Deceased donor urinary DKK3 associates with future allograft function following kidney transplantation.

Predicting future kidney allograft function is challenging. Novel biomarkers, such as urinary Dickkopf-3 (uDKK3), may help guide donor selection and improve allograft outcomes. In this prospective multicenter pilot trial, we investigated whether donor uDKK3 reflects organ quality and is associated with future allograft function. We measured uDKK3/creatinine ratios (uDKK3/crea) from 95 deceased and 46 living kidney donors. Pre-nephrectomy uDKK3/crea levels were 100x higher in deceased than in living donors (9888 pg/mg versus 113 pg/mg, p<0.001). Among deceased donor transplantations, recipients were stratified by their corresponding uDKK3/crea donor levels ranging below (group A, n=68) or above (group B, n=65) median. The primary endpoint of best estimated glomerular filtration rate (eGFR) within the first 3 months after kidney transplantation was superior in group A (56.3 ml/min/1.73 m2) compared to group B (44.2 ml/min/1.73 m2, p=0.0139). Second, the composite clinical endpoint consisting of death, allograft failure or eGFR decline >50% occurred less frequent in group A. By mixed linear regression modelling, donor uDKK3/crea remained an independent predictor of eGFR after transplantation, with a slope of -4.282 ml/min/1.73 m2 per logarithmic increase in donor uDKK3/crea. In summary, urinary DKK3 may serve as a non-invasive, donor-dependent biomarker for assessing organ quality and future allograft function.

CT Texture Analysis of Perihilar Cholangiocarcinoma-Associations With Tumor Grading, Tumor Markers and Clinical Outcome.

BACKGROUND: Texture analysis derived from computed tomography (CT) may provide clinically relevant imaging biomarkers associated with tumor histopathology. Perihilar cholangiocarcinoma is a malignant disease with an overall poor prognosis. AIMS: The present study sought to elucidate possible associations between texture features derived from CT images with grading, tumor markers, and survival in extrahepatic, perihilar cholangiocarcinomas tumors. METHODS: This retrospective study included 22 patients (10 females, 45%) with a mean age of 71.8 ± 8.7 years. Texture analysis was performed using the free available Mazda software. All tumors were histopathologically confirmed. Survival and clinical parameters were used as primary study outcomes. RESULTS: In discrimination analysis, "S(1,1)SumVarnc" was statistically significantly different between patients with long-term survival and nonlong-term survival (mean 275.8 ± 32.6 vs. 239.7 ± 26.0, p = 0.01). The first-order parameter "skewness" was associated with the tumor marker "carcinoembryonic antigen" (CEA) (r = -0.7, p = 0.01). A statistically significant correlation of the texture parameter "S(5,0)SumVarnc" with tumor grading was identified (r = -0.6, p < 0.01). Several other texture features correlated with tumor markers CA-19-9 and AFP, as well as with T and N stage of tumors. CONCLUSION: Several texture features derived from CT images were associated with tumor characteristics and survival in patients with perihilar cholangiocarcinomas. CT texture features could be used as valuable novel imaging markers in clinical routine.

Sex hormones differently regulate lipid metabolism genes in primary human hepatocytes.

BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration. METHODS: Primary human hepatocytes (PHHs) were isolated from liver specimen of female and male donors and cultured with sex hormones (17ß-estradiol, testosterone and progesterone) for up to 72 h. mRNA expression levels of 8 hepatic lipid metabolism genes were analyzed by RT-qPCR. Sex hormones and their metabolites were determined in cell culture supernatants by LC-MS analyses. RESULTS: A sex-specific expression was observed for LDLR (low density lipoprotein receptor) with higher mRNA levels in male than female PHHs. All three sex hormones were metabolized by PHHs and the effects of hormones on gene expression levels varied depending on hepatocyte sex. Only in female PHHs, 17ß-estradiol treatment affected expression levels of PPARA (peroxisome proliferator-activated receptor alpha), LIPC (hepatic lipase) and APOL2 (apolipoprotein L2). Further changes in mRNA levels of female PHHs were observed for ABCA1 (ATP-binding cassette, sub-family A, member 1) after testosterone and for ABCA1, APOA5 (apolipoprotein A-V) and PPARA after progesterone treatment. Only the male PHHs showed changing mRNA levels for LDLR after 17ß-estradiol and for APOA5 after testosterone treatment. CONCLUSIONS: Male and female PHHs showed differences in their expression levels of hepatic lipid metabolism genes and their responsiveness towards sex hormones. Thus, cellular sex should be considered, especially when investigating the pathophysiological mechanisms of MASLD.

Cell atlas of the regenerating human liver after portal vein embolization.

The liver has the remarkable capacity to regenerate. In the clinic, regeneration is induced by portal vein embolization, which redirects portal blood flow, resulting in liver hypertrophy in locations with increased blood supply, and atrophy of embolized segments. Here, we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the regenerating liver. Our data unveils pervasive upregulation of genes associated with developmental processes, cellular adhesion, and inflammation in post-portal vein embolization liver, disrupted portal-central hepatocyte zonation, and altered cell subtype composition of endothelial and immune cells. Interlineage crosstalk analysis reveals mesenchymal cells as an interaction hub between immune and endothelial cells, and highlights the importance of extracellular matrix proteins in liver regeneration. Moreover, we establish tissue-scale iterative indirect immunofluorescence imaging for high-dimensional spatial analysis of perivascular microenvironments, uncovering changes to tissue architecture in regenerating liver lobules. Altogether, our data is a rich resource revealing cellular and histological changes in human liver regeneration.

Diagnostic accuracy and reliability of CT-based Node-RADS for colon cancer.

OBJECTIVE: The Node-RADS classification was recently published as a classification system to better characterize lymph nodes in oncological imaging. The present analysis investigated the diagnostic benefit of the Node-RADS classification of staging computed tomography (CT) images to categorize and stage lymph nodes in patients with colon cancer. MATERIALS AND METHODS: All patients were surgically resected and the lymph nodes were histopathological analyzed. All investigated lymph nodes were scored in accordance to the Node-RADS classification by two experienced radiologists. Interreader variability was assessed with Cohen's kappa analysis, discrimination analysis was performed with Mann-Whitney-U test and diagnostic accuracy was assessed with receiver-operating characteristics (ROC) curve analysis. RESULTS: Overall, 108 patients (n = 49 females, 45.3%) with a mean age of 70.08 ± 14.34 years were included. In discrimination analysis, the total Node-RADS score showed statistically significant differences between N- and N + stage (for reader 1: mean 1.89 ± 1.09 score for N- versus 2.93 ± 1.62 score for N+, for reader 2: 1.33 ± 0.48 score for N- versus 3.65 ± 0.94 score for N+, p = 0.001, respectively). ROC curve analysis for lymph node discrimination showed an area under the curve of 0.68. A threshold value of 2 resulted in a sensitivity of 0.62 and a specificity of 0.71. CONCLUSION: Node-RADS score derived from staging CT shows only limited diagnostic accuracy to correctly predict nodal positivity in colon cancer. The interreader variability seems to be high and should question the clinical translation for this tumour entity.

Does Timepoint of Surgical Procedure Affect the Outcome in Simultaneous Pancreas-Kidney Transplantation? A Retrospective Single-Center Analysis over 20 Years.

Background: Sleep deprivation and disturbances in circadian rhythms may hinder surgical performance and decision-making capabilities. Solid organ transplantations, which are technically demanding and often begin at uncertain times, frequently during nighttime hours, are particularly susceptible to these effects. This study aimed to assess how transplant operations conducted during daytime versus nighttime influence both patient and graft outcomes and function. Methods: simultaneous pancreas-kidney transplants (SPKTs) conducted at the University Hospital of Leipzig from 1998 to 2018 were reviewed retrospectively. The transplants were categorized based on whether they began during daytime hours (8 a.m. to 6 p.m.) or nighttime hours (6 p.m. to 8 a.m.). We analyzed the demographics of both donors and recipients, as well as primary outcomes, which included surgical complications, patient survival, and graft longevity. Results: In this research involving 105 patients, 43 SPKTs, accounting for 41%, took place in the daytime, while 62 transplants (59%) occurred at night. The characteristics of both donors and recipients were similar across the two groups. Further, the rate of (surgical) pancreas graft-related complications and reoperations (daytime 39.5% versus nighttime 33.9%; p = 0.552) were also not statistically significant between both groups. In this study, the five-year survival rate for patients was comparable for both daytime and nighttime surgeries, with 85.2% for daytime and 86% for nighttime procedures (p = 0.816). Similarly, the survival rates for pancreas grafts were 75% for daytime and 77% for nighttime operations (p = 0.912), and for kidney grafts, 76% during the day compared to 80% at night (p = 0.740), indicating no significant statistical difference between the two time periods. In a multivariable model, recipient BMI > 30 kg/m2, donor age, donor BMI, and cold ischemia time > 15 h were independent predictors for increased risk of (surgical) pancreas graft-related complications, whereas the timepoint of SPKT (daytime versus nighttime) did not have an impact. Conclusions: The findings from our retrospective analysis at a big single German transplant center indicate that SPKT is a reliable procedure, regardless of the start time. Additionally, our data revealed that patients undergoing nighttime transplants have no greater risk of surgical complications or inferior results concerning long-term survival of the patient and graft. However, due to the small number of cases evaluated, further studies are required to confirm these results.

Clinical management, pathogen spectrum and outcomes in patients with pyogenic liver abscess in a German tertiary-care hospital.

Pyogenic liver abscesses (PLA) are life-threatening disorders and require immediate treatment, but structured evidence is sparse and treatment guidelines are not established. In a retrospective observational study of 221 adult PLA patients (mean age 63 years, 63% men) treated between 2013 and 2019 at the Leipzig University Medical Center, we characterized pathogen spectrum, clinical management and outcomes. Biliary malignancies (33%), cholelithiasis (23%) and ischemic biliary tract disease (16%) were most common causes of PLA. Comorbidities included malignancies (40%) and diabetes mellitus (35%). Abdominal ultrasound was the preferred initial imaging modality (58%). Enterobacterales (58%), enterococci (42%) and streptococci (18%) were identified as most frequent pathogens. 97% of patients were treated with antibiotics and 75% of patients underwent an invasive treatment procedure. The 30-day mortality was almost identical in patients with and without underlying malignancy (14.6% vs. 14.4%, p = 0.96), while the one-year outcome differed significantly (58.4% vs. 29.6%, p < 0.001). Positive blood cultures (OR 4.78, 95% CI 1.39 to 22.5, p = 0.023) and detection of Enterobacterales (OR 3.55, 95% CI 1.40 to 9.97, p = 0.010) were associated with increased 30-day-mortality. We conclude that ultrasound, extensive microbiologic diagnosis, adequate anti-infective therapy and early intervention are crucial for the management of PLA.

Towards a Standardization of Learning Curve Assessment in Minimally Invasive Liver Surgery.

OBJECTIVE: The aim was to analyze the learning curves of minimal invasive liver surgery(MILS) and propose a standardized reporting. SUMMARY BACKGROUND DATA: MILS offers benefits compared to open resections. For a safe introduction along the learning curve, formal training is recommended. However, definitions of learning curves and methods to assess it lack standardization. METHODS: A systematic review of PubMed, Web of Science, and CENTRAL databases identified studies on learning curves in MILS. The primary outcome was the number needed to overcome the learning curve. Secondary outcomes included endpoints defining learning curves, and characterization of different learning phases(competency, proficiency and mastery). RESULTS: 60 articles with 12'241 patients and 102 learning curve analyses were included. The laparoscopic and robotic approach was evaluated in 71 and 18 analyses and both approaches combined in 13 analyses. Sixty-one analyses (60%) based the learning curve on statistical calculations. The most often used parameters to define learning curves were operative time (n=64), blood loss (n=54), conversion (n=42) and postoperative complications (n=38). Overall competency, proficiency and mastery were reached after 34 (IQR 19-56), 50 (IQR 24-74), 58 (IQR 24-100) procedures respectively. Intraoperative parameters improved earlier (operative time: competency to proficiency to mastery: -13%, 2%; blood loss: competency to proficiency to mastery: -33%, 0%; conversion rate (competency to proficiency to mastery; -21%, -29%), whereas postoperative complications improved later (competency to proficiency to mastery: -25%, -41%). CONCLUSIONS: This review summarizes the highest evidence on learning curves in MILS taking into account different definitions and confounding factors. A standardized three-phase reporting of learning phases (competency, proficiency, mastery) is proposed and should be followed.

The Apparent Diffusion Coefficient of the Paraspinal and Psoas Muscles Are of Prognostic Relevance in Patients With Hepatocellular Carcinoma Undergoing Transarterial Radioembolization.

Background/Aim: Transarterial radioembolization (TARE) is a treatment option for early or intermediate stage hepatocellular carcinoma (HCC). Sarcopenia is defined as loss of muscle strength and quality which can be estimated by imaging modalities and has been associated with prognosis and treatment response in HCC patients. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted imaging (DWI) can reflect the tissue composition and might be better to determine muscle changes of sarcopenia than the standard method of computed tomography (CT). The present study sought to elucidate ADC values of the abdominal wall muscles as a prognostic factor in patients undergoing TARE. Patients and Methods: A retrospective analysis was performed between 2016 and 2020. Overall, 52 patients, 9 women (17.3%) and 43 men (82.7%), with a mean age of 69±8.5 years were included into the analysis. In every case, the first pre-interventional magnetic resonance imaging (MRI) including DWI was used to measure the ADC values of paraspinal and psoas muscle. The 12-month survival after TARE was used as the primary study outcome. Results: Overall, 40 patients (76.9%) of the patient cohort died within the 12-month observation period. Mean overall survival was 10.9 months after TARE for all patients. Mean ADC values for all muscles were 1.31±0.13×10-3mm2/s. The ADC values of the paraspinal muscles were statistically significantly higher compared to the ADC values of the psoas muscles (p=0.0031). A positive correlation was identified between mean ADC and the thrombocyte count (r=0.37, p=0.005) and serum bilirubin (r=-0.30, p=0.03). In the multivariate Cox regression analysis, the mean ADC values of all muscles were associated with the survival after 12 months (HR=0.98, 95% CI=0.97-0.99, p=0.04). Conclusion: ADC values of the abdominal wall muscles could be used as a prognostic biomarker in patients with HCC undergoing TARE. These preliminary results should be confirmed by further studies using external validation cohorts and other treatment modalities.

The impact of surgical timing on outcome in acute appendicitis in adults: a retrospective observational population-based cohort study.

BACKGROUND: Acute appendicitis is a global disease with high incidence. The main objective was to assess the association between time from admission to surgery (TAS) and surgery during emergency hours with operative outcome in light of conflicting evidence. METHODS: This is a retrospective population-wide analysis of hospital billing data (2010-2021) of all adult patient records of surgically treated cases of acute appendicitis in Germany by TAS. The primary outcome was a composite clinical endpoint (CCE; prolonged length of stay, surgical site infection, interventional draining after surgery, revision surgery, ICU admission and/or in-hospital mortality). Cases of complicated appendicitis were identified using diagnosis (ICD-10) and procedural codes (resection beyond appendectomy). RESULTS: 855 694 patient records were included, of which 27·6% (236,481) were complicated cases of acute appendicitis. 49·0% (418,821) were females and median age was 37 (interquartile range 22·5-51·5). Age, male sex, and comorbidity were associated with an increased proportion of CCE and in-hospital mortality. TAS was associated with a clinically relevant increase of CCE after 12 h in complicated appendicitis [Odd's ratio (OR), 1·19, 95% CI: 1·14-1·21] and after 24 h in uncomplicated appendicitis (OR 1·10, 95% CI: 1·02-1·19). Beyond the primary endpoint, the proportion of complicated appendicitis increased after TAS of 72 h. Surgery during emergency hours (6 pm-6.59 am) was associated with an increase of CCE and mortality (OR between 1·14 and 1·49). Age, female sex, night-time admission, weekend admission, a known previous surgery, obesity, and therapeutic anticoagulation were associated with delayed performance of surgery. CONCLUSION: This work found an increase of a CCE after TAS of 12 h for complicated appendicitis and an increase of the CCE after TAS of 24 h for uncomplicated appendicitis with a stable proportion of complicated appendicitis in these time windows. Both CCE and mortality were increased if appendectomy was performed during emergency hours.

Portal venous contrast enhancement ratio of the adrenal glands and spleen as prognostic marker of mortality in patients with acute mesenteric ischemia.

PURPOSE: Contrast enhancement of the adrenal gland defined by computed tomography (CT) was previously analyzed as a prognostic factor for critically ill patients in various diseases. However, no study investigated this quantitative parameter in patients with acute mesenteric ischemia. Therefore, the aim of this study was to evaluate the prognostic value of the contrast enhancement of the adrenal glands in patients with clinically suspected AMI. METHODS: All patients with clinically suspected AMI were retrospectively assessed between 2016 and 2020. All patients underwent surgical exploration after CT imaging. Overall, 134 patients (52 female patients, 38.8%) with a mean age of 69.2 ± 12.4 years were included into the present analysis. For all patients, the preoperative CT was used to calculate the contrast media enhancement of the adrenal glands and the spleen. RESULTS: A total of 27 patients (18.5%) died within the first 24 h and over the following 30-day 94 patients (68.6%) died. There were statistically significant differences regarding the mean values for adrenal-to-spleen ratio for 24-h mortality (p = 0.001) and 30-day mortality (p = 0.004), whereas the radiodensity of the inferior vena cava and the radiodensity of the spleen was statistically significant between survivors and non-survivors after 30 days (p = 0.037 and p = 0.028, respectively). In Cox regression analysis, mean adrenal radiodensity was associated with 24-h mortality (HR 1.09, 95% CI 1.02-1.16, p = 0.01) but not with 30-day mortality (HR 1.03, 95% CI 0.99-1.07, p = 0.13). CONCLUSION: The contrast media enhancement of the adrenal gland is associated with the 24-h and 30-day mortality in patients with AMI. However, the prognostic relevance for translation into clinical routine needs to be validated in other cohorts.

The GALAD score and the BALAD-2 score correlate with transarterial and systemic treatment response and survival in patients with hepatocellular carcinoma.

PURPOSE: The GALAD score and the BALAD-2 score are biomarker-based scoring systems used to detect hepatocellular carcinoma (HCC). Both incorporate levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP). Our objective was to examine the relationship between the GALAD score as well as the BALAD-2 score and treatment response to transarterial or systemic treatments in patients with HCC. METHODS: A total of 220 patients with HCC treated with either transarterial (n = 121) or systemic treatments (n = 99; mainly Sorafenib) were retrospectively analyzed. The GALAD score and the BALAD-2 score were calculated based on AFP-L3, AFP, and DCP levels measured in serum samples collected before treatment. The results were correlated with 3-month treatment efficacy based on radiologic mRECIST criteria. RESULTS: The GALAD score showed a strong correlation with BCLC stage (p < 0.001) and total tumor diameter before treatment (p < 0.001).The GALAD score at baseline was significantly lower in patients with a 3-month response to transarterial (p > 0.001) than in refractory patients. Among patients receiving systemic treatment, the median BALAD-2 score at baseline showed a strong association with response at month 3 (p < 0.001). In the transarterial treatment group, the GALAD score (AUC = 0.715; p < 0.001) as well as the BALAD score (AUC = 0.696; p < 0.001) were associated with overall survival, hereby outperforming AFP, AFP-L3 and DCP. CONCLUSION: The GALAD score as well as the BALAD-2 score hold significant promise as a prognostic tool for patients with early or intermediate-stage HCC who are undergoing transarterial or systemic treatments.

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease.

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.