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  • 1
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    Analysis of Volatile Anesthetic-Induced Organ Protection in Simultaneous Pancreas–Kidney Transplantation
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 12 ( 2022-06-13), p. 3385-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 12 ( 2022-06-13), p. 3385-
    Abstract: Background: Despite recent advances in surgical procedures and immunosuppressive regimes, early pancreatic graft dysfunction, mainly specified as ischemia–reperfusion injury (IRI)—Remains a common cause of pancreas graft failure with potentially worse outcomes in simultaneous pancreas-kidney transplantation (SPKT). Anesthetic conditioning is a widely described strategy to attenuate IRI and facilitate graft protection. Here, we investigate the effects of different volatile anesthetics (VAs) on early IRI-associated posttransplant clinical outcomes as well as graft function and outcome in SPKT recipients. Methods: Medical data of 105 patients undergoing SPKT between 1998–2018 were retrospectively analyzed and stratified according to the used VAs. The primary study endpoint was the association and effect of VAs on pancreas allograft failure following SPKT; secondary endpoint analyses included “IRI- associated posttransplant clinical outcome” as well as long-term graft function and outcome. Additionally, peak serum levels of C-reactive protein (CRP) and lipase during the first 72 h after SPKT were determined and used as further markers for “pancreatic IRI” and graft injury. Typical clinicopathological characteristics and postoperative outcomes such as early graft outcome and long-term function were analyzed. Results: Of the 105 included patients in this study three VAs were used: isoflurane (n = 58 patients; 55%), sevoflurane (n = 22 patients; 21%), and desflurane (n = 25 patients, 24%). Donor and recipient characteristics were comparable between both groups. Early graft loss within 3 months (24% versus 5% versus 8%, p = 0.04) as well as IRI-associated postoperative clinical complications (pancreatitis: 21% versus 5% versus 5%, p = 0.04; vascular thrombosis: 13% versus 0% versus 5%; p = 0.09) occurred more frequently in the Isoflurane group compared with the sevoflurane and desflurane groups. Anesthesia with sevoflurane resulted in the lowest serum peak levels of lipase and CRP during the first 3 days after transplantation, followed by desflurane and isoflurane (p = 0.039 and p = 0.001, respectively). There was no difference with regard to 10-year pancreas graft survival as well as endocrine/metabolic function among all three VA groups. Multivariate analysis revealed the choice of VAs as an independent prognostic factor for graft failure three months after SPKT (HR 0.38, 95%CI: 0.17–0.84; p = 0.029). Conclusions: In our study, sevoflurane and desflurane were associated with significantly increased early graft survival as well as decreased IRI-associated post-transplant clinical outcomes when compared with the isoflurane group and should be the focus of future clinical studies evaluating the positive effects of different VA agents in patients receiving SPKT.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11123385
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 2
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    Influence of Multiple Donor Renal Arteries on the Outcome and Graft Survival in Deceased Donor Kidney Transplantation
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 19 ( 2021-09-26), p. 4395-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 19 ( 2021-09-26), p. 4395-
    Abstract: Aim: Complex arterial reconstruction in kidney transplantation (KT) using kidneys from deceased donors (DD) warrants additional study since little is known about the effects on the mid- and long-term outcome and graft survival. Methods: A total of 451 patients receiving deceased donor KT in our department between 1993 and 2017 were included in our study. Patients were divided into three groups according to the number of arteries and anastomosis: (A) 1 renal artery, 1 arterial anastomosis (N = 369); (B) 〉 1 renal artery, 1 arterial anastomosis (N = 47); and (C) 〉 1 renal artery, 〉 1 arterial anastomosis (N = 35). Furthermore, the influence of localization of the arterial anastomosis (common iliac artery (CIA), versus non-CIA) was analyzed. Clinicopathological characteristics, outcome, and graft and patient survival of all groups were compared retrospectively. Results: With growing vascular complexity, the time of warm ischemia increased significantly (groups A, B, and C: 40 ± 19 min, 45 ± 19 min, and 50 ± 17 min, respectively; p = 0.006). Furthermore, the duration of operation was prolonged, although this did not reach significance (groups A, B, and C: 175 ± 98 min, 180 ± 35 min, and 210 ± 43 min, respectively; p = 0.352). There were no significant differences regarding surgical complications, post-transplant kidney function (delayed graft function, initial non-function, episodes of acute rejection), or long-term graft survival. Regarding the localization of the arterial anastomosis, non-CIA was an independent prognostic factor for deep vein thrombosis in multivariate analysis (CIA versus non-CIA: OR 11.551; 95% CI, 1.218–109.554; p = 0.033). Conclusion: Multiple-donor renal arteries should not be considered a contraindication to deceased KT, as morbidity rates and long-term outcomes seem to be comparable with grafts with single arteries and less complex anastomoses.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10194395
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 3
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    Prognostic Relevance of the Eighth Edition of TNM Classification for Resected Perihilar Cholangiocarcinoma
    MDPI AG ; 2020
    In:  Journal of Clinical Medicine Vol. 9, No. 10 ( 2020-09-29), p. 3152-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 10 ( 2020-09-29), p. 3152-
    Abstract: Objectives: In our study, we evaluated and compared the prognostic value and performance of the 6th, 7th, and 8th editions of the American Joint Committee on Cancer (AJCC) staging system in patients undergoing surgery for perihilar cholangiocarcinoma (PHC). Methods: Patients undergoing liver surgery with curative intention for PHC between 2002 and 2019 were identified from a prospective database. Histopathological parameters and stage of the PHC were assessed according to the 6th, 7th, and 8th editions of the tumor node metastasis (TNM) classification. The prognostic accuracy between staging systems was compared using the area under the receiver operating characteristic curve (AUC) model. Results: Data for a total of 95 patients undergoing liver resection for PHC were analyzed. The median overall survival time was 21 months (95% CI 8.1–33.9), and the three- and five-year survival rates were 46.1% and 36.2%, respectively. Staging according to the 8th edition vs. the 7th edition resulted in the reclassification of 25 patients (26.3%). The log-rank p-values for the 7th and 8th editions were highly statistically significant (p ≤ 0.01) compared to the 6th edition (p = 0.035). The AJCC 8th edition staging system showed a trend to better discrimination, with an AUC of 0.69 (95% CI: 0.52–0.84) compared to 0.61 (95% CI: 0.51–0.73) for the 7th edition. Multivariate survival analysis revealed male gender, age 〉 65 years, positive resection margins, presence of distant metastases, poorly tumor differentiation, and lymph node involvement, such as no caudate lobe resection, as independent predictors of poor survival (p 〈 0.05). Conclusions: In the current study, the newly released 8th edition of AJCC staging system showed no significant benefit compared to the previous 7th edition in predicting the prognosis of patients undergoing liver resection for perihilar cholangiocarcinoma. Further research may help to improve the prognostic value of the AJCC staging system for PHC—for instance, by identifying new prognostic markers or staging criteria, which may improve that individual patient’s outcome.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm9103152
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
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  • 4
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    Diagnostic Benefit of High b-Value Computed Diffusion-Weighted Imaging in Patients with Hepatic Metastasis
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 22 ( 2021-11-14), p. 5289-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 22 ( 2021-11-14), p. 5289-
    Abstract: Diffusion-weighted imaging (DWI) has rapidly become an essential tool for the detection of malignant liver lesions. The aim of this study was to investigate the usefulness of high b-value computed DWI (c-DWI) in comparison to standard DWI in patients with hepatic metastases. In total, 92 patients with histopathologic confirmed primary tumors with hepatic metastasis were retrospectively analyzed by two readers. DWI was obtained with b-values of 50, 400 and 800 or 1000 s/mm2 on a 1.5 T magnetic resonance imaging (MRI) scanner. C-DWI was calculated with a monoexponential model with high b-values of 1000, 2000, 3000, 4000 and 5000 s/mm2. All c-DWI images with high b-values were compared to the acquired DWI sequence at a b-value of 800 or 1000 s/mm2 in terms of volume, lesion detectability and image quality. In the group of a b-value of 800 from a b-value of 2000 s/mm2, hepatic lesion sizes were significantly smaller than on acquired DWI (metastases lesion sizes b = 800 vs. b 2000 s/mm2: mean 25 cm3 (range 10–60 cm3) vs. mean 17.5 cm3 (range 5–35 cm3), p 〈 0.01). In the second group at a high b-value of 1500 s/mm2, liver metastases were larger than on c-DWI at higher b-values (b = 1500 vs. b 2000 s/mm2, mean 10 cm3 (range 4–24 cm3) vs. mean 9 cm3 (range 5–19 cm3), p 〈 0.01). In both groups, there was a clear reduction in lesion detectability at b = 2000 s/mm2, with hepatic metastases being less visible compared to c-DWI images at b = 1500 s/mm2 in at least 80% of all patients. Image quality dropped significantly starting from c-DWI at b = 3000 s/mm2. In both groups, almost all high b-values images at b = 4000 s/mm2 and 5000 s/mm2 were not diagnostic due to poor image quality. High c-DWI b-values up to b = 1500 s/mm2 offer comparable detectability for hepatic metastases compared to standard DWI. Higher b-value images over 2000 s/mm2 lead to a noticeable reduction in imaging quality, which could hamper diagnosis.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10225289
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 5
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    Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 2 ( 2019-01-16), p. 347-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 2 ( 2019-01-16), p. 347-
    Abstract: Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards ‘normal’ liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20020347
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
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  • 6
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    Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 19 ( 2020-09-26), p. 7097-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 19 ( 2020-09-26), p. 7097-
    Abstract: Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21197097
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 7
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    Dickkopf-Related Protein 1 as Response Marker for Transarterial Chemoembolization of Hepatocellular Carcinomas
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 19 ( 2022-09-30), p. 4807-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 19 ( 2022-09-30), p. 4807-
    Abstract: Background and Aims: In the treatment of hepatocellular carcinoma (HCC), response prediction to transarterial chemoembolization (TACE) based on serum biomarkers is not established. We have studied the association of circulating Dickkopf-related protein 1 (DKK-1) with baseline characteristics and response to TACE in European HCC patients. Methods: Patients with HCC treated with TACE from 2010 to 2018 at a tertiary referral hospital were retrospectively enrolled. Levels of DKK-1 were measured in serum samples collected before TACE. Response was assessed according to mRECIST criteria at week 12 after TACE. Results: Ninety-seven patients were enrolled, including seventy-nine responders and eighteen refractory. Before TACE, median DKK-1 serum levels were 922 [range, 199–4514] pg/mL. DKK-1 levels were lower in patients with liver cirrhosis (p = 0.002) and showed a strong correlation with total radiologic tumor size (r = 0.593; p 〈 0.001) and with Barcelona Clinic Liver Cancer stages (p = 0.032). Median DKK-1 levels were significantly higher in refractory patients as compared to responders (1471 pg/mL [range, 546–2492 pg/mL] versus 837 pg/mL [range, 199–4515 pg/mL] ; p 〈 0.001), and DKK-1 could better identify responders than AFP (AUC = 0.798 vs. AUC = 0.679; p 〈 0.001). A DKK-1 cutoff of ≤1150 pg/mL was defined to identify responders to TACE with a sensitivity of 78% and specificity of 77%. DKK-1 levels were suitable to determine response to TACE in patients with low AFP serum levels (AFP levels 〈 20 ng/mL; AUC = 0.843; 95% CI [0.721–0.965]; p = 0.003). Conclusion: DKK-1 levels in serum are strongly associated tumor size and with response to TACE in European HCC patients, including those patients with low AFP levels.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14194807
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 8
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    Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions
    MDPI AG ; 2018
    In:  Bioengineering Vol. 5, No. 1 ( 2018-03-15), p. 24-
    Details
    In: Bioengineering, MDPI AG, Vol. 5, No. 1 ( 2018-03-15), p. 24-
    Abstract: The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p 〈 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p 〈 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p 〈 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.
    Type of Medium: Online Resource
    ISSN: 2306-5354
    URL: Article
    DOI: 10.3390/bioengineering5010024
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2746191-9
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  • 9
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    In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System
    MDPI AG ; 2016
    In:  International Journal of Molecular Sciences Vol. 17, No. 4 ( 2016-04-16), p. 584-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 17, No. 4 ( 2016-04-16), p. 584-
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms17040584
    Language: English
    Publisher: MDPI AG
    Publication Date: 2016
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
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    Hyperspectral Imaging (HSI)—A New Tool to Estimate the Perfusion of Upper Abdominal Organs during Pancreatoduodenectomy
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 11 ( 2021-06-07), p. 2846-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 11 ( 2021-06-07), p. 2846-
    Abstract: Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact of using HSI during pancreatoduodenectomy (PD). In total, 20 consecutive patients were included. HSI was recorded during surgery as part of a pilot study approved by the local Ethics Committee. Data were collected prospectively with the TIVITA® Tissue System. Intraoperative HS images were recorded before and after gastroduodenal artery (GDA) clamping. We detected four patients with celiac artery stenosis (CAS) caused by a median arcuate ligament (MAL). In two of these patients, a reduction in liver oxygenation (StO2) was discovered 15 and 30 min after GDA clamping. The MAL was divided in these patients. HSI showed an improvement of liver StO2 after MAL division (from 61% to 73%) in one of these two patients. There was no obvious decrease in liver StO2 in the other two patients with CAS. HSI, as a non-invasive procedure, could be helpful in evaluating liver and gastric perfusion during PD, which might assist surgeons in choosing the best surgical approach and in improving patients’ outcomes.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13112846
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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