousand isolated and combined PCL reconstructions were performed. The medical charts and surgical reports of all patients were analysed regarding epidemiological factors. The PCL lesions were divided into isolated and combined lesions with at least one additional ligamentous injury. The influence of activity during accident and additional injury on the presence of isolated or combined lesions and injury patterns was calculated.

Results: In 388 patients (38.8%), sporting activity was the main activity in PCL lesions, followed by traffic accidents in 350 patients (35.0%). Combined injuries were present in 227 patients (58.5%) with sports injuries and 251 patients (71.7%) with traffic accidents. Only during handball, an isolated PCL lesion (69.1%) was more common than a combined lesion. Highest rate of combined lesions was present in car accidents (91.7%). In all activities except skiing and biking, the most common additional peripheral injury was a tear of the posterolateral corner. In skiing and biking accidents, the most common additional peripheral lesion was a lesion of the medial collateral ligament. In patients with PCL lesion and additional fracture of the same lower extremity, a combined lesion was more common than an isolated lesion (p = 0.001).

Conclusion: Combined PCL lesions are more common than isolated lesions, even in sports injuries (except handball). Incidence and injury pattern vary depending on activity during trauma. Main additional peripheral lesion is a lesion of the posterolateral corner, except biking and skiing accidents where a medial lesion is more common.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1007/s00167-020-05919-4DOI Listing
July 2020
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