Liver Function Research Articles

Type one autoimmune pancreatitis based on clinical diagnosis: A case report

BACKGROUND Autoimmune pancreatitis (AIP) is a rare form of autoimmune-mediated pancreatitis, which is easily misdiagnosed as pancreatic cancer and thus treated surgically. We studied the diagnosis and treatment of a patient with type 1 AIP recently admitted to our hospital, and reviewed the literature to provide a reference for clinical diagnosis of AIP. CASE SUMMARY The chief complaint was yellowing of the body, eyes and urine for 21 d. The patient's clinical presentation was obstructive jaundice and imaging suggested pancreatic swelling. It was difficult to distinguish between inflammation and tumor. Serum immunoglobulin G4 (IgG4) was markedly elevated. IgG4 is an important serological marker for type 1 AIP. The patient was diagnosed with AIP, IgG4-related cholangitis, acute cholecystitis and hepatic impairment. After applying hormonal therapy, the patient's symptoms improved significantly. At the same time, imaging suggested that pancreatic swelling subsided, and liver function and other biochemical indicators decreased. The treatment was effective. CONCLUSION In patients with pancreatic swelling, the possibility of AIP should be considered.

Undifferentiated high-grade pleomorphic sarcoma of the common bile duct: A case report and review of literature

BACKGROUND Undifferentiated pleomorphic sarcoma (UPS) is a rare malignant mesenchymal tumor with a poor prognosis. It mainly occurs in the extremities, trunk, head and neck, and retroperitoneum regions. Owing to the lack of specific clinical manifestations and imaging features, UPS diagnosis mainly depends on pathological and immunohistochemical examinations for exclusive diagnosis. Here we report an extremely rare case of high-grade UPS in the common bile duct (CBD). There are limited available data on such cases. CASE SUMMARY A 70-year-old woman was admitted to our department with yellow eyes and urine accompanied by upper abdominal distending pain for 2 wk. Her laboratory data suggested significantly elevated hepatorenal function levels. The imaging data revealed calculous cholecystitis, intrahepatic and extrahepatic bile duct dilation with extrahepatic bile duct calculi, and a space-occupying lesion at the distal CBD. After endoscopic biliary stenting and symptomatic support therapy, CBD exploration and biopsy were performed. The frozen section indicated malignant spindle cell tumor of the CBD mass, and further radical pancreaticoduodenectomy was performed. Finally, the neoplasm was diagnosed as a high-grade UPS combined with the light-microscopic morphology and immunohistochemical results. CONCLUSION This extremely rare case highlighted the need for increasing physicians' vigilance, reducing the odds of misdiagnosis, and providing appropriate treatment strategies.

Albumin–bilirubin grade as a predictor of survival in hepatocellular carcinoma patients with thrombocytopenia

BACKGROUND The models for assessing liver function, mainly the Child–Pugh (CP), albumin–bilirubin (ALBI), and platelet–ALBI (PALBI) classifications, have been validated for use in estimating the prognosis of hepatocellular carcinoma (HCC) patients. However, thrombocytopenia is a common finding and may influence the prognostic value of the three models in HCC. AIM To investigate and compare the prognostic performance of the above three models in thrombocytopenic HCC patients. METHODS A total of 135 patients with thrombocytopenic HCC who underwent radical surgery were retrospectively analyzed. Preoperative scores on the CP, ALBI and PALBI classifications were estimated accordingly. Kaplan–Meier curves with log-rank tests and Cox regression models were used to explore the significant factors associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS The preoperative platelet counts were significantly different among the CP, ALBI and PALBI groups. After a median follow-up of 28 mo, 39.3% (53/135) of the patients experienced postoperative recurrence, and 36.3% (49/135) died. Univariate analysis suggested that α-fetoprotein levels, tumor size, vascular invasion, and ALBI grade were significant predictors of OS and RFS. According to the multivariate Cox regression model, ALBI was identified as an independent prognostic factor. However, CP and PALBI grades were not statistically significant prognostic indicators. CONCLUSION The ALBI grade, rather than CP or PALBI grade, is a significant prognostic indicator for thrombocytopenic HCC patients.

Patients' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC]). This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC. A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator. Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n=341) and with (n=59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points). When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors.

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dersimelagon (MT-7117), an Oral Melanocortin-1 Receptor Agonist.

Dersimelagon is an orally administered selective melanocortin-1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n=7) or moderate (n=8) hepatic impairment or normal hepatic function (n=8) received a single oral 100-mg dersimelagon dose. Participants with mild (n=8), moderate (n=8), or severe (n=8) renal impairment or normal renal function (n=8) received a single 300-mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.

Beneficial effects of maintaining liver function during hepatic arterial infusion chemotherapy combined with tyrosine kinase and programmed cell death protein-1 inhibitors on the outcomes of patients with unresectable hepatocellular carcinoma

Background and aimCombination therapy is the primary treatment for unresectable hepatocellular carcinoma (u-HCC). The hepatic functional reserve is also critical in the treatment of HCC. In this study, u-HCC was treated with combined hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed cell death protein-1 (PD-1) inhibitors to analyze the therapeutic response, progression-free survival (PFS), and safety.MethodsOne hundred sixty-two (162) patients with u-HCC were treated by combination therapy of HAIC, TKIs, and PD-1 inhibitors. PFS was assessed by Child–Pugh (CP) classification subgroups and the change in the CP score during treatment.ResultsThe median PFS was 11.7 and 5.1 months for patients with CP class A (CPA) and CP class B (CPB), respectively (p = 0.013), with respective objective response rates of 61.1 and 27.8% (p = 0.002) and conversion rates of 16 and 0% (p = 0.078). During treatment, the CP scores in patients with CPA worsened less in those with complete and partial response than in those with stable and progressive disease. In the CP score 5, patients with an unchanged CP score had longer PFS than those with a worsened score (Not reached vs. 7.9 months, p = 0.018). CPB was an independent factor negatively affecting treatment response and PFS. Patients with CPA responded better to the combination therapy and had fewer adverse events (AEs) than those with CPB.ConclusionsThus, triple therapy is more beneficial in patients with good liver function, and it is crucial to maintain liver function during treatment.

The potential modulatory impact of garlic-selenium nanoparticles coated with synthetic tocopherol polyethylene glycol-succinate against lead acetate toxicity in male rabbits

Toxic heavy metal lead enters in the environment due to industrial and anthropogenic activity threatens ecosystems and public health. Natural garlic extract (GE) exhibits antioxidant properties and various applications against several ailments. Therefore, this study scrutinized the protective effects of tocopherol polyethylene glycol succinate-coated garlic selenium (TPGS-GSNP) against lead acetate (LA) toxicity in rabbits. Sixty-four mature male rabbits were involved and divided into 8 equal groups. They received distilled water (negative control; T1), 30 mg/kg bw of LA (positive control; T2), 800 mg/kg bw of GE (T3), GE + LA (T4), 1 mg/kg bw of TPGS-Selenium (T5), TPGS-S + LA (T6), 1 mg/kg bw of TPGS-GSNP (T7), and TPGS-GSNP + LA (T8). Consequently, treatments were administered three times a week for 12 weeks. Following the treatment period, serum oxidant-antioxidant, protein, and lipid profiles, liver and kidney function, histopathological findings of the adrenal, liver, and kidneys, femur bone marrow chromosomal aberrations, and mitotic activity were collected and analysed. LA exposure showed significant reductions in antioxidant levels, organ weights, and mitotic activity while increasing oxidative stress, corticosteroid levels, and chromosomal aberrations. Importantly, TPGS-GSNP administration significantly improved these markers compared to the LA group. In addition, histological analysis revealed structural improvements of the studied organs in the TPGS-GSNP group compared to the LA group, which displayed high cellular necrotic and degenerative changes. In conclusion, synthetic TPGS-GSNP demonstrated higher protective efficacy against LA-induced toxicity compared to natural GE or selenium alone. However, more future studies could be conducted to explore the potential of TPGS-GSNP as an anticancer or immunomodulatory agent.

Predictive Value of Inflammatory Markers NLR, PLR, APRI, SII, and Liver Function Tests in Systemic Inflammatory Response Syndrome Detection in Full-Term Newborns

Predictive Value of Inflammatory Markers NLR, PLR, APRI, SII, and Liver Function Tests in Systemic Inflammatory Response Syndrome Detection in Full-Term Newborns

Comparative Analysis of Pediatric Patients with Different Involvements of Brucellosis.

Brucellosis is a zoonotic disease that mimics many other diseases, making diagnosis difficult in pediatric patients. If the clinical signs of the disease are not well known and there is a delay in diagnosis and treatment, complicated brucellosis involving different body sites can develop. This study aimed to analyze the demographics, clinical information, laboratory test results, and imaging findings of children with brucellosis. Particular attention was paid to the involvement of organs and potential complications. Pediatric patients diagnosed with brucellosis at the Sanlıurfa Training and Research Hospital in Turkey were retrospectively evaluated. In total, 101 patients diagnosed with brucellosis were included in this study. Bone-joint involvement was observed in 21 (20.7%) patients. High Brucella Coombs gel test (CT) titers (≥1/640) and increased erythrocyte sedimentation rate (ESR) were significant in the bone-joint brucellosis group (P = 0.022 and P = 0.0205, respectively). Fourteen (13.9%) patients had at least one organomegaly in which Brucella CT titers and C-reactive protein (CRP) levels were substantially higher than those in patients without organomegaly (P = 0.02 and P = 0.0049, respectively). Anemia, leukopenia, and thrombocytopenia were observed in 36 (35.6%), 10 (9.9%), and 4 (3.9%) patients, respectively. At least one elevation in liver function test (LFT) results was observed in 32 (31.7%) patients. High acute-phase reactants, such as ESR, CRP levels, and Brucella CT titers, may help identify complicated brucellosis. This study highlights that pediatric brucellosis can lead to cytopenia and elevated LFT results and should therefore be considered as a differential diagnosis.

In Vivo and In Silico Studies Assessment of the Effects of Oral Exposure to 1-Methylcyclopropene on Liver Function in Male Albino Rats

In Vivo and In Silico Studies Assessment of the Effects of Oral Exposure to 1-Methylcyclopropene on Liver Function in Male Albino Rats

Efficient hepatocyte differentiation of primary human hepatocyte-derived organoids using three dimensional nanofibers (HYDROX) and their possible application in hepatotoxicity research

Human liver organoids are in vitro three dimensionally (3D) cultured cells that have a bipotent stem cell phenotype. Translational research of human liver organoids for drug discovery has been limited by the challenge of their low hepatic function compared to primary human hepatocytes (PHHs). Various attempts have been made to develop functional hepatocyte-like cells from human liver organoids. However, none have achieved the same level of hepatic functions as PHHs. We here attempted to culture human liver organoids established from cryopreserved PHHs (PHH-derived organoids), using HYDROX, a chemically defined 3D nanofiber. While the proliferative capacity of PHH-derived organoids was lost by HYDROX-culture, the gene expression levels of drug-metabolizing enzymes were significantly improved. Enzymatic activities of cytochrome P450 3A4 (CYP3A4), CYP2C19, and CYP1A2 in HYDROX-cultured PHH-derived organoids (Org-HYDROX) were comparable to those in PHHs. When treated with hepatotoxic drugs such as troglitazone, amiodarone and acetaminophen, Org-HYDROX showed similar cell viability to PHHs, suggesting that Org-HYDROX could be applied to drug-induced hepatotoxicity tests. Furthermore, Org-HYDROX maintained its functions for up to 35 days and could be applied to chronic drug-induced hepatotoxicity tests using fialuridine. Our findings demonstrated that HYDROX could possibly be a novel biomaterial for differentiating human liver organoids towards hepatocytes applicable to pharmaceutical research.

The Role of Phthalocyanine-Gold Nanoconjugates (Pc-Au NCs) in Ameliorating the Hepatic and Renal Toxicity-Induced by Silver Nanoparticles (Ag NPs) in Male Rats.

Recently, gold nanoparticles (Au Nps) have gained tremendous attention for its unique properties as a safe nanocarrier for delivering drugs that are used in different disease diagnoses. Although silver nanoparticles (Ag NPs) have been generally applied due to their strong antibacterial, antiviral, antifungal, and antimicrobial properties, their toxicity is a subject of sustained debate, thus requiring further studies. The present study aims to evaluate the potential protective effect of gold nanoparticles and phthalocyanine-gold nanoconjugates (Pc-Au NCs) against the hepatorenal toxicity of silver nanoparticles in male rats. Herein, 60 adult male Rattus norvegicus rats were divided into six equal groups (n = 10/group); the first group was kept as control, the second received gold nanoparticles (Au NPs) intraperitoneally (10 µg/kg) daily for 3 weeks, the third group is gold-phthalocyanine (Pc-Au) group where rats were injected intraperitoneally with gold-phthalocyanine for 3 weeks (10 µg/kg), the fourth group received silver nanoparticles (Ag NPs) (4 mg/kg) daily intraperitoneally for 3 weeks, the fifth group is silver + gold nanoparticles group (Ag + Au), and the sixth is silver + gold-phthalocyanine nanoconjugates (Ag + Pc-Au) group in which rats were intraperitoneally injected firstly with Ag NPs (4 mg/kg) for 3 weeks then with gold or gold-phthalocyanine for another 3 weeks (10 µg/kg). Our results revealed that Ag NPs could increase the serum AST, ALT, ALP, urea, creatinine, and lipid profile and significantly decreased the total protein and albumin. Moreover, histopathological alterations detected in the kidney and the liver of the Ag NPs group included vascular congestion, inflammatory cell infiltration, and tissue distortion. Alongside, exposure to Ag NPs induces hepatic and renal oxidative stress by suppressing the antioxidant-related genes including glutathione peroxidase 1 (gpx1), superoxide dismutase (sod), and catalase (cat). Ag NPs also upregulated the hepatic and renal genes involved in inflammation such as the interleukin-6 (il-6) and tumor necrosis factor-α (tnf-α), nuclear factor kappa B (nf-κβ), apoptosis such as the BCL2 associated X (bax), casp3, and other related to metabolism including asparagine synthetase (asns), suppressor of cytokine signaling 3 (socs3), MYC proto-oncogene (myc), and C-C motif chemokine ligand 2 (ccl2). On the other hand, treatment with Au NPs and Pc-Au NCs could effectively ameliorate the hepatorenal damages induced by Ag NPs and improve liver and kidney architecture and function, especially in the Pc-Au NCs group. Briefly, our study revealed the underlined mechanism of Ag NPs hepatotoxic and nephrotoxic effects and that Pc-Au NCs could alleviate these adverse impacts via their anti-oxidative, anti-apoptotic, and anti-inflammatory activities.

Predictors of Hepatic Decompensation after Yttrium90 Transarterial Radioembolization—Optimizing Patient Selection

Abstract Objective Yttrium 90 (Y90) transarterial radioembolization (TARE) is effective for unresectable hepatocellular carcinoma (HCC) or to bridge/downstage before transplant; however, optimal patient selection is not well-described. This study aims to identify factors that increase risk of liver decompensation resulting in hospital admissions after TARE. Methods Patients who received Y90 as their first treatment during 2012 to 2022 were identified from a prospectively collected database of 1675 HCC patients. Clinically significant hepatic decompensation was defined as total bilirubin more than or equal to 3 mg/dL or any increase in Model for End-stage Liver Disease (MELD) score resulting in readmission within 60 days or death. Results Of 137 patients, 7 (5.1%) developed hepatic decompensation requiring admission within 30 days and an additional 8 (10.9%) within 60 days. Two of these patients (1.4%) died and two (1.4%) required urgent transplant within 2 months. Preprocedure albumin less than 3.5 gm/dL (p = 0.0207), international normalized ratio more than 1.2 (p = 0.017), ascites (p = 0.036), elevated MELD (p = 0.012), and Child-Pugh (p = 0.007) scores were significant predictors of decompensation, while creatinine and sodium were not. Patients with Child-Pugh B score were three to four times more likely to decompensate (28 vs. 8%) compared to Child-Pugh A. For every unit increase in Child-Pugh score more than 6, odds of decompensation increased by a factor of 2.15. Conclusion Y90 TARE is safe and effective; however, 10.9% patients require readmission for worsened liver function. Because ascites is a significant factor in predicting decompensation and all patients require adequate renal function to receive Y90 TARE, Child-Pugh score may be more useful than MELD for patient selection. Further risk stratification may be required for those with a Child-Pugh score more than or equal to 7.

The clinical significance of long non-coding RNAs MALAT1 and CASC2 in the diagnosis of HCV-related hepatocellular carcinoma.

Globally, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death due to a lack of early predictive and/or diagnostic tools. Thus, research for a new biomarker is important. LncRNAs play a functional role in target gene regulation and their deregulation is associated with several pathological conditions including HCC. This study aimed to explore the diagnostic potential of two LncRNAs MALAT1 and CASC2 in HCC compared to the routinely used diagnostic biomarker. The current study is a case-control study carried out at Fayoum University Hospital and conducted on 89 individuals. The study included three groups of 36 HCC patients on top of HCV(HCC/HCV), 33 HCV patients, and 20 healthy volunteers as a control group. All study subjects were subjected to radiological examinations. The determination of CBC was performed by the automated counter and liver function tests by the enzymatic method were performed. In addition, HCV RNA quantification and the expression level of two LncRNAs (MALAT1 and CASC2) were performed by qRT-PCR. The results revealed a statistically significant difference between study groups regarding liver function tests with a higher mean in HCC/HCV group. Also, serum MALAT1 significantly up-regulated in HCV (11.2±2.8) and HCC/HCV (4.56±1.4) compared to the control group. Besides, serum CASC2 levels in the HCV group were significantly upregulated (14.9±3.6), while, downregulated in the HCC group (0.16± 0.03). Furthermore, The ROC analysis for diagnostic efficacy parameters indicated that CASC2 has higher accuracy (94.6%) and sensitivity (97.2%) for HCC diagnosis than AFP with an accuracy of (90.9%), sensitivity (69.4%), and MALAT1 showed an accuracy of (56.9%), sensitivity (72.2%). Our study results indicated that CASC2 is a promising biomarker and is considered better and could help in HCC diagnosis on top of HCV than MALAT1 and the routine biomarker AFP.

Bone mesenchymal stem cells improve cholestatic liver fibrosis by targeting ULK1 to regulate autophagy through PI3K/AKT/mTOR pathway.

Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial role in CLD development. Bone mesenchymal stem cells (BMSCs) treatment was demonstrated to be beneficial in liver diseases. However, the therapeutic effect and mechanism of BMSCs on CLD are poorly known. In the present study, we investigated the therapeutic effects and underlying mechanisms of BMSCs transplantation in mouse models of bile duct ligation-induced cholestatic liver fibrosis (CLF). The results revealed that BMSCs significantly improved liver function and reduced the formation of fibrosis after portal vein transplantation. Mechanistically, after coculturing BMSCs and HSCs, we identified that BMSCs alleviated starvation-induced HSCs activation. Further, BMSCs inhibited HSCs activation by decreasing autophagy, and PI3K/AKT/mTOR pathway was involved in the regulation. More importantly, ULK1 is identified as the main autophagy-related gene regulated by BMSCs in HSCs autophagy. Overexpression of ULK1 reversed the suppression of HSCs autophagy by BMSCs. Collectively, our results provide a theoretical basis for BMSCs targeting ULK1 to attenuate HSCs autophagy and activation and suggest that BMSCs or ULK1 may be an alternative therapeutic approach/target for the treatment of CLF.

Graft repair during machine perfusion: a current overview of strategies.

With changing donor characteristics (advanced age, obesity), an increase in the use of extended criteria donor (ECD) livers in liver transplantation is seen. Machine perfusion allows graft viability assessment, but still many donor livers are considered nontransplantable. Besides being used as graft viability assessment tool, ex situ machine perfusion offers a platform for therapeutic strategies to ameliorate grafts prior to transplantation. This review describes the current landscape of graft repair during machine perfusion. Explored anti-inflammatory therapies, including inflammasome inhibitors, hemoabsorption, and cellular therapies mitigate the inflammatory response and improve hepatic function. Cholangiocyte organoids show promise in repairing the damaged biliary tree. Defatting during normothermic machine perfusion shows a reduction of steatosis and improved hepatobiliary function compared to nontreated livers. Uptake of RNA interference therapies during machine perfusion paves the way for an additional treatment modality. The possibility to repair injured donor livers during ex situ machine perfusion might increase the utilization of ECD-livers. Application of defatting agents is currently explored in clinical trials, whereas other therapeutics require further research or optimization before entering clinical research.

In Situ Self-Assembling Liver Spheroids with Synthetic Nanoscaffolds for Preclinical Drug Screening Applications.

Drug-induced liver injury (DILI) is one of the most common reasons for acute liver failure and a major reason for the withdrawal of medications from the market. There is a growing need for advanced in vitro liver models that can effectively recapitulate hepatic function, offering a robust platform for preclinical drug screening applications. Here, we explore the potential of self-assembling liver spheroids in the presence of electrospun and cryomilled poly(caprolactone) (PCL) nanoscaffolds for use as a new preclinical drug screening tool. This study investigated the extent to which nanoscaffold concentration may have on spheroid size and viability and liver-specific biofunctionality. The efficacy of our model was further validated using a comprehensive dose-dependent acetaminophen toxicity protocol. Our findings show the strong potential of PCL-based nanoscaffolds to facilitate in situ self-assembly of liver spheroids with sizes under 350 μm. The presence of the PCL-based nanoscaffolds (0.005 and 0.01% w/v) improved spheroid viability and the secretion of critical liver-specific biomarkers, namely, albumin and urea. Liver spheroids with nanoscaffolds showed improved drug-metabolizing enzyme activity and greater sensitivity to acetaminophen compared to two-dimensional monolayer cultures and scaffold-free liver spheroids. These promising findings highlight the potential of our nanoscaffold-based liver spheroids as an in vitro liver model for drug-induced hepatotoxicity and drug screening.

Surgical Resection in Colorectal Liver Metastasis: An Umbrella Review

Surgical resection is the gold standard for treating synchronous colorectal liver metastases (CRLM). The resection of the primary tumor and metastatic lesions can follow different sequences: “simultaneous”, “bowel-first”, and “liver-first”. Conservative approaches, such as parenchymal-sparing surgery and segmentectomy, may serve as alternatives to major hepatectomy. A comprehensive search of Medline, Epistemonikos, Scopus, and the Cochrane Library was conducted. Studies evaluating patients who underwent surgery for CRLM and reported survival results were included. Other secondary outcomes were analyzed, including disease-free survival, perioperative complications and mortality, and recurrence rates. Quality assessment was performed using the AMSTAR-2 method. No significant differences in overall survival, disease-free survival, and secondary outcomes were observed when comparing simultaneous to “bowel-first” resections, despite a higher rate of perioperative mortality in the former group. The 5-year OS was significantly higher for simultaneous resection compared to “liver-first” resection. No significant differences in OS and DFS were noted when comparing “liver-first” to “bowel-first” resection, or anatomic to non-anatomic resection. Our umbrella review validates simultaneous surgery as an effective oncological approach for treating SCRLM, though the increased risk of perioperative morbidity highlights the importance of selecting suitable patients. Non-anatomic resections might be favored to preserve liver function and enable future surgical interventions.

Immunotherapy as a Complement to Surgical Management of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver tumor in adults, and the fourth leading cause of cancer-related deaths worldwide. While surgical and ablative therapies remain the standard of care in early localized disease, late presentation with advanced stages of disease, impaired hepatic function, or local recurrence following surgical resection preclude operative management as the sole treatment modality in a subgroup of patients. As such, systemic therapies, namely immunotherapy, have become an integral part of the HCC treatment algorithm over the past decade. While agents, such as atezolizumab/bevacizumab, have well-established roles as first-line systemic therapy in intermediate- and advanced-stage HCC, the role of immunotherapy in disease amenable to surgical management continues to evolve. In this review, we will discuss the current evidence and aggregate impact of immunotherapy in the context of HCC amenable to surgical management, including its application in the neoadjuvant and adjuvant settings.

Beta-Cyfluthrin-Induced Hepatic Alterations in Zebrafish: Enzymatic Profiles and Oxidative Stress Responses

Beta-Cyfluthrin is a widely used pesticide belonging to class of synthetic pyrethroids which affects the central and peripheral nervous systems. The current study investigates the impact of beta-Cyfluthrin on the biochemical parameters of liver of zebrafish (Danio sp.). Adult zebrafish were exposed to concentrations of 0.25, 0.5, 1.0, 2.0 and 4.0 µg/L of beta-Cyfluthrin for acute (96 hours) and chronic (21 days) exposure periods respectively (n=20). It was observed that exposure to beta-Cyfluthrin led to variations in biochemical markers in both acute and chronic exposure groups. Liver function tests revealed significant elevated activity of alanine transaminase (ALT) and aspartate transaminase (AST) at exposure concentrations of 2.0 and 4.0 µg/L of beta-Cyfluthrin in both acute and chronic groups, while acid phosphatase (ACP) and alkaline phosphatase (ALP) activity decreased significantly at concentrations of 1.0, 2.0 and 4.0 µg/L in the chronic group. Lipid peroxidation exhibited a concentration and time-dependent increase with significant difference at 1.0, 2.0 and 4.0 µg/L in both acute and chronic groups, while superoxide dismutase (SOD) and peroxidase (PER) levels declined significantly in both acute and chronic exposure groups at exposure concentrations of 1.0, 2.0 and 4.0 µg/L for SOD and 2.0 and 4.0 µg/L for PER. Catalase (CAT) initially increased significantly in acute groups of 1.0, 2.0 and 4.0 µg/L but decreased in chronic ones. Glutathione S-transferase (GST) levels exhibited a significant increase at lower concentrations of 0.25 µg/L but a decrease at higher concentrations, 1.0, 2.0 and 4.0 µg/L of beta-Cyfluthrin. The level of significance were considered at p<0.05 and p<0.01. This research suggests that exposure to beta-Cyfluthrin leads to hepatic damage in adult zebrafish. This indicates a potential risk to non-target aquatic fauna, through runoff where beta-Cyfluthrin is used as an agricultural pesticide.