Perfusion Computed Tomography in Rectal Carcinoma: Influence of Optimization of the Patlak Range on Calculation of Equivalent Blood Volume and Flow Extraction.

PURPOSE: The aim of the study is to assess the influence of manual adjustment of the Patlak range in computed tomography (CT) perfusion analysis of rectal carcinoma compared with default range of the perfusion software. METHODS: This study was approved by the institutional review board and informed consent was obtained. Twenty-one patients (12 male, 9 female; mean age ± SD, 59 ± 11 years) with rectal cancer were included and underwent perfusion CT before preoperative chemoradiotherapy. Equivalent blood volume (BV) and flow-extraction (FE) were calculated using the Patlak plot model. Two perfusion sets were calculated per patient, a perfusion set using the default setting as provided by the software (dBV, dFE) and an optimized perfusion set after manual adaption of the Patlak range (aBV, aFE), which was limited to the intravascular space clearance of contrast to the extravascular space. Perfusion values calculated with both methods were compared for significance in differences using the Wilcoxon test. A P value of 0.05 or less was defined as statistically significant. RESULTS: Adjustment of the Patlak range statistically significantly influenced BV and FE calculation. Median dBV was 23.2 mL/100 mL (interquartile range [IQR], 12.1 mL/100 mL), whereas median aBV was 20.3 mL/100 mL (IQR, 10.9 mL/100 mL). The difference in BV was statistically significant ( P = 0.021). Median dFE was 8.3 mL/min/100 mL (IQR, 4.7 mL/min/100 mL), whereas median aFE was 15.4 mL/min/100 mL (IQR, 5.8 mL/min/100 mL). The difference in FE was statistically significant ( P < 0.001). CONCLUSIONS: Our findings indicate that in perfusion CT of rectal carcinoma, adjustment of the Patlak range may significantly influence BV and FE compared with default setting of the software. This may contribute to standardization in the use of this technique for functional imaging of rectal cancer.

Thermoneutral housing promotes hepatic steatosis in standard diet-fed C57BL/6N mice, with a less pronounced effect on NAFLD progression upon high-fat feeding.

Introduction: Non-alcoholic fatty liver disease (NAFLD) can progress to more severe stages, such as steatohepatitis and fibrosis. Thermoneutral housing together with high-fat diet promoted NAFLD progression in C57BL/6J mice. Due to possible differences in steatohepatitis development between different C57BL/6 substrains, we examined how thermoneutrality affects NAFLD progression in C57BL/6N mice. Methods: Male mice were fed standard or high-fat diet for 24 weeks and housed under standard (22°C) or thermoneutral (30°C) conditions. Results: High-fat feeding promoted weight gain and hepatic steatosis, but the effect of thermoneutral environment was not evident. Liver expression of inflammatory markers was increased, with a modest and inconsistent effect of thermoneutral housing; however, histological scores of inflammation and fibrosis were generally low (<1.0), regardless of ambient temperature. In standard diet-fed mice, thermoneutrality increased weight gain, adiposity, and hepatic steatosis, accompanied by elevated de novo lipogenesis and changes in liver metabolome characterized by complex decreases in phospholipids and metabolites involved in urea cycle and oxidative stress defense. Conclusion: Thermoneutrality appears to promote NAFLD-associated phenotypes depending on the C57BL/6 substrain and/or the amount of dietary fat.

Krill Oil Supplementation Reduces Exacerbated Hepatic Steatosis Induced by Thermoneutral Housing in Mice with Diet-Induced Obesity.

Preclinical evidence suggests that n-3 fatty acids EPA and DHA (Omega-3) supplemented as phospholipids (PLs) may be more effective than triacylglycerols (TAGs) in reducing hepatic steatosis. To further test the ability of Omega-3 PLs to alleviate liver steatosis, we used a model of exacerbated non-alcoholic fatty liver disease based on high-fat feeding at thermoneutral temperature. Male C57BL/6N mice were fed for 24 weeks a lard-based diet given either alone (LHF) or supplemented with Omega-3 (30 mg/g diet) as PLs (krill oil; ω3PL) or TAGs (Epax 3000TG concentrate; ω3TG), which had a similar total content of EPA and DHA and their ratio. Substantial levels of TAG accumulation (~250 mg/g) but relatively low inflammation/fibrosis levels were achieved in the livers of control LHF mice. Liver steatosis was reduced by >40% in the ω3PL but not ω3TG group, and plasma ALT levels were markedly reduced (by 68%) in ω3PL mice as well. Krill oil administration also improved hepatic insulin sensitivity, and its effects were associated with high plasma adiponectin levels (150% of LHF mice) along with superior bioavailability of EPA, increased content of alkaloids stachydrine and trigonelline, suppression of lipogenic gene expression, and decreased diacylglycerol levels in the liver. This study reveals that in addition to Omega-3 PLs, other constituents of krill oil, such as alkaloids, may contribute to its strong antisteatotic effects in the liver.

The Lipase/Amylase Ratio (LAR) in Peripheral Blood Might Represent a Novel Prognostic Marker in Patients with Surgically Resectable Pancreatic Cancer.

Pancreatic enzymes might play a pivotal role in the pathophysiology and prognosis of pancreatic cancer. The aim of this study is to investigate the lipase/amylase ratio (LAR), representing a marker previously used in the differentiation of pancreatitis, as a potential prognostic marker in pancreatic cancer. Data from 157 surgically treated patients with ductal pancreatic adenocarcinoma and 351 patients with metastatic disease were evaluated retrospectively. Cancer-specific survival (CSS) was considered the endpoint of the study. After applying Kaplan-Meier curve analysis, uni- and multivariate Cox regression models were calculated to evaluate the prognostic relevance of LAR. An elevated LAR at diagnosis of localized pancreatic cancer was significantly associated with higher CA19-9 levels (p < 0.05). In univariate analysis, we observed an increased LAR as a significant factor for lower CSS in localized pancreatic cancer patients (HR = 1.63; 95% CI = 1.12-2.36; p = 0.01), but not in metastatic patients (HR = 1.12; 95% CI = 0.87-1.43; p = 0.363). In multivariate analysis, including age, gender, tumor stage, Karnofsky Performance Status, tumor grade, administration of chemotherapy and the LAR, an increased LAR was confirmed to represent an independent prognostic factor regarding CSS (HR = 1.81; 95% CI = 1.17-2.77; p = 0.007) in localized pancreatic cancer patients. In conclusion, our study identified the LAR as an independent prognostic factor in surgically treated pancreatic cancer patients.

External validation of the prognostic relevance of the advanced lung cancer inflammation index (ALI) in pancreatic cancer patients.

BACKGROUND: The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy. METHODS: In our single-center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m2 ) × serum albumin levels (g/dL)/neutrophil-lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC-analysis. Kaplan-Meier method as well as uni- and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer-specific survival (CSS) as the primary endpoint of the study. RESULTS: The ALI showed a significant negative correlation with CA19-9 levels and C-reactive protein levels whereas we found an association with localized tumor stage and better performance status (P < .05 for all mentioned variables). As opposed to patients with a high ALI, decreased ALI was significantly associated with shorter CSS (HR = 0.606, 95% CI: 0.471-0.779, P = .001). Multivariate analysis demonstrated tumor grade, tumor stage, chemotherapy, C-reactive protein levels, and CA19-9 levels to independently predict for CSS (all P < .05). In contrast the ALI failed to independently predict for CSS in the performed multivariate models (HR = 0.878, 95% CI: 0.643-1.198, P = .411). CONCLUSION: In this large cohort of PC patients, the ALI did not complement existing clinicopathological factors for outcome determination.

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan-Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129-1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10-1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

Non-invasive diagnosis of cirrhosis and long-term disease monitoring by transient elastography in patients with Wilson disease.

BACKGROUND & AIMS: The value of liver stiffness measurement (LSM) by transient elastography (TE) for non-invasive fibrosis staging and disease monitoring has not been established in patients with Wilson disease (WD). METHODS: Liver stiffness measurement by TE and non-invasive fibrosis scores (APRI, FIB-4) were analysed from 188 WD patients with liver biopsy (LBX). Longitudinal LSM was performed in 128 (68.1%) patients. RESULTS: One hundred and eighty-eight patients (mean age: 35 ± 14 years, 54.8% women; 27.1% with histological cirrhosis) were studied. Forty-four[23.4%] patients were recently diagnosed with WD, while 144[76.6%] were previously diagnosed (>1 year between LBX and LSM). Overall, LSM (11.3 vs 6.1 kPa, P < .001), APRI (0.72 vs 0.38, P < .001) and FIB-4 (1.54 vs 0.89, P < .001) were higher in cirrhotic than in non-cirrhotic patients. This was even more pronounced in recently diagnosed patients (35.2 kPa vs 6.4 kPa, P < .001). Accuracy for diagnosing cirrhosis at an LSM cut-off ≥9.9 kPa was better in recently diagnosed (PPV: 74%, NPV: 100%) vs previously diagnosed (PPV: 53%, NPV: 82%) patients. Recently diagnosed patients had higher Area Under the Curve (AUC) for APRI (0.79 vs 0.61) and FIB-4 (0.84 vs 0.65) than previously diagnosed patients. At APRI <1.5 and FIB-4 <3.25 cirrhosis was ruled out with a specificity of 93% and 95% respectively. During a median follow-up of 46 (24-66) months, only 5.9% (5/85) of non-cirrhotic WD patients showed progression to cirrhotic LSM values, while 30.8% (4/13) of cirrhotic WD patients showed LSM suggestive of cirrhosis regression. CONCLUSION: TE-based LSM ≥9.9 kPa accurately identifies cirrhosis in WD patients. Next to TE-LSM <9.9 kPa, APRI <1.5 and FIB-4 <3.25 values assist to non-invasively rule out cirrhosis. LSM remains stable in most non-cirrhotic patients on WD therapy, while one-third of cirrhotic patients present clinically relevant decreases in LSM.

Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy.

tRNA synthetase deficiencies are a growing group of genetic diseases associated with tissue-specific, mostly neurological, phenotypes. In cattle, cytosolic isoleucyl-tRNA synthetase (IARS) missense mutations cause hereditary weak calf syndrome. Exome sequencing in three unrelated individuals with severe prenatal-onset growth retardation, intellectual disability, and muscular hypotonia revealed biallelic mutations in IARS. Studies in yeast confirmed the pathogenicity of identified mutations. Two of the individuals had infantile hepatopathy with fibrosis and steatosis, leading in one to liver failure in the course of infections. Zinc deficiency was present in all affected individuals and supplementation with zinc showed a beneficial effect on growth in one.

Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations.

BACKGROUND & AIMS: The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), is strongly associated with appearance of in NAFLD. This study evaluated the role of PNPLA3 and hepatic copper content for development of steatosis in patients with WD. METHODS: Liver biopsies obtained at diagnosis and the PNPLA3 genotype were analyzed in 98 Caucasian patients with WD (male: 52 [53.1%]; mean age: 27.6 years [CI 95%: 24.8-30.4, range: 5.8-61.5]). Steatosis was graded as percentage of lipid containing hepatocytes by an expert hepatopathologist unaware of the results of genetic testing. RESULTS: Moderate/severe steatosis (>33% of hepatocytes) was observed in 28 patients (pediatric: n=13/26 [50.0%], adult: n=15/72 [20.8%]; p=0.01). Forty-six patients (46.9%; pediatric: n=7, adult: n=39; p=0.022) had cirrhosis. Multivariate logistic regression identified PNPLA3 G allele (OR: 2.469, CI 95%: 1.203-5.068; p=0.014) and pediatric age (OR: 4.348; 1.577-11.905; p=0.004) as independent variables associated with moderate/severe steatosis. In contrast, hepatic copper content did not impact on moderate/severe steatosis (OR: 1.000, CI 95%: 1.000-1.001; p=0.297). CONCLUSIONS: Steatosis is common in WD and the PNPLA3 G allele contributes to its pathogenesis. The role of hepatic copper concentration and ATP7B mutations in steatosis development deserve further investigations.

Non-invasive separation of alcoholic and non-alcoholic liver disease with predictive modeling.

BACKGROUND & OBJECTIVE: Currently, a major clinical challenge is to distinguish between chronic liver disease caused by metabolic syndrome (non-alcoholic fatty liver disease, NAFLD) from that caused by long term or excessive alcohol consumption (ALD). The etiology of severe liver disease affects treatment options and priorities for liver transplantation and organ allocation. Thus we compared physiologically similar NAFLD and ALD patients to detect biochemical differences for improved separation of these mechanistically overlapping etiologies. METHODS: In a cohort of 31 NAFLD patients with BMI below 30 and a cohort of ALD patient with (ALDC n = 51) or without cirrhosis (ALDNC n = 51) serum transaminases, cell death markers and (adipo-)cytokines were assessed. Groups were compared with One-way ANOVA and Tukey's correction. Predictive models were built by machine learning techniques. RESULTS: NAFLD, ALDNC or ALDC patients did not differ in demographic parameters. The ratio of alanine aminotransferase/aspartate aminotransferase--common serum parameters for liver damage--was significantly higher in the NAFLD group compared to both ALD groups (each p<0.0001). Adiponectin and tumor necrosis factor(TNF)-alpha were significantly lower in NAFLD than in ALDNC (p<0.05) or ALDC patients (p<0.0001). Significantly higher serum concentrations of cell death markers, hyaluronic acid, adiponectin, and TNF-alpha (each p<0.0001) were found in ALDC compared to ALDNC. Using machine learning techniques we were able to discern NAFLD and ALDNC (up to an AUC of 0.9118±0.0056) or ALDC and ALDNC (up to an AUC of 0.9846±0.0018), respectively. CONCLUSIONS: Machine learning techniques relying on ALT/AST ratio, adipokines and cytokines distinguish NAFLD and ALD. In addition, severity of ALD may be non-invasively diagnosed via serum cytokine concentrations.