Assessing Non-Invasive Liver Function in Patients With Intestinal Failure Receiving Total Parenteral Nutrition-Results From the Prospective PNLiver Trial

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB-4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests

Mathematics Without Apologies: Portrait of a Problematic Vocation (Book Review)

Reviewed Title: Mathematics Without Apologies: Portrait of a Problematic Vocation by Michael Harris. Princeton, NJ: Princeton University Press, 2015. 438 pages. ISBN: 9780691154237

Prognostic Factors for Mortality in Acute Mesenteric Ischemia.

Postoperative mortality in patients undergoing surgical and/or interventional treatment for acute mesenteric ischemia (AMI) has remained an unsolved problem in recent decades. Here, we investigated clinical predictors of postoperative mortality in a large European cohort of patients undergoing treatment for AMI. In total, 179 patients who underwent surgical and/or interventional treatment for AMI between 2009 and 2021 at our institution were included in this analysis. Associations between postoperative mortality and various clinical variables were assessed using univariate and multivariable binary logistic regression analysis. Most of the patients were diagnosed with arterial ischemia (AI; n = 104), while venous ischemia (VI; n = 21) and non-occlusive mesenteric ischemia (NOMI; n = 54) were present in a subset of patients. Overall inhouse mortality was 55.9% (100/179). Multivariable analyses identified leukocytes (HR = 1.08; p = 0.008), lactate (HR = 1.25; p = 0.01), bilirubin (HR = 2.05; p = 0.045), creatinine (HR = 1.48; p = 0.039), etiology (AI, VI or NOMI; p = 0.038) and portomesenteric vein gas (PMVG; HR = 23.02; p = 0.012) as independent predictors of postoperative mortality. In a subanalysis excluding patients with fatal prognosis at the first surgical exploration (n = 24), leukocytes (HR = 1.09; p = 0.004), lactate (HR = 1.27; p = 0.003), etiology (AI, VI or NOMI; p = 0.006), PMVG (HR = 17.02; p = 0.018) and intraoperative FFP transfusion (HR = 4.4; p = 0.025) were determined as independent predictors of postoperative mortality. Further, the risk of fatal outcome changed disproportionally with increased preoperative lactate values. The clinical outcome of patients with AMI was determined using a combination of pre- and intraoperative clinical and radiological characteristics. Serum lactate appears to be of major clinical importance as the risk of fatal outcome increases significantly with higher lactate values

Impact of Angiogenesis- and Hypoxia-Associated Polymorphisms on Tumor Recurrence in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection

Simple Summary: Hepatocellular carcinoma remains a leading cause of cancer-related death and the most common primary hepatic malignancy in the Western hemisphere. Previous research found that angiogenesis-related cytokines and elevated levels of interleukin 8 and vascular endothelial growth factor (VEGF) shorten the expected time of survival. Moreover, factors of tumor angiogenesis- and hypoxia-driven signaling pathways are already associated with worse outcome in disease-free survival in several tumor entities. Our study investigates the prognosis of hepatocellular carcinoma patients based on a selection of ten different single-nucleotide polymorphisms from angiogenesis, carcinogenesis, and hypoxia pathways. Our study with 127 patients found supporting evidence that polymorphisms in angiogenesis-associated pathways corelate with disease-free survival and clinical outcome in patients with hepatocellular carcinoma. Abstract: Tumor angiogenesis plays a pivotal role in hepatocellular carcinoma (HCC) biology. Identifying molecular prognostic markers is critical to further improve treatment selection in these patients. The present study analyzed a subset of 10 germline polymorphisms involved in tumor angiogenesis pathways and their impact on prognosis in HCC patients undergoing partial hepatectomy in a curative intent. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 127 HCC patients at a German primary care hospital. Genomic DNA was extracted, and genotyping was carried out using polymerase chain reaction (PCR)-restriction fragment length polymorphism-based protocols. Polymorphisms in interleukin-8 (IL-8) (rs4073; p = 0.047, log-rank test) and vascular endothelial growth factor (VEGF C + 936T) (rs3025039; p = 0.045, log-rank test) were significantly associated with disease-free survival (DFS). After adjusting for covariates in the multivariable model, IL-8 T-251A (rs4073) (adjusted p = 0.010) and a combination of "high-expression" variants of rs4073 and rs3025039 (adjusted p = 0.034) remained significantly associated with DFS. High-expression variants of IL-8 T-251A may serve as an independent molecular marker of prognosis in patients undergoing surgical resection for HCC. Assessment of the patients' individual genetic risks may help to identify patient subgroups at high risk for recurrence following curative-intent surgery

The Influence of Hepatic Steatosis and Fibrosis on Postoperative Outcomes After Major Liver Resection of Perihilar Cholangiocarcinoma

Background: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients. Methods: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality. Results: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69–2.68) or 90-day mortality (OR 1.22; 95% CI 0.62–2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41–1.41) or 90-day mortality (OR 0.60; 95% CI 0.33–1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36–4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31–4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36–4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30–3.87). Conclusion: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.</p

Application of the 13C liver function test LiMAx in context of oxaliplatin- based chemotherapy, ECMO treatment and general anesthesia

Einleitung: Für den dynamische Leberfunktionstest LiMAx (maximum liver function capacity) konnte zuletzt ein ausgezeichneter prognostischer Wert im Bereich der Leberchirurgie und Lebertransplantation gezeigt werden. Ziel dieser Arbeit war es das Potential des Tests zur Diagnostik der hepatischen Schädigung im Rahmen einer Oxaliplatin-basierten Chemotherapie, seine Reliabilität im perioperativen Setting sowie die technische Umsetzbarkeit unter ECMO- Therapie und seinen prädikativen Wert für die Lebensqualität bei Leberzirrhosepatienten zu bestimmen. Methodik: Hierzu wurden drei prospektive Beobachtungsstudien zur Untersuchung der Thematiken durchgeführt. Zur dynamischen Leberfunktionsmessung wurden jeweils der 13C- Atemtest LiMAx – basierend auf der hepatozytenspezfischen Verstoffwechselung von 13C- Methacetin – und der ICG (Indocyaningrün)-Test verwendet. Die Lebensqualitätsanalyse erfolgte mittels der deutschen Version des CLDQ (Chronic liver disease questionnaire). Ergebnisse: Im Rahmen einer adjuvanten Oxaliplatin-basierten Chemotherapie nach UICC Stadium III Kolonkarzinom konnte mittels LiMAx trotz unveränderter laborchemischer Parameter eine Reduktion der Leberfunktion detektiert werden. Im Anschluss zeigte sich eine patienten- individuelle Regenerationsdauer zur Wiederherstellung der Initialfunktion (4 Wochen bis mehr als 8 Wochen nach applizierter Chemotherapie). Der LiMAx Test zeigte sowohl im perioperativen Setting nach extra-abdomineller Chirurgie in Allgemeinanästhesie als auch im gesunden Kontrollkollektiv eine auszeichnete Reliabilität (ICC = 0,81 bzw. ICC = 0,85). Unter laufender ECMO-Therapie kann LiMAx ohne Veränderungen der therapeutischen ECMO- Einstellung technisch durchgeführt werden. Im Rahmen der Lebensqualitätsanalyse bei Leberzirrhosepatienten in der Transplantationsevaluation zeigen die Ergebnisse der dynamischen Leberfunktionstests keinen direkten Einfluss auf die gesundheitsassoziierte Lebensqualität. Stattdessen sind multivariat R2 = 0,474) der Aszitesgrad (Bs = 0,486; p<0,001) und die Pseudocholinesterase (Bs = 0.196; p = 0,002 signifikant mit einer reduzierten globalen Lebensqualität assoziiert. Schlussfolgerung: Das Indikationsspektrum des LiMAx- Testverfahrens konnte durch die Untersuchungen erweitert werden. LiMAx hat das Potenzial im Rahmen eines patienten-individuellen Ansatzes das chemotherapiefreie Intervall vor ausgedehnten Leberteilresektion zu bestimmen und so die perioperative Morbidität und Mortalität dieser Patientengruppe zu reduzieren. Testtheoretisch wurde gezeigt, dass 13C- Atemtests unter laufender ECMO-Therapie möglich sind und klinisch valide Ergebnisse liefern. Weiterhin konnte die Reliabilität des Verfahrens sowohl im perioperativen Setting als auch im gesunden Kontrollkollektiv als exzellent bestimmt werden. Im Kontext der gesundheits-assoziierten Lebensqualität bei Leberzirrhosepatienten zeigte der LiMAx-Test neben anderen quantitativen Tests und Scores keinen prädikativen Wert. Stattdessen ist ein adäquates Aszites- und Ernährungsmanagement entscheidend für die gesundheitsassoziierte Lebensqualität in diesem Patientenkollektiv.Introduction: LiMAx (maximum liver function capacity) has recently been shown to provide prognostic ability in the context of liver transplantation and partial liver resection. Aim of this study was to determine the ability of LiMAx to detect chemotherapy-associated liver impairment, to determine the repeatability of the test and to proof technical feasibility in patients undergoing ECMO therapy. Moreover we evaluated the prognostic value of LiMAx in the context of health related quality of life in patients with end stage liver disease. Methods: Three prospective clinical trials were carried out independently. The 13C-breath test LiMAx – based on the liver specific metabolism of 13C-Methacetin – and the ICG (indocyanine green) test were used to access dynamic liver function in each study. Health related quality of life was determined by the German version of the chronic liver disease questionnaire (CLDQ). Results: Despite showing no relevant alterations in standard liver function tests, LiMAx was able to detect chemotherapy- associated hepatic impairment in patients that underwent adjuvant Oxaliplatin- based chemotherapy. Liver regeneration as assessed by LiMAx was significantly correlated with hepatic regeneration after cessation of chemotherapy. LiMAx also showed to have an excellent repeatability in patients undergoing general anaesthesia for extraabdominal surgery as well as in healthy controls (ICC = 0.81 and ICC = 0.85, respectively). In addition, LiMAx can be carried out safely in patients undergoing ECMO therapy without changing the settings of the ECMO device. No dynamic liver function test was associated with health related quality of life in patients with end stage liver disease. As such, we identified grade of ascites and butyrylchlolinesterase as two independent predictors of quality of life in these cohorts. Conclusion: LiMAx might have the ability to determine an individual chemotherapy-free interval prior partial liver resection to allow a safe resection without increased perioperative morbidity and mortality due to chemotherapy. We have shown that 13C-breath tests are feasible in patients requiring ECMO therapy. Moreover, test results were in accordance with the particular clinical course of each patient. The LiMAx test showed excellent repeatability in complex clinical situations underlining its clinical use in the perioperative setting. Nevertheless, adequate management of ascites and nutrition remain key aspects in health related quality of life adapted treatment of patients with liver cirrhosis awaiting liver transplantation

Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma

It has been shown that the presence and density of nerve fibers (NFs; NFD) in the tumor microenvironment (TME) may play an important prognostic role in predicting long-term oncological outcomes in various malignancies. However, the role of NFD in the prognosis of hepatocellular carcinoma (HCC) is yet to be explored. To this end, we aimed to investigate the impact of NFs on oncological outcomes in a large European single-center cohort of HCC patients. In total, 153 HCC patients who underwent partial hepatectomy in a curative-intent setting between 2010 and 2021 at our university hospital were included in this study. Group comparisons between patients with and without NFs were conducted and the association of recurrence-free survival (RFS) and overall survival (OS) with the presence of NFs and other clinico-pathological variables were determined by univariate and multivariable Cox regression models. Patients with NFs in the TME presented with a median OS of 66 months (95% CI: 30&ndash;102) compared to 42 months (95% CI: 20&ndash;63) for patients without NFs (p = 0.804 log-rank). Further, RFS was 26 months (95% CI: 12&ndash;40) for patients with NFs compared to 18 months (95% CI: 9&ndash;27) for patients without NFs (p = 0.666 log-rank). In a subgroup analysis, patients with NFD &le; 5 showed a median OS of 54 months (95% CI: 11&ndash;97) compared to 48 months (95% CI: 0&ndash;106) for the group of patients with NFD &gt; 5 (p = 0.787 log-rank). Correspondingly, the RFS was 26 months (95% CI: 10&ndash;42) in patients with NFD &le; 5 and 29 months (95% CI: 14&ndash;44) for the subcohort with NFD &gt; 5 (p = 0.421 log-rank). Further, group comparisons showed no clinico-pathological differences between patients with NFs (n = 76) and without NFs (n = 77) and NFs were not associated with OS (p = 0.806) and RFS (p = 0.322) in our Cox regression models. In contrast to observations in various malignancies, NFs in the TME and NFD are not associated with long-term oncological outcomes in HCC patients undergoing surgery