Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient ...performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches.
Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1±10.1kg/m2) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m2).
EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS≤4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate.
A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions.
Abstract Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant ...metastases is limited to a year, yet‐to‐be‐defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision‐making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox‐Lasso regression machine learning, adapted to a high‐dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis‐free interval) at first diagnosis of metastatic disease as predictors for time‐to‐treatment failure and overall survival. Taken together, the risk stratification models, built by our machine‐learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases.
BACKGROUND AND AIMS
To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first ...contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo.
APPROACH AND RESULTS
The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL interleukin 1B, IL6, and TNF tumor necrosis factor). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune‐inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA‐positive and protein‐rich fractions after heparin column separation, still had immune‐inducing capacity in PHH. The HBV‐induced gene expression profile was similar to that induced by toll‐like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7‐9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal–regulated kinase), JNK, and p38 mitogen‐activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV‐induced gene expression could be neutralized by TLR2‐specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2‐mediated response to HBV, suggesting a receptor binding‐related mechanism. In liver‐humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen.
CONCLUSIONS
PHHs are able to sense HBV particles through TLR2, leading to an activation of anti‐HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.
The absence of primary tumor desmoplasia, a marker of node metastases, on frozen section may help reduce the extent of surgery without compromising the biochemical cure. We aimed to clarify whether ...hemithyroidectomy with diagnostic ipsilateral central neck dissection can replace total thyroidectomy with routine central neck dissection in patients with sporadic medullary thyroid cancer.
We retrospectively evaluated data collected from patients who had undergone primary neck surgery for hypercalcitoninemic sporadic medullary thyroid cancer between January 2017 and December 2022 at one institution.
Of the 25 patients we examined, 19 had desmoplasia-negative and 6 desmoplasia-positive primary thyroid tumors on frozen section. The desmoplasia-negative patients had undergone less surgery with fewer nodes removed than the desmoplasia-positive patients (medians of 6 vs 31 nodes, P < .001). The desmoplasia-negative patients had predominantly undergone hemithyroidectomy with ipsilateral central neck dissection. None of the desmoplasia-negative tumors was multifocal (0 of 19 desmoplasia-negative vs 2 of 6 desmoplasia-positive or 0% vs 33%, P = .050) or node-positive (0 of 19 vs 6 of 6 patients or 0% vs 100%; medians of 0 vs 3.5 node metastases; both P < .001). Despite limited surgery, all desmoplasia-negative patients attained and maintained biochemical cure.
Hemithyroidectomy combined with diagnostic ipsilateral central neck dissection is a viable risk-reducing and curative strategy for desmoplasia-negative and node-negative, nonmetastatic unifocal tumors, for which we propose the term sporadic noninvasive medullary thyroid neoplasm (SNMTP).
To assess the diagnostic accuracy of liver maximum capacity (LiMAx®) test compared to transient elastography (TE) and serum biomarkers for the noninvasive detection of different stages of liver ...fibrosis and cirrhosis.
We retrospectively correlated LiMAx®, TE, aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) score with histological specimens in 102 patients with chronic liver disease (CLD) who underwent liver biopsy (either percutaneously or via mini-laparoscopy) at the University Clinic of Essen between 10/2016 and 12/2017.
Median LiMAx® values showed a tendency to decrease in accordance with increasing histological degree of fibrosis based on the Desmet scoring system (F0: 446.5 381.0-592.5 µg/h/kg, F1: 405.0 343.0-547.0 µg/h/kg, F2: 337.0 250.0-394.0 µg/h/kg, F3: 281.0 262.0-364.0 µg/h/kg, and F4: 181.5 130.0-256.5 µg/h/kg. Furthermore, -LiMAx® was superior to TE, FIB-4, AAR, and APRI in detecting different stages of fibrosis, while Spearman's rank correlation test showed a statistically significant association of -0.68, 0.62, 0.61, 0.46, and 0.42, respectively. However, the combination of TE and LiMAx® had the highest diagnostic accuracy in detecting liver cirrhosis (sensitivity 88.9%, specificity 84.6%, Youden index 0.735).
Enzymatic liver function measured by LiMAx® showed strong correlation with histology in patients with CLD irrespective of its underlying etiology and was superior to TE and serum biomarkers, possibly making it useful as a novel and noninvasive tool for the determination of hepatic disease severity.
Controlled oxygenated rewarming (COR) up to 20°C during ex vivo machine perfusion limits reperfusion‐induced tissue injury upon graft implantation. Rewarming up to normothermia might add further ...benefits and provide better prediction of post‐transplantation organ function. The effect of 90 minutes of oxygenated machine perfusion with Aqix RS‐I after cold storage combined with gentle rewarming up to 20°C (COR20) or 35°C (COR35) was studied in rat livers and compared with cold storage alone (CS, n = 6, resp). Postpreservation recovery was evaluated upon warm reperfusion using an established in vitro system. COR generally resulted in significantly improved energetic recovery, increased bile flow, less activities alanine aminotransferase (ALT) release, and improved histopathology upon reperfusion as compared to only cold‐stored livers, without significant differences between COR20 and COR35. Parameters obtained during COR, especially during COR35, also allowed for prediction of hepatic recovery upon reperfusion. For instance, ulterior bile production upon reperfusion was found closely correlated to bile flow observed already during COR35 (R2 = 0.91). COR significantly improved liver quality after static cold storage. Elevation of machine perfusion temperature up to 35°C may prove promising to refine ex vivo evaluation of the graft prior to transplantation.
In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial ...natriuretic peptide (NP) and B-type NP, with their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation.
We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI.
Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (knockout mice with endothelial GC-A deletion) or cGKI (knockout mice with endothelial cGKI deletion). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2 days after AMI were attenuated in knockout mice with endothelial GC-A deletion and unaltered in knockout mice with endothelial cGKI deletion. Molecular studies revealed that hypoxia and tumor necrosis factor-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase 2A (PDE2A) levels. Real-time cAMP measurements in endothelial microdomains using a novel fluorescence resonance energy transfer biosensor revealed that PDE2 mediates NP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that tumor necrosis factor-α-induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions.
Hypoxia and cytokines, such as tumor necrosis factor-α, modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A, and altered cGMP/cAMP cross talk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NP/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.
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