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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Improving preoperative detection of synchronous liver metastases in pancreatic cancer with combined contrast-enhanced and diffusion-weighted MRI

Purpose: To explore the value of gadolinium-enhanced MRI combined with diffusion-weighted MRI (Gd-enhanced MRI with DWI) in addition to contrast-enhanced CT (CECT) for detection of synchronous liver metastases for potentially resectable pancreatic cancer. Methods: By means of a retrospective cohort study we included patients with potentially resectable pancreatic cancer on CECT, who underwent Gd-enhanced MRI with DWI between January 2012 and December 2016. A single observer evaluated MRI and CT and was blinded to imaging, pathology, and surgery reports. Liver lesions were scored in both modalities, using a 3-point scale: 1-benign, 2-indeterminate, 3- malignant (i.e., metastasis). The primary outcome parameters were the presence of liver metastases on Gd-enhanced MRI with DWI and the sensitivity of Gd-enhanced MRI with DWI for synchronous liver metastases. Results: We included 66 patients (42 men, 24 women; median age 65 years, range 36–82 years). In 19 patients, liver metastases were present, which were confirmed by histopathology (n = 12), {sup 18}FDG-PET (n = 6), or surgical inspection (n = 1). Gd-enhanced MRI with DWI showed metastases in 16/19 patients (24%), which resulted in a sensitivity of 84% (95% CI 60–97%). Contrast-enhanced MRI showed 156 and DWI 397 metastases (p = 0.051), and 339 were particularly small (< 5 mm). Conclusions: In this study, Gd-enhanced MRI with DWI detected synchronous liver metastases in 24% of patients with potentially resectable pancreatic cancer on CECT with a sensitivity of 84%. Diffusion-weighted MRI showed a greater number of metastases than any other sequence, particularly small metastases (< 5 mm).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Laparoscopic Isolated Total Caudate Lobectomy for Hepatocellular Carcinoma Located in the Paracaval Portion of the Cirrhotic Liver

Background: Despite the widespread use of laparoscopic hepatectomies in past decades, laparoscopic isolated total caudate lobectomy for hepatocellular carcinoma (HCC) remains challenging,{sup 1,2} especially for patients with cirrhosis. Moreover, a laparoscopic isolated total caudate lobectomy for HCC originating in the paracaval portion of the caudate lobe is very rare. We herein present a video showing laparoscopic total caudate lobectomy for a cirrhotic patient with HCC located in the paracaval portion of the caudate lobe. Methods: A 58-year-old woman who suffered from hepatitis C virus-related cirrhosis was admitted to our institution. The preoperative computed tomography showed a 2.5 × 2.0 cm liver mass located in segment I that was very close to the right hepatic pedicle. Although her liver function was Child–Pugh A, the indocyanine green (ICG)-15 test was high at 10.9%. Right hepatectomy plus caudate lobectomy was not adopted because of the severe cirrhosis and the elevated ICG-15. Thus, laparoscopic isolated total caudate lobectomy was contemplated. Results: The patient was placed in the supine position. After full mobilization, the caudate lobe was exposed. The third porta of the liver was then dissected and the short hepatic veins were controlled with clips and LigaSure. The dissection was finished when the whole third porta of the liver was freed. Subsequently, the portal branches to the caudate lobe were ligated and cut. The combination between the left- and right-sided laparoscopic approaches was used to transect liver parenchyma. The superficial parenchyma was divided using an harmonic scalpel, while the deeper tissue was divided using a Cavitron ultrasonic aspirator (CUSA). The Pringle maneuver was used intermittently during the parenchymal transection as necessary. In the left-sided approach, the caudate lobe was resected along the left and middle hepatic vein toward the right side, to expose the dorsal semicircle of the right hepatic vein. In the right-sided approach, the resection started from the right border of the process portion to the root of the right hepatic vein in the cranial direction. Finally, the whole caudate lobe was resected and the three main hepatic veins were exposed on the cutting plane. The specimen was removed from suprapubic incision. The operative time was 300 min and the total Pringle time was 50 min. The postoperative course was uneventful. Conclusions: A laparoscopic isolated total caudate lobectomy for HCC located in the paracaval portion of the cirrhotic liver seems to be feasible and safe in selected patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease

In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Toward Revealing Microcystin Distribution in Mouse Liver Tissue Using MALDI-MS Imaging

Cyanotoxins can be found in water and air during cyanobacterial harmful algal blooms (cHABs) in lakes and rivers. Therefore, it is very important to monitor their potential uptake by animals and humans as well as their health effects and distribution in affected organs. Herein, the distribution of hepatotoxic peptide microcystin-LR (MC-LR) is investigated in liver tissues of mice gavaged with this most common MC congener. Preliminary matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging experiments performed using a non-automated MALDI matrix deposition device and a MALDI-time-of-flight (TOF) mass spectrometer yielded ambiguous results in terms of MC-LR distribution in liver samples obtained from MC-LR-gavaged mice. The tissue preparation for MALDI-MS imaging was improved by using an automated sprayer for matrix deposition, and liver sections were imaged using an Nd:YAG MALDI laser coupled to a 15 Tesla Fourier-transform ion cyclotron resonance (FT-ICR)-mass spectrometer. MALDI-FT-ICR-MS imaging provided unambiguous detection of protonated MC-LR (calculated m/z 995.5560, z = +1) and the sodium adduct of MC-LR (m/z 1017.5380, z = +1) in liver sections from gavaged mice with great mass accuracy and ultra-high mass resolution. Since both covalently bound and free MC-LR can be found in liver of mice exposed to this toxin, the present results indicate that the distribution of free microcystins in tissue sections from affected organs, such as liver, can be monitored with high-resolution MALDI-MS imaging.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Misclassification of primary liver cancer in the Life Span Study of atomic bomb survivors

Primary liver cancer is difficult to diagnose accurately at death, due to metastases from nearby organs and to concomitant diseases, such as chronic hepatitis and cirrhosis. Trends in diagnostic accuracy could affect radiation risk estimates for incident liver cancer by altering background rates or by impacting risk modification by sex and age. We quantified the potential impact of death‐certificate inaccuracies on radiation risk estimates for liver cancer in the Life Span Study of atomic bomb survivors. True‐positive and false‐negative rates were obtained from a previous study that compared death‐certificate causes of death with those based on pathological review, from 1958 to 1987. We assumed various scenarios for misclassification rates after 1987. We obtained estimated true positives and estimated false negatives by stratified sampling from binomial distributions with probabilities given by the true‐positive and false‐negative rates, respectively. Poisson regression methods were applied to highly stratified person‐year tables of corrected case counts and accrued person years. During the study period (1958–2009), there were 1,885 cases of liver cancer, which included 383 death‐certificate‐only (DCO) cases; 1,283 cases with chronic liver disease as the underlying cause of death; and 150 DCO cases of pancreatic cancer among 105,444 study participants. Across the range of scenarios considered, radiation risk estimates based on corrected case counts were attenuated, on average, by 13–30%. Our results indicated that radiation risk estimates for liver cancer were potentially sensitive to death‐certificate inaccuracies. Additional data are needed to inform misclassification rates in recent years.

French, Benjamin↗
DOE OSTI2019

MR elastography of liver at 3 Tesla: comparison of gradient-recalled echo (GRE) and spin-echo (SE) echo-planar imaging (EPI) sequences and agreement across stiffness measurements

Purpose: To compare 2D gradient-recalled echo (GRE) and 2D spin-echo (SE) echo-planar imaging (EPI) MR elastography (MRE) for measurement of hepatic stiffness in adult patients with known or suspected liver disease at 3 Tesla. Materials and methods: Three hundred and eighty-seven consecutive patients underwent MRE of the liver at 3 Tesla with 2D-GRE and 2D-SE-EPI sequences. ‘Mean liver stiffness (LS)’ calculated by averaging 3 ROIs in the right lobe, ‘Maximum LS’ calculated by an ROI in the right lobe; and ‘Freehand LS’ calculated by an ROI in the entire liver were measured by two independent readers. Inter-observer and inter-class variability in stiffness measurements were assessed. Stiffness values were correlated with degree of liver fibrosis (METAVIR scores) in 97 patients who underwent biopsy. The diagnostic performance was compared by a receiver-operating characteristic analysis. Results: The technical failure rate was 2.8% for 2D-SE-EPI (11/387) and 4.1% for 2D-GRE (16/387, 9 had R{sub 2}* > 80 s{sup −1} indicating iron overload). There is high reproducibility for both GRE and SE-EPI variants (ICC = 0.84–0.94 for both GRE and SE-EPI MRE). The highest sensitivity, specificity, and accuracy of differentiating mild fibrosis (F0–F2) from advanced fibrosis (F3–F4) are 0.84 (GRE Freehand measurement), 0.92 (GRE Maximum stiffness measurement), and 0.88 (GRE Freehand measurement), respectively. Conclusions: High intra-class correlation and intra-reader correlation are seen on measured hepatic stiffness for both 2D-GRE and 2D-SE-EPI MRE. 2D-SE-EPI has lower failure rate. Diagnostic performance of both sequences is equivalent, with highest sensitivity for 2D-GRE Freehand stiffness measurement, and highest specificity 2D-GRE Maximum stiffness measurement.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Comparison of CT methods for determining graft steatosis in living donor liver transplantation

Purpose: To evaluate and compare the diagnostic performance of non-enhanced computed tomography (NECT) and contrast-enhanced CT (CECT) attenuation indices in the assessment of hepatic steatosis by using biopsy as the reference standard. Materials and methods: This retrospective study was approved by our Institutional Review Board. 55 Potential donors who underwent both NECT and triphasic CECT and core liver biopsy, were included the study. Average attenuation measurements that were obtained from multiple regions in liver, spleen, and psoas muscle on both unenhanced and CECT were used for analysis. Hepatic attenuation measurements were analyzed with and without normalization with the spleen and psoas muscle. Linear regression and receiver operating characteristic (ROC) curve analysis were used to evaluate the statistical association between CT indices and steatosis at histology. Results: Linear regression analysis confirmed the strongest correlation between steatosis and normalized measurements of hepatic attenuation with splenic attenuations on hepatic venous phase of CECT scan (R 0.821; R{sup 2} 0.674 and R 0.816; R{sup 2} 0.665, respectively). The use of ROC curve analysis also demonstrated that normalized measurements of hepatic attenuation with splenic attenuations on hepatic venous phase of CECT showed high diagnostic performance regarding the qualitative distinction of steatosis (AUC values greater than 0.9). Conclusion: Attenuation measurements of liver normalized with spleen on hepatic venous phase may be useful in evaluating steatosis in donor candidates with moderate to severe steatosis who are unacceptable for liver donation. In this manner unnecessary liver biopsy may be avoided in those donor candidates.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Monitoring of Thermal-Induced Changes in Liver Stiffness During Controlled Hyperthermia and Microwave Ablation in an Ex Vivo Bovine Model Using Point Shear Wave Elastography

Purpose: To investigate liver stiffness changes—evaluated by point shear wave elastography (pSWE)—in controlled hyperthermia and microwave ablation (MWA) in an ex vivo animal model. Materials and Methods: Five samples of ex vivo bovine liver were uniformly heated to temperatures ranging from 40 to 100 °C. B-mode ultrasound imaging and pSWE were acquired simultaneously, and shear wave velocity (SWV) was measured in a region of interest (ROI). The threshold value of SWV at 60 °C (avg60) was identified. Subsequently, MWA was performed in 11 liver samples at 60 W until avg60 + 0.5 m/s was reached. SWV was measured in ROIs at 10–40 mm from the antenna feed. The correlation of mean values of SWV with location (within, border, or outside necrotic area) at gross pathology was evaluated. Results: In controlled hyperthermia experiments, a steep transition in liver stiffness was observed at 63.0 ± 2.4 °C (SWV 3.54 ± 0.68 m/s). Avg60 was of 2.5 m/s. In 8/9 MWA experiments, interrupted when SWV of 3 m/s was measured, the ROI was at the inner side of the necrotic area border at pathology (accuracy 89%). No correlation between SWV values for outside, border, and within necrosis could be identified. Conclusions: pSWE can provide a velocity threshold predictive of the presence of coagulation necrosis during MWA in ex vivo liver model. However, pSWE is not able to reliably capture changes in stiffness within, at the border, and outside the necrotic zone in this experimental model.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Simulation and analysis of different approaches towards fiber optic plasmonic sensing for detection of human-liver tissues

Three types of plasmonic sensors are applied for the detection of five types of human-liver tissues (normal N, metastatic MET, non-cancerous metastatic NMET, hepatocellular carcinoma HCC and non-cancerous hepatocellular carcinoma NHCC). The first type of the fiber with seven layers is made by a ZBLAN core surrounded by NaF, silicon, silver, graphene, Al{sub 2}O{sub 3} and liver layers. The second type of the fiber with six layers is similar to the first one but without the graphene layer. The third type of the fiber with five layers is made by a SiO{sub 2} core surrounded by GaP, gold, Al{sub 2}O{sub 3} and liver layers. For optimized thicknesses of the interior layers at a laser wavelength (1.53 μm) one obtains large values of the figure of merit and amplitude sensitivity at an angle very close to the resonance angle. The advantage of the third (second) type of the fiber for normal liver is a large figure of merit (maximum amplitude sensitivity) in comparison with that for the second (third) type of the sensor. For all variants of the sensors, the figure of merit and maximum of the amplitude sensitivity are decreasing in the same order (N, MET, NMET, NHCC and HCC) for the liver tissues.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2019

Single-Dose Vaccination with a Hepatotropic Adeno-associated Virus Efficiently Localizes T Cell Immunity in the Liver with the Potential To Confer Rapid Protection against Hepatitis C Virus

Hepatitis C virus (HCV) is a significant contributor to the global disease burden, and development of an effective vaccine is required to eliminate HCV infections worldwide. CD4 + and CD8 + T cell immunity correlates with viral clearance in primary HCV infection, and intrahepatic CD8 + tissue-resident memory T (T RM ) cells provide lifelong and rapid protection against hepatotropic pathogens. Consequently, we aimed to develop a vaccine to elicit HCV-specific CD4 + and CD8 + T cells, including CD8 + T RM cells, in the liver, given that HCV primarily infects hepatocytes. To achieve this, we vaccinated wild-type BALB/c mice with a highly immunogenic cytolytic DNA vaccine encoding a model HCV (genotype 3a) nonstructural protein (NS5B) and a mutant perforin (pVAX-NS5B-PRF), as well as a recombinant adeno-associated virus (AAV) encoding NS5B (rAAV-NS5B). A novel fluorescent target array (FTA) was used to map immunodominant CD4 + T helper (T H ) cell and cytotoxic CD8 + T cell epitopes of NS5B in vivo , which were subsequently used to design a K d NS5B 451-459 tetramer and analyze NS5B-specific T cell responses in vaccinated mice in vivo . The data showed that intradermal prime/boost vaccination with pVAX-NS5B-PRF was effective in eliciting T H and cytotoxic CD8 + T cell responses and intrahepatic CD8 + T RM cells, but a single intravenous dose of hepatotropic rAAV-NS5B was significantly more effective. As a T-cell-based vaccine against HCV should ideally result in localized T cell responses in the liver, this study describes primary observations in the context of HCV vaccination that can be used to achieve this goal. There are currently at least 71 million individuals with chronic HCV worldwide and almost two million new infections annually. Although the advent of direct-acting antivirals (DAAs) offers highly effective therapy, considerable remaining challenges argue against reliance on DAAs for HCV elimination, including high drug cost, poorly developed health infrastructure, low screening rates, and significant reinfection rates. Accordingly, development of an effective vaccine is crucial to HCV elimination. An HCV vaccine that elicits T cell immunity in the liver will be highly protective for the following reasons: (i) T cell responses against nonstructural proteins of the virus are associated with clearance of primary infection, and (ii) long-lived liver-resident T cells alone can protect against malaria infection of hepatocytes. Thus, in this study we exploit promising vaccination platforms to highlight strategies that can be used to evoke highly functional and long-lived T cell responses in the liver for protection against HCV.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis

Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3) -/- mice are completely protected from ethanol-induced liver injury, Mlkl -/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury. Bone marrow transplants between Mlkl -/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced hepatic injury, steatosis, and inflammation were exacerbated in Mlkl -/- →wild-type (WT) mice, whereas Mlkl deficiency in nonmyeloid cells (WT→Mlkl -/- ) had no effect on Gao-binge ethanol-induced injury. Importantly, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden and accumulation of immune cells in livers. Mechanistically, challenging macrophages with lipopolysaccharide (LPS) induced signal transducer and activator of transcription 1–mediated expression and phosphorylation of MLKL, as well as translocation and oligomerization of MLKL to intracellular compartments, including phagosomes and lysosomes but not plasma membrane. Importantly, pharmacological or genetic inhibition of MLKL suppressed the phagocytic capability of primary mouse Kupffer cells (KCs) at baseline and in response to LPS with/without ethanol as well as peripheral monocytes isolated from both healthy controls and patients with alcohol-associated hepatitis. Further, in vivo studies revealed that KCs of Mlkl -/- mice phagocytosed fewer bioparticles than KCs of WT mice. Together, these data indicate that myeloid MLKL restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Diagnostic accuracy of acoustic radiation force impulse elastography (ARFI) in comparison to other non-invasive modalities in staging of liver fibrosis in chronic HCV patients: single-center experience

Purpose: To evaluate the reliability of ARFI elastography for liver fibrosis staging and compare it to other non-invasive assessment of hepatic fibrosis (FIB-4 and APRI) in chronic HCV (CHC) patients. Methods: A single-center, prospective study included 2103 CHC patients. Liver stiffness (LS) was evaluated by TE and ARFI elastography. FIB-4 and APRI were calculated. The area under the receiver-operating characteristic curve (AUROCs) was used to assess the diagnostic performance of ARFI elastography for staging of liver fibrosis using TE as a reference standard. Results: The best cut off values of ARFI elastography for diagnosis of ≥ F2, ≥ F3and F4 were 1.36 m/s, 1.45 m/s, and 1.7 m/s with AUROCs of 0.89, 0.94 and 0.95, respectively. ARFI elastography cut offs are lower in patients with normal ALT level compared to those with ALT level (1.1–< 3 ULN) and those with ALT level ≥ 3ULN (1.35 m/s vs 1.39 m/s vs 1.54 for F ≥ 2, 1.44 m/s vs 1.58 m/s vs 1.6 m/s for F3, 1.69 m/s, 1.84 m/s, 1.86 m/s for F4). FIB-4 (0.82–0.86) and APRI (0.78–0.82) yielded lower AUC in prediction of significant fibrosis and cirrhosis than ARFI elastography (0.89–0.95). Conclusion: ARFI elastography is a reliable method for non-invasive staging of liver fibrosis in CHC patients when compared to TE with a good diagnostic performance comparable to FIB-4 and APRI scores for the prediction of significant fibrosis and cirrhosis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

R2 relaxometry based MR imaging for estimation of liver iron content: A comparison between two methods

Purpose: To compare the reproducibility and accuracy of R2-relaxometry MRI for estimation of liver iron concentration (LIC) between in-house analysis and FDA-approved commercially available third party results. Methods: All MR studies were performed on a 1.5T scanner. Multi-echo spin-echo scans with a fixed TR and increasing TE values of 6 ms, 9 ms, 12 ms, 15 ms, and 18 ms (spaced at 3 ms intervals) were used. Post-processing of the images to calculate mean relaxivity, R2, included drawing of regions of interest to include the whole liver on mid-slice. The relationship between liver R2 values and estimated LIC calculated with in-house analysis and values reported by an external company (FerriScan{sup ®}, Resonance Health, Australia) were assessed with correlation coefficients and Bland–Altman difference plots. Continuous variables are presented as mean ± standard deviation. Significance was set at p value < 0.05. Results: 474 studies from 175 patients were included in the study (mean age 10.4 ± 4.2 years (range 1–18 years); 254 studies from girls, 220 studies from boys). LIC ranged from 0.6 to 43 mg/g dry tissue, covering a broad range from normal levels to extremely high iron levels. Linearity between proprietary and in-house methods was excellent across the observed range for R2 (31.5 to 334.8 s{sup −1}); showing a correlation coefficient of r = 0.87, p < 0.001. Bland–Altman R2 difference plot between the two methods shows a mean bias of + 21.5 s{sup −1} (range − 47.0 to + 90.0 s{sup −1} between two standard deviations). LIC reported by FerriScan{sup ®} compared with LIC estimated in-house with R2 as reported by FerriScan{sup ®} agreed strongly, (r = 1.0, p < 0.001). Conclusion: R2 relaxometry MR imaging for liver iron concentration estimation is reproducible between proprietary FDA-approved commercial software and in-house analysis methods.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

5-Fluorouracil induced liver toxicity in patients with colorectal cancer: role of computed tomography texture analysis as a potential biomarker

Purpose: To assess if CT texture analysis (TA) can serve as a biomarker of liver toxicity in patients with colorectal cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. Methods: In this IRB-approved, HIPAA-compliant retrospective study, patients with colorectal cancer treated with 5-FU-based regimens during 2008–2010 were identified from institutional electronic database. Total 43 patients (23 women; mean age 56 years) with normal baseline liver function tests (LFTs), availability of baseline (pre-chemotherapy) and first follow-up CT (median 1.7 months, interquartile range (IQR) 1.5–2.5) performed during chemotherapy were included. Two single-slice ROI of right and left liver lobe were obtained on baseline and first follow-up CT for TA. Texture features [mean, entropy, kurtosis, skewness, mean of positive pixel, standard deviation (SD)] were extracted using a commercially available software (TexRAD; Feedback Medical Ltd, Cambridge, UK). Changes in texture parameters between baseline and follow-up CT were evaluated with Wilcoxon signed-rank test for patients with and without LFT elevation during chemotherapy. Results: Patients with LFT elevation (n = 34; 79%) showed significantly different mean, entropy, skewness, and SD (p values range 0.007–0.047) between baseline and first follow-up CT. No significant changes in features were observed in patients without LFT elevation (n = 9; 21%). In 19 patients (56%), first follow-up CT was performed before elevation of LFTs was observed. Conclusions: This proof-of-concept study shows that there are early changes in liver texture on first follow-up CT in patients with LFT elevation during 5-FU-based chemotherapy for colorectal cancer. In more than 50% of cases, these changes occur before LFT elevation becomes evident on blood tests.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Outcomes After Transarterial Embolization of Neuroendocrine Tumor Liver Metastases Using Spherical Particles of Different Sizes

Purpose: To evaluate initial response and overall survival of neuroendocrine tumor (NET) liver metastases initially treated with transarterial embolization (TAE) using spherical particles of different sizes. Methods: A single-institution retrospective review was performed of 160 patients with NET liver metastases initially treated with TAE using < 100 µm (n = 77) or only ≥ 100 µm (n = 83) spherical particles. For each patient, we evaluated: initial response by mRECIST, time to progression, overall survival, complications, primary site, tumor grade and degree of differentiation, volume of liver disease, extrahepatic disease, NET-related symptoms, comorbidities, Child–Pugh score, performance status, lobar versus selective embolization, and arteriovenous shunting. Results: Initial response was higher for TAE using particles < 100 versus TAE using only particles ≥ 100 μm (64 vs 42%, p = 0.007). Multivariate logistic regression showed that use of particles < 100 μm and liver < 50% replaced with tumor were independent predictors of a better initial response rate. There was no difference in major or minor complications between the two particle size groups. Median overall survival after TAE was 55 months for well- to moderately differentiated NET and 13 months for poorly differentiated or undifferentiated NET. There was no significant difference in survival between TAE patients treated with < 100 versus only ≥ 100-μm particles. Conclusion: NET patients treated with TAE using particles < 100 μm had better initial response, but the same overall survival, compared to TAE using only particles ≥ 100 μm.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Liver Resection with In Situ Hypothermic Perfusion: An Old but Effective Method

Background: More than 40 years ago, patients with tumors infiltrating the confluence of the hepatic veins were deemed unresectable; however, in situ hypothermic perfusion, first described by Fortner et al. (Ann Surg 180(4):644–652, 1974), allowed resection of these tumors. In order to prevent liver ischemia after total vascular exclusion, the liver was flushed with a cooled organ preservation solution. The surgeon was able to resect the tumor and reconstruct the hepatic veins with occlusion of the hepatic inflow and outflow. Methods: A 55-year-old female suffering from a leiomyosarcoma of the inferior vena cava (IVC) presented to our clinic. Three years ago, the IVC was replaced with a synthetic graft. During the patient’s follow-up, a computed tomography (CT) scan revealed three hepatic metastases of the sarcoma. A central metastasis in Segment 8 infiltrated the right hepatic vein (RHV), and two additional metastases were located in the left lateral segments. We used Fortner’s technique to resect these tumors. Results: The postoperative course of the patient was prolonged due to a hematoma that partially compressed the new RHV graft. A re-laparotomy was performed and drains were placed. On the 15th postoperative day, the patient was discharged in good health. Conclusions: Although nowadays patients with these unfortunate tumor locations can, to some extent, be managed non-operatively, surgery remains an option with a chance of cure. Azoulay et al. (Ann Surg 262(1):93–104, 2015) were able to show satisfactory 5-year-survival in 77 patients (30.4%), however 90-day mortality was high (19.5%). Therefore, patients need to be selected carefully. In the era of minimally invasive liver surgery, these old techniques should not vanish from the armamentarium of liver surgeons.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4 + γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2020

Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens

Abstract Traditional methods for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. In this study, we investigated whether quantitative genomic data from short-term studies may be used to set protective thresholds for potential tumorigenic effects. We hypothesized that gene expression biomarkers measuring activation of the key early events in established pathways for rodent liver cancer exhibit cross-chemical thresholds for tumorigenesis predictive for liver cancer risk. We defined biomarker thresholds for 6 major liver cancer pathways using training sets of chemicals with short-term genomic data (3–29 days of exposure) from the TG-GATES (n = 77 chemicals) and DrugMatrix (n = 86 chemicals) databases and then tested these thresholds within and between datasets. The 6 pathway biomarkers represented genotoxicity, cytotoxicity, and activation of xenobiotic, steroid, and lipid receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Thresholds were calculated as the maximum values derived from exposures without detectable liver tumor outcomes. We identified clear response values that were consistent across training and test sets. Thresholds derived from the TG-GATES training set were highly predictive (97%) in a test set of independent chemicals, whereas thresholds derived from the DrugMatrix study were 96%–97% predictive for the TG-GATES study. Threshold values derived from an abridged gene list (2/biomarker) also exhibited high predictive accuracy (91%–94%). These findings support the idea that early genomic changes can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life health outcomes.

Hill, III,, Thomas↗