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Combined hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) is a rare liver tumor comprising histologic features of both HCC and CCA. Due to its heterogeneous nature, treatment of combined HCC-CCA is a significant clinical challenge and prognosis remains poor. Therefore, further understanding of the tumor biology underlying the individual subtypes of this mixed tumor is required to improve treatment stratification and optimize treatment strategies. This study sought to identify altered epigenetic regulation and gene expression patterns in the individual components of combined HCC-CCA. Formalin fixed paraffin embedded (FFPE) tumor specimens from 9 patients diagnosed with combined HCC-CCA were utilized in this study. Hematoxylin and eosin (H&E) staining was performed for each sample, and regions representative of the individual HCC and CCA components were delineated. Adjacent unstained slides were cut and dissected to separate HCC and CCA components. DNA and RNA extraction was performed for each sample for DNA methylation (n = 7 HCC and 7 CCA) and gene expression (n = 7 HCC and 8 CCA) profiling via reduced representation bisulfite sequencing (RRBS) and RNA-seq, respectively. Samples did not cluster by tumor type when comparing genome-wide DNA methylation or gene expression patterns. Of the 5 patients with DNA methylation data available for both subtypes, 4 clustered by patient as opposed to cancer subtype, suggesting similar epigenetic regulatory patterns arising from development in the same microenvironment and genetic background. Differential analysis resulted in the identification of 57 differentially expressed genes (DEGs) and 808 differentially methylated regions (DMRs) between the HCC and CCA subtypes. Genes associated with DMRs were associated with Wnt signaling, voltage-gated channels, metal binding, and cellular regulation. Finally, increased expression of several genes previously implicated in tumor aggressiveness, prognosis, and treatment responses were identified. These results highlight the potential importance of accounting for underlying HCC and CCA tumor biology when determining the optimal course of treatment for this deadly disease.

Background It is important for porcine models to replicate gene mutations present in human diseases to improve the translatability of animal studies. In this study, the high efficacy of a whole exome sequencing kit was demonstrated for the improved pig reference genome ( Sus scrofa 11.1) to profile biomedically relevant swine breeds and enable high-depth sequencing required for intratumor heterogeneity profiling. Results We identify a total of 751,624 single nucleotide variants (SNVs) and 113,597 insertions and deletions (INDELs) across 93 samples from 12 porcine breeds. The identified mutations and affected pathways are correlated to muscle-to-fat ratios between different porcine breeds and further inform their utility as models of obesity and cardiovascular disease. Finally, 7935 SNVs and 358 INDELs are present in an Oncopig hepatocellular carcinoma (HCC) cell line and samples from a single Oncopig HCC tumor, with pathways related to hepatic fibrosis, WNT/B-catenin, ATM signaling, and p53 signaling enriched. Conclusions These results demonstrate the kit’s high efficacy and utility for identifying mutations in the context of obesity, cardiovascular disease, and cancer across a range of pig models used in biomedical research.

Purpose To assess the incidence, prognostic factors, and clinical outcomes of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. Materials and Methods In this single-institution retrospective study, 191 patients (m:f = 114:77, median age 54 years, median Model for End-Stage Liver Disease or MELD score 14) who underwent TIPS creation between 1999 and 2013 were studied. Medical record review was used to identify demographic characteristics, liver disease, procedure, and outcome data. Post-TIPS HE within 30 days was defined by new mental status changes and was graded according to the West Haven classification system. The influence of data parameters on HE occurrence and 90-day mortality was assessed using binary logistic regression. Results TIPS was successfully created with hemodynamic success in 99 % of cases. Median final PSG was 7 mmHg. HE incidence within 30 days was 42 % (81/191; 22 % de novo, 12 % stable, and 8 % worsening). Degrees of HE included grade 1 (46 %), grade 2 (29 %), grade 3 (18 %), and grade 4 (7 %). Medical therapy typically addressed HE, and shunt reduction was necessary in only three cases. MELD score ( P  = 0.020) and age ( P  = 0.009) were significantly associated with HE development on multivariate analysis. Occurrence of de novo HE post-TIPS did not associate with 90-day mortality ( P  = 0.400), in contrast to worsening HE ( P  < 0.001). Conclusions The incidence of post-TIPS HE is non-trivial, but symptoms are typically mild and medically managed. HE rates are higher in older patients and those with worse liver function and should be contemplated when counseling on expected TIPS outcomes and post-procedure course.

Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.

The VX2 tumor is a leporine anaplastic squamous cell carcinoma characterized by rapid growth, hypervascularity, and facile propagation in the skeletal muscle. Since its introduction over 70 years ago, it has been used to model a variety of malignancies, and is commonly employed by interventional radiologists in preclinical investigations of hepatocellular carcinoma. However, despite the widespread and lasting popularity of the model, there are few technical resources detailing its use. Herein, we present a comprehensive pictorial outline of the technical methodology for development, growth, propagation, and angiographic utilization of the rabbit VX2 liver tumor model.

The purpose of this study is to assess the incremental effect of tissue plasminogen activator (t-PA) dose on pulmonary artery pressure (PAP) and bleeding during catheter directed thrombolysis (CDT) of submassive pulmonary embolism (PE). Records of 46 consecutive patients (25 men, 21 women, mean age 55±14 y) who underwent CDT for submassive PE between September 2009 and February 2017 were retrospectively reviewed. Mean t-PA rate was 0.7±0.3 mg/h. PAP was measured at baseline and daily until CDT termination. Mixed-effects regression modeling was performed of repeated PAP measures in individual patients. Bleeding events were classified by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) and t-PA dose at onset. Mean t-PA dose was 43.0±30.0 mg over 61.9± 28.8 h. Mean systolic PAP decreased from 51.7±15.5 mmHg at baseline to 35.6±12.7 mmHg at CDT termination (p<0.001). Mixed-effects regression revealed a linear decrease in systolic PAP over time (β = -0.37 (SE = 0.05), p<0.001) with reduction in mean systolic PAP to 44.8±1.9 mmHg at 12 mg t-PA/20 h, 39.5±2.0 mmHg at 24 mg t-PA/40 h, and 34.9±2.1 mmHg at 36 mg/60 h. No severe, one moderate, and 8 mild bleeding events occurred; bleeding onset was more frequent at ≤24 mg t-PA (p <0.001). One patient expired from cardiopulmonary arrest after 16 h of CDT (15.4 mg t-PA); no additional intra-procedural fatalities occurred. Increased total t-PA dose and CDT duration were associated with greater PAP reduction without increased bleeding events.

Purpose To describe volumetric changes of “radiation lobectomy,” a manifestation of hepatic parenchymal response to lobar 90 Y microsphere radioembolization. Methods Twenty patients exhibiting this phenomenon were identified. Pre- and posttreatment absolute right and left hepatic lobar volume (HLV), relative HLV (rHLV = HLV/total liver volume), and degree of lobar atrophy (DA) or hypertrophy (DH) (DA or DH = |posttreatment rHLV – pretreatment rHLV|) were determined. Laboratory toxicities, tumor response, and patient survival were also assessed. Results Twenty patients with primary (HCC, n  = 17; peripheral cholangiocarcinoma, n  = 3) liver malignancies demonstrated findings of radiation lobectomy. Initial absolute right and left HLV was 955 cm 3 (range 644–1,842 cm 3 , rHLV = 57%) and 719 cm 3 (range 328–1,387 cm 3 , rHLV = 43%), respectively. Following 90 Y, absolute right HLV decreased to 460 cm 3 (range 185–948 cm 3 , 52% reduction, rHLV = 31%, DA = 26%, P  < 0.0001), while absolute left HLV increased to 1,004 cm 3 (range 560–1,558 cm 3 , 40% increase, rHLV = 69%, DH = 26%, P  < 0.0001). No grade 3 or 4 bilirubin toxicities were encountered. Tumor response ranged from 55% to 70% by size criteria. Forty-six percent 5-year survival was achieved in HCC patients. Conclusions Radiation lobectomy following 90 Y radioembolization of right lobe tumors manifests extensive contralateral lobar hypertrophy, high response rates, and prolonged survival. This phenomenon was noted in 6.4% (20/315) of the entire cohort and 19.8% (20/101) of patients with unilobar right lobe tumors. Further investigation is necessary to determine contributing factors that may predict this effect.

Purpose The purpose of this study was to assess safety, efficacy, and clinical outcomes following transcatheter arterial embolization (TAE) of acute gastrointestinal (GI) bleeding. Materials and Methods Ninety-five patients (male:female ratio = 53:42, mean age 62 years) that underwent 95 TAEs for GI hemorrhage between 2002 and 2010 were retrospectively studied. Seventy-six of 95 (80 %) patients had upper GI bleeds and 19/95 (20 %) patients had lower GI bleeds. A mean of 7 (range 0–27) packed red blood cell units were transfused pre-procedure, and 90/95 (95 %) procedures were urgent or emergent. Twenty-seven of 95 (28 %) patients were hemodynamically unstable. Measured outcomes included procedure technical success, adverse events, and 30-day rebleeding and mortality rates. Results Bleeding etiology included peptic ulcer disease (45/95, 47 %), cancer (14/95, 15 %), diverticulosis (13/95, 14 %), and other (23/95, 24 %). Vessels embolized ( n  = 109) included gastroduodenal (42/109, 39 %), pancreaticoduodenal (22/109, 20 %), gastric (21/109, 19 %), superior mesenteric (12/109, 11 %), inferior mesenteric (8/109, 7 %), and splenic (4/109, 4 %) artery branches. Technical success with immediate hemostasis was achieved in 93/95 (98 %) cases. Most common embolic agents included coils (66/109, 61 %) and/or gelatin sponge (19/109, 17 %). Targeted versus empiric embolization were performed in 57/95 (60 %) and 38/95 (40 %) cases, respectively. Complications included bowel ischemia (4/95, 4 %) and coil migration in 3/95 (3 %). 30-day rebleeding rate was 23 % (22/95). Overall 30-day mortality rate was 18 % (16/89). Empiric embolization resulted in similar rebleeding (23 vs 24 %) but higher mortality (31 vs 9 %) rates compared to embolization for active extravasation. Conclusions TAE controlled GI bleeding with high technical success, safety, and efficacy, and should be considered when endoscopic therapy is not feasible or unsuccessful.

This pilot study investigated the feasibility of using magnetic resonance elastography (MRE) for the non-invasive detection and quantification of liver fibrosis in the Oncopig cancer model. Seven 8-week-old Oncopigs underwent alcoholic liver fibrosis induction and serial MRE imaging and liver biopsy at 1, 2, and 3 months post procedure. MRE was utilized to quantify liver stiffness, and liver fibrosis was histologically graded using the METAVIR system. The primary outcome measure was the capability to detect and quantify liver fibrosis using MRE with radiologic–pathologic correlation. Liver fibrosis induction, MRE imaging, and liver biopsy were successfully performed. MRE liver fibrosis was evident in 57% (4/7), 50% (3/6), and 40% (2/5) animal subjects 1, 2, and 3 months after fibrosis induction, with mean liver stiffness of 2.94, 3.25, and 2.91 kPa, respectively. Histological liver fibrosis was noted in 71% (5/7), 100% (5/5), and 100% (5/5) of animal subjects with available tissue samples. There was no significant statistical correlation between the MRE-measured liver stiffness and the METAVIR fibrosis scores. In conclusion, quantifiable liver fibrosis may be induced in the Oncopig. MRE has potential utility in non-invasively detecting liver stiffness in this large-animal preclinical model, though tissue biopsy was more sensitive in demonstrating disease.

This study was performed to assess the safety, efficacy, and clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation for treatment of medically refractory ascites and to identify prognostic factors for clinical response, morbidity, and mortality. In this retrospective study, 80 patients (male:female, 52:28; mean age, 56 years; mean Model for End-Stage Liver Disease [MELD] score, 15.1) who underwent elective TIPS creation for refractory ascites between 1999-2012 were studied. A medical record review was performed to identify data on demographics, liver disease, procedures, and outcome. The influence of these parameters on 30-day, 90-day, and one-year mortality was assessed using binary logistic regression. Overall survival was analyzed with Kaplan-Meier statistics. TIPS was successfully created using covered (n=70) or bare metal (n=10) stents. Hemodynamic success was achieved in all cases. The mean final portosystemic pressure gradient (PSG) was 6.8 mmHg. Thirty-day complications included mild encephalopathy in 35% of patients. Clinical improvement in ascites occurred in 78% of patients, with complete resolution or a ≥50% decrease in 66% of patients. No predictors of response or optimal PSG threshold were identified. The 30-day, 90-day, and one-year mortality rates were 14%, 23%, and 33%, respectively. Patient age (P = 0.026) was associated with 30-day mortality, while final PSG was associated with 90-day (P = 0.020) and one year (P = 0.032) mortality. No predictors of overall survival were identified. TIPS creation effectively treats medically refractory ascites with nearly 80% efficacy. The incidence of mild encephalopathy is nontrivial. Older age and final PSG are associated with mortality, and these factors should be considered in patient selection and procedure performance.