Preserved Liver Function Research Articles

Impact of underlying liver disease on unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) are standard therapy for unresectable HCC, but many patients do not respond. Non-viral HCC, particularly non-alcoholic steatohepatitis (NASH), have been implicated in ICI resistance.MethodsWe reviewed 288 patients with unresectable HCC who received ICI from 1/2017 to 12/2021. The overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between patients with viral HCC and non-viral HCC were compared using the full and Child Pugh (CP) class A only cohorts.ResultsIn total, 206 patients (71.5%) had viral HCC (most HCV), and 82 patients had non-viral HCC. Non-viral HCC was associated with worse OS (HR 1.6, 95% CI: 1.1–2.1, P = 0.006) and PFS (HR 1.5, 95% CI: 1.2–2, P = 0.002) in univariate but not multivariate analyses. For the CP class A cohort, non-viral HCC was independently associated with worse OS (HR 1.8, 95% CI: 1.2–2.7, P = 0.005) and PFS (HR 1.9, 95% CI: 1.3–2.7, P < 0.001). Viral HCC and CP class A liver disease was associated with better ORR than non-viral HCC (38% vs. 16%, P = 0.001).ConclusionsFollowing ICI treatment, non-viral HCC correlated with worse OS, PFS, and ORR than viral HCC, particularly in patients with preserved liver function.

Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .

Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.

509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]

Liver transplant recipients with polycystic liver disease have longer waiting times but better long-term clinical outcomes than those with liver disease due to other causes: A retrospective cross-sectional study.

Liver transplantation is the only curative option for patients with polycystic liver disease (PLD). In the United Kingdom, these patients are listed on the variant syndrome list due to their preserved liver function reflected in the United Kingdom End-stage Liver Disease (UKELD) score. The transplantation and survival rates for this patient group in the UK have not been previously reported. A retrospective cross-sectional analysis of patients receiving liver transplantation between 2010 and 2017 was performed using the NHS blood and transplantation database. This database contains the demographic, clinical parameters, indication for transplantation and follow-up of all patients in UK-based transplant centres. Basic statistics was performed using SPSS version 27. 5412 recipients received elective liver allografts in the study period. 1.6% (100) of recipients had PLD as their primary indication for transplantation with 60 receiving liver only allografts and 40 receiving combined liver-kidney allografts. PLD patients had a >3-fold longer mean waiting time for transplantation compared to non-PLD patients, 508 days v 154 days respectively. PLD patients receiving combined liver-kidney allografts had a longer waiting time than those receiving a liver only allograft, 610 days v 438 days respectively. There were comparable patient survival rates for people with PLD and non-PLD primary indications at 30 days (94.0% vs 97.6%) and 1 year (92.0% vs 93.2%) but improved survival rates at 5 years (81.3% vs 76.5%). There were also comparable allograft survival rates for people with PLD and non-PLD primary indications at 30 days (93.9% vs 95.3%) and 1 year (91.9% vs 91.2%) but improved survival rates at 5 years (82.5% vs 77.3%). Transplant centre-level analysis identified variation in the proportion of liver transplantations for people with PLD as their primary listed indication. Patients with PLD wait significantly longer for liver transplantation compared to other indications. However, transplanted PLD patients demonstrate better longer-term patient and liver allograft survival rates compared to transplanted non-PLD patients. The unexpected variation between individual UK centres transplanting for PLD deserves further study.

Pre-emptive transjugular intrahepatic portosystemic shunt in pediatric cystic fibrosis-related liver disease and portal hypertension: prospective long-term results.

Portal hypertension (PHT) and its sequelae are the most clinically important manifestations in cystic fibrosis-related liver disease (CFLD). This paper aimed to evaluate the safety and efficacy of a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) to prevent PHT-related complications in pediatric patients with CFLD. This was a prospective single-arm study on pediatric patients with CFLD, signs of PHT, and preserved liver function who underwent a pre-emptive TIPS in a single tertiary CF center between 2007 and 2012. The long-term safety and clinical efficacy were assessed. A pre-emptive TIPS was performed on seven patients with a mean age of 9.2 years (± standard deviation: 2.2). The procedure was technically successful in all patients, with an estimated median primary patency of 10.7 years [interquartile range (IQR) 0.5-10.7)]. No variceal bleeding was observed during the median follow-up of 9 years (IQR 8.1-12.9). In two patients with advanced PHT and rapidly progressive liver disease, severe thrombocytopenia could not be stopped. Subsequent liver transplantation revealed biliary cirrhosis in both patients. In the remaining patients with early PHT and milder porto-sinusoidal vascular disease, symptomatic hypersplenism did not occur, and liver function remained stable until the end of the follow-up. Inclusion for pre-emptive TIPS was discontinued in 2013 following an episode of severe hepatic encephalopathy. TIPS is a feasible treatment with encouraging long-term primary patency to avoid variceal bleeding in selected patients with CF and PHT. However, as the progression of liver fibrosis, thrombocytopenia, and splenomegaly is inevitable, the clinical benefits due to pre-emptive placement appear to be minor.

Similar Efficacy Between Atezolizumab Plus Bevacizumab Versus Hepatic Arterial Infusion Chemotherapy For Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Retrospective Cohort Study.

The landscape of treatments for hepatocellular carcinoma (HCC), including immune checkpoint inhibitors, has expanded significantly. However, unresectable HCC patients with portal vein tumor thrombus (PVTT) continue to face a poor prognosis. This investigation examined the survival outcomes and determinants influencing survival rates in advanced HCC patients with PVTT undergoing treatment with atezolizumab plus bevacizumab (ATZ+BEV) or hepatic arterial infusion chemotherapy (HAIC). Between December 2003 and June 2023, 48 advanced HCC with PVTT underwent treatment with either ATZ+BEV (16 patients) or HAIC (32 patients). The analysis revealed no significant disparities in overall survival (OS) or treatment efficacy between the ATZ+BEV and HAIC groups (ATZ+BEV: 10.0 months, HAIC: 15.3 months). Treatment with either ATZ+BEV or HAIC resulted in minimal alterations in the ALBI score and preserved hepatic function. Independent prognostic factors for OS, identified via multivariate logistic regression, included serum α-fetoprotein levels >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], the existence of more than five tumors (HR=1.55; p=0.043), and the Child-Pugh score (HR=2.53; p=0.002). This investigation revealed no significant variance in OS and response rates between patients receiving ATZ+BEV and those treated with HAIC. The survival of advanced HCC patients with PVTT is intricately linked to the preservation of liver function, emphasizing the necessity for additional research to enhance treatment approaches for this patient population.

Ablative therapies versus non ablative therapies in solitary hepatocellular carcinoma ≤ 5 cm in cirrhotic patients with preserved liver function listed for liver transplantation: an intention to treat analysis

Ablative therapies versus non ablative therapies in solitary hepatocellular carcinoma ≤ 5 cm in cirrhotic patients with preserved liver function listed for liver transplantation: an intention to treat analysis

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension

Background and AimsCirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. MethodsCCl4 or BDL surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. ResultsUroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. ConclusionsWe for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Protective Effect of Aspirin Against Gentamicin-Induced Hepatotoxicity in Rats Model

Gentamicin is an extensively used antibiotic with potent antimicrobial exertion, but its clinical mileage is limited by its eventuality to induce hepatotoxicity. This study aimed to probe the defensive effect of aspirin against gentamicin-convinced hepatotoxicity in a rat model. Adult manly Wistar rats were divided into four groups control, aspirin, gentamicin, and aspirin- gentamicin. The creatures were treated for 15 successive days, and colorful biochemical parameters were estimated. Pre-treatment with aspirin significantly downgraded the adverse goods of gentamicin on liver weight. It also eased the elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) situations, indicating the preservation of liver function. Aspirin treatment suppressed hepatic lipid peroxidation, as substantiated by a reduction in malondialdehyde (MDA) situations. likewise, it averted the reduction of glutathione (GSH) situations and catalase exertion convinced by gentamicin administration. These findings suggest that aspirin exerts a hepatoprotective effect by reducing oxidative stress and enhancing antioxidant defense mechanisms. The protective mechanisms of aspirin may involve its anti-inflammatory properties, as well as its antioxidant effects. Aspirin has the potential to inhibit inflammation-induced liver injury and modulate signaling pathways involved in cell survival and apoptosis. However, further investigations are needed to elucidate the precise molecular mechanisms underlying its protective effects. Overall, pre-treatment with aspirin demonstrated a protective effect against gentamicin-induced hepatotoxicity in this rat model. It mitigated liver damage, preserved liver function, and enhanced antioxidant defense mechanisms. These findings suggest that aspirin could be a potential therapeutic agent for the prevention and management of drug-induced liver injury. Further studies, including clinical trials, are necessary to determine the optimal dosage, duration, and safety profile of aspirin in humans.

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis.

A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function. To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Systematic review and network meta-analysis. Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research. Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials. Many studies were small and of poor quality. No comparative studies were found for some therapies. The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection. PROSPERO CRD42020221357. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

Early Experience of Transarterial Therapy in Ruptured Hepatocellular Carcinoma

Introduction: Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related mortality. Ruptured HCC carries a high mortality if untreated. Peripherally located HCC has a higher risk of rupture. However, most of the ruptured HCCs on presentation are in an advanced stage and, hence are unresectable. Henceforth treatment options available are conservative and transcatheter embolization. Methods: Retrospectively, 8 patients with ruptured HCC who underwent trans arterial embolization were studied for hemostasis and 30-day mortality. Clinical history and laboratory data were obtained from the medical records of the patients, and radiological images were extracted from picture archiving and communication systems and studied. Results: The age ranged between 31 to 78 years and 7 were male. In patients presenting with sudden onset pain abdomen, ruptured HCC was suspected if there was a hemoperitoneum with or without extravasation of contrast adjacent to peripherally located HCC on CT angiography. Angiography revealed tumour blush with sentinel vessels in all. Two showed active contrast extravasation. Seven patients with relatively preserved liver function (Child A and B) attained both radiological and clinical hemostasis. One patient with Child C status died due to MODS on day 3 of embolisation. Three patients survived more than a year with additional liver-directed therapies. Two patients were lost to follow-up after discharge and two after six months. Conclusions: Transarterial embolization for ruptured HCC is an effective method of hemostasis and helps in achieving better survival by the additional benefit of tumor control and poor functional status of the liver predicts lower survival.

Soluble suppression of tumorigenicity 2 is a potential predictor of post-liver transplant renal outcomes.

Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

Tenofovir versus Entecavir on Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma After FOLFOX-Hepatic Arterial Infusion Chemotherapy.

The efficacy of entecavir (ETV) versus tenofovir (TDF) on the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who underwent FOLFOX-hepatic arterial infusion chemotherapy (HAIC) remains unclear. In this study, we compared the outcomes between ETV and TDF in HBV-related advanced HCC patients who underwent FOLFOX-HAIC. A total of 683 patients diagnosed with HBV-related HCC who underwent FOLFOX-HAIC and received TDF or ETV between January 2016 and December 2021 were included. Overall survival (OS), progression-free survival (PFS), HBV reactivation, and liver function of patients were compared between the ETV and TDF groups by propensity score matching (PSM). In the PSM cohort, for all patients and patients with ≥ 4 cycles of FOLFOX-HAIC, the median OS in the ETV group (15.2 months, 95% CI: 13.0-17.4 months; 16.6 months, 95% CI: 14.8-18.5 months; respectively) was shorter than that in the TDF group (23.0 months, 95% CI: 10.3-35.6 months; 27.3 months, 95% CI: 16.5-NA months; p=0.024, p=0.028; respectively). The median PFS in the ETV group (8.7 months, 95% CI: 7.9-9.5 months; 8.9 months, 95% CI: 8.0-9.8 months; respectively) was also shorter than that in the TDF group (11.8 months, 95% CI: 8.0-15.6 months; 12.7 months, 95% CI: 10.8-14.6 months; p=0.036, p=0.025; respectively). The rate of HBV reactivation in the ETV group was higher than that in the TDF group (12.3% vs 6.3%, p=0.040; 16.5% vs 6.2%, p=0.037, respectively). For liver function, the rate of ALBI grade that remained stable or improved in the ETV group was lower than that in the TDF group (44.6% vs 57.6%, p=0.006; 37.2% vs 53.8%, p=0.019, respectively). Compared with ETV, TDF was associated with a better prognosis, lower proportion of HBV reactivation, and better preservation of liver function in advanced HBV-HCC patients who underwent FOLFOX-HAIC, especially those who received ≥ 4 cycles.

Exogenous Volatile Organic Compound (EVOC®) Breath Testing Maximizes Classification Performance for Subjects with Cirrhosis and Reveals Signs of Portal Hypertension.

Background: Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based on dynamic breath testing. Methods: We enrolled 29 subjects with cirrhosis (Child-Pugh A and B), and 29 controls. All subjects fasted overnight. Breath samples were taken using Breath Biopsy® before and at different time points after the administration of 100 mg limonene. Absolute limonene breath levels were measured using gas chromatography-mass spectrometry. Results: All subjects showed a >100-fold limonene spike in breath after administration compared to baseline. Limonene breath kinetics showed first-order decay in >90% of the participants, with higher bioavailability in the cirrhosis group. At the Youden index, baseline limonene levels showed classification performance with an area under the roc curve (AUROC) of 0.83 ± 0.012, sensitivity of 0.66 ± 0.09, and specificity of 0.83 ± 0.07. The best performing timepoint post-administration was 60 min, with an AUROC of 0.91, sensitivity of 0.83 ± 0.07, and specificity of 0.9 ± 0.06. In the cirrhosis group, limonene bioavailability showed a correlation with MELD and fibrosis indicators, and was associated with signs of portal hypertension. Conclusions: Dynamic limonene breath testing enhances diagnostic performance for cirrhosis compared to static testing. The correlation with disease severity suggests potential for monitoring therapeutic interventions. Given the non-invasive nature of breath collection, a dynamic limonene breath test could be implemented in primary care.

Radiation Major Hepatectomy Using Ablative Dose Yttrium-90 Radioembolization in Patients with Hepatocellular Carcinoma 5 cm or Larger

PurposeTo evaluate the safety and effectiveness of ablative radioembolization for large hepatocellular carcinoma (HCC) while preserving a small future liver remnant (FLR). Materials and MethodsTwenty-five patients with large HCC of ≥5 cm requiring treatment for >60% of the total liver volume and having well-preserved liver function were treated with ablative glass microsphere radioembolization at a single institution from January 2017 to December 2021. Radioembolization was performed with a mean absorbed dose of >150 Gy, and the FLR per nontumor liver volume (NTLV) was set at >30%. Changes in liver function, adverse events, duration of response (DoR) in a treated area, time-to-progression (TTP), and overall survival (OS) were retrospectively investigated. ResultsThe largest tumor diameter and planned dose per treated volume were 11.4 cm ± 3.9 and 242.3 Gy ± 63.6 (169.4 Gy ± 45.9 per whole liver volume), respectively. All patients remained at Child–Pugh Class A for 90 days. No patient experienced Grade 3‒4 hyperbilirubinemia or new ascites. One patient (lung dose, 27.8 Gy) developed radiation pneumonitis requiring transient steroid treatment. According to the posttreatment dosimetry, the tumorous and nontumorous liver absorbed doses were 418.8 Gy ± 227.4 and 69.0 Gy ± 32.1, respectively. The median DoR in a treated area and TTP were 22.0 and 17.1 months, respectively. The 5-year OS rate was 83.2%. ConclusionsAblative radioembolization of large HCC of ≥5 cm can be performed safely and effectively in patients with preserved liver function when FLR/NTLV exceeds 30%.

Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells.

In this study, we developed functionalized polymeric micelles (FPMs) loaded with simvastatin (FPM-Sim) as a drug delivery system to target liver sinusoidal endothelial cells (LSECs) for preserving liver function in chronic liver disease (CLD). Polymeric micelles (PMs) were functionalized by coupling peptide ligands of LSEC membrane receptors CD32b, CD36 and ITGB3. Functionalization was confirmed via spectroscopy and electron microscopy. In vitro and in vivo FPM-Sim internalization was assessed by means of flow cytometry in LSECs, hepatocytes, Kupffer and hepatic stellate cells from healthy rats. Maximum tolerated dose assays were performed in healthy mice and efficacy studies of FPM-Sim were carried out in bile duct ligation (BDL) and thioacetamide (TAA) induction rat models of cirrhosis. Functionalization with the three peptide ligands resulted in stable formulations with a greater degree of in vivo internalization in LSECs than non-functionalized PMs. Administration of FPM-Sim in BDL rats reduced toxicity relative to free simvastatin, albeit with a moderate portal-pressure-lowering effect. In a less severe model of TAA-induced cirrhosis, treatment with FPM-CD32b-Sim nanoparticles for two weeks significantly decreased portal pressure, which was associated with a reduction in liver fibrosis, lower collagen expression as well as the stimulation of nitric oxide synthesis. In conclusion, CD32b-FPM stands out as a good nanotransporter for drug delivery, targeting LSECs, key inducers of liver injury.

Analysis and prediction of liver volume change maps derived from computational tomography scans acquired pre- and post-radiation therapy

External beam radiation therapy (EBRT) of liver cancers can cause local liver atrophy as a result of tissue damage or hypertrophy as a result of liver regeneration. Predicting those volumetric changes would enable new strategies for liver function preservation during treatment planning. However, understanding of the spatial dose/volume relationship is still limited. This study leverages the use of deep learning-based segmentation and biomechanical deformable image registration (DIR) to analyze and predict this relationship. Pre- and Post-EBRT imaging data were collected for 100 patients treated for hepatocellular carcinomas, cholangiocarcinoma or CRC with intensity-modulated radiotherapy (IMRT) with prescription doses ranging from 50 to 100 Gy delivered in 10–28 fractions. For each patient, DIR between the portal and venous (PV) phase of a diagnostic computed tomography (CT) scan acquired before radiation therapy (RT) planning, and a PV phase of a diagnostic CT scan acquired after the end of RT (on average 147 ± 36 d) was performed to calculate Jacobian maps representing volume changes in the liver. These volume change maps were used: (i): to analyze the dose/volume relationship in the whole liver and individual Couinaud’s segments; and (ii): to investigate the use of deep-learning to predict a Jacobian map solely based on the pre-RT diagnostic CT and planned dose distribution. Moderate correlations between mean equivalent dose in 2 Gy fractions (EQD2) and volume change was observed for all liver sub-regions analyzed individually with Pearson correlation r ranging from −0.36 to −067. The predicted volume change maps showed a significantly stronger voxel-wise correlation with the DIR-based volume change maps than when considering the original EQD2 distribution (0.63 ± 0.24 versus 0.55 ± 23, respectively), demonstrating the ability of the proposed approach to establish complex relationships between planned dose and liver volume response months after treatment, which represents a promising prediction tool for the development of future adaptive and personalized liver radiation therapy strategies.

Compensatory Enlargement of the Liver after Proton Beam Therapy for Hepatocellular Carcinoma

Charged particle therapy (CPT) has been applied as a safe and effective treatment option for hepatocellular carcinoma (HCC). Although most HCC patients have cirrhosis, favorable treatment outcome has been achieved with CPT preserving liver function. After proton beam therapy (PBT) for patients with HCC, the liver volume in the non-irradiated area is often enlarged. Here, we evaluated whether enlargement of the non-irradiated liver affects preserving hepatic function and prognosis in HCC patients treated with PBT. Among consecutive patients with HCC treated with PBT between April 2011 and July 2017, we retrospectively identified patients who fulfilled the following criteria: (i) receiving PBT to the right hepatic lobe, (ii) the left lateral segment was not irradiated, (iii) no local treatment was performed for liver within 12 months after PBT, and (iv) the albumin-bilirubin (ALBI) score was evaluable at 12 months after PBT. The left lateral segment was defined as the non-irradiated region and measured by contrast-enhanced CT just before and 3 months after PBT. ALBI scores just before and 12 months after PBT were compared to evaluate changes of hepatic function. Overall survival rate was estimated using the Kaplan-Meier method, and differences in survival between subgroups were examined using the log-rank test. The ALBI scores were compared using the Wilcoxon signed-rank test. We identified 40 patients (male/female = 32/8). The median age at the start date of PBT was 72 (range, 54-87) years. The prescribed dose was 66.0-76.0 Gy (relative biological effectiveness) delivered in 10-38 fractions. The median follow-up was 61 (range, 12-126) months. The 5-year overall survival rates were 79.0% (95% CI: 60.4-100.0%) in the larger enlargement group (n = 16, enlarged volume of non-irradiated region 3 months after PBT ≥75 cm3) and 53.7% (95% CI: 36.0-79.9%) in the smaller enlargement group (n = 24, as above, <75 cm3), respectively (p = 0.21). The median ALBI scores just before and 12 months after PBT were -3.14 (95% CI: -3.22- (-2.53)) and -2.74 (95% CI: -3.07- (-2.42)) in the larger enlargement group (p = 0.09), and -2.91 (95% CI: -3.15- (-2.40)) and -2.59 (95% CI: -2.74- (-2.12)) in the smaller enlargement group (p = 0.006), respectively. Our study suggests that larger enlargement of the non-irradiated liver after PBT is related to well-preserved liver function at 1 year and modestly associated with a favorable prognosis.

The rapidly evolving landscape of HCC: Selecting the optimal systemic therapy.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

Albumin-Bilirubin Score at Post-Hepatectomy Hepatocellular Carcinoma Recurrence: Impact on Survival and Association with Post-Hepatectomy Liver Failure

PurposeOur objective was to investigate the impact of albumin-bilirubin (ALBI) score at the time of post-hepatectomy hepatocellular carcinoma (HCC) recurrence on survival after recurrence (SAR). We further explored the perioperative factors associated with the ALBI score at recurrence. MethodsPatients who underwent primary hepatectomy for HCC between 2007 and 2018 and developed recurrence were included in the study. Cox regression models were used to assess the association between the ALBI score at recurrence and SAR. Linear regression models were used to explore factors associated with ALBI score at recurrence. ResultsOf the 233 patients analyzed, 158 developed recurrence within the Milan criteria (RWM) and 76 developed recurrence beyond the Milan criteria (RBM). Multivariable cox regression analysis demonstrated that higher ALBI scores at recurrence were associated with poorer SAR in both RWM and RBM groups (hazard ratios 4.5, 5.0; 95% confidence intervals 2.3–8.8, 2.2–11.6, respectively). In addition, multivariable linear regression analysis revealed that higher ALBI scores at hepatectomy and post-hepatectomy liver failure (PHLF) ≥ grade B were associated with higher ALBI scores at recurrence (β = 0.21, 0.11; 95% confidence intervals 0.15–0.26, 0.06–0.17, respectively). ConclusionsThe ALBI score at recurrence was a significant prognostic factor for SAR, and the ALBI scores at hepatectomy and PHLF ≥ Grade B were independently associated with the ALBI score at recurrence. Prevention of PHLF and consequent preservation of liver function at recurrence may be paramount to achieving better survival after HCC recurrence.