Baseline Albumin-Bilirubin grade as a predictor of response and outcome of regorafenib therapy in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The use of regorafenib in the treatment of hepatocellular carcinoma (HCC) is widespread. Albumin-Bilirubin (ALBI) has been shown to be a potential prognostic marker for regorafenib treatment, but its prognostic value remains controversial. Therefore, we conducted a meta-analysis to investigate the value of the baseline ALBI grade in predicting the efficacy and survival outcomes of HCC patients after regorafenib treatment. METHODS: PubMed, Embase, Cochrane library, Web of Science, CNKI, Wan Fang Data, and Vip Database were searched from January 2010 to October 2022. Studies treating HCC patients with regorafenib and with ALBI as a categorical variable, overall survival (OS) and progression-free survival (PFS) as outcome indicators were included. After applying Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included studies, Review Manager 5.4 was used to statistically analyze. Chi-square Q test and I2 statistics were used to detect heterogeneity. Funnel plot asymmetry, Egger's and Begg's test were used to evaluate publication bias. RESULTS: A total of 12 studies, comprising 1,918 patients, were included in the meta-analysis. The included studies were all evaluated as high quality. Compared to the high-grade baseline ALBI group, patients in the low-grade group had a longer survival time after receiving regorafenib and also more suitable for regorafenib treatment [odds ratio (OR) = 6.50, 95% confidence interval (CI): 2.22-18.96, P < 0.01]. The low-grade baseline ALBI group before sorafenib treatment was significantly correlated with better OS [hazard ratio (HR) = 2.36, 95% CI: 1.68-3.31, P < 0.00001] and PFS (HR = 1.56, 95% CI: 1.16-2.08, P = 0.003). Likewise, the low-grade baseline ALBI group before regorafenib was also significantly correlated with better OS (HR = 1.56, 95% CI: 1.15-2.13, P = 0.005) and PFS (HR = 2.06, 95% CI: 1.37-3.11, P = 0.0005). In addition, the ALBI grade was significantly correlated with disease control rate (DCR) (OR = 2.90, 95% CI: 1.45-5.79, P = 0.003), but not the objective response rate (OR = 1.98, 95% CI: 0.71-5.46, P = 0.19). CONCLUSIONS: The baseline ALBI grade could be a valuable prognostic indicator for predicting response and outcomes in HCC patients treated with regorafenib.

Assessing the Educational Value of Pancreatic Cancer Videos on YouTube®.

Online resources such as YouTube® can serve as the go-to resource for patients and their caregivers after a life-changing diagnosis of pancreatic cancer. There is a need to analyze the content and educational value of these videos for patients with pancreatic cancer. The top 100 most viewed videos on pancreatic cancer on YouTube® were assessed and data were collected on various variables such as views, likes, dislikes, and comments. Videos categorized as patient educational videos were further analyzed for their content, source, and educational value. Videos uploaded by patients were the most discussed (p = 0.014) and liked (p = 0.0028) videos on YouTube®. The content of the videos (personal experience, advertisement, patient education, medical professional education, alternative treatments, and increased pancreatic cancer awareness) varied depending on the uploader (patients, healthcare providers, professional societies, media) of the videos (p = 0.0007). Patient education videos were poor in being comprehensive on their education of pancreatic cancer based on our rubric (mean score of 7.67 ± 2.63 of 20 possible points). The current study shows that the educational values of YouTube® videos related to pancreatic cancer remain limited. There is significant room for healthcare providers to use the platform to develop and share comprehensive videos that can be used as more effective sources of patient education.

SLAMF1 is expressed and secreted by hepatocytes and the liver in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disease in the United States and worldwide. Nonalcoholic steatohepatitis (NASH), the most advanced form of NAFLD, is characterized by hepatic steatosis associated with inflammation and hepatocyte death. No treatments are currently available for NASH other than lifestyle changes, and the disease lacks specific biomarkers. The signaling lymphocytic activation molecule family 1 (SLAMF1) protein is a self-ligand receptor that plays a role in orchestrating an immune response to some pathogens and cancers. We found that livers from humans and mice with NASH showed a more prominent immunohistochemistry staining for SLAMF1 than non-NASH controls. Furthermore, SLAMF1 levels are significantly increased in NASH plasma samples from mice and humans compared with their respective controls. In mice, the levels of SLAMF1 correlated significantly with the severity of the NASH phenotype. To test whether SLAMF 1 is expressed by hepatocytes, HepG2 cells and primary murine hepatocytes were treated with palmitic acid (PA) to induce a state of lipotoxicity mimicking NASH. We found that PA treatments of HepG2 cells and primary hepatocytes lead to significant increases in SLAMF1 levels. The downregulation of SLAMF1 in HepG2 cells improved the cell viability and reduced cytotoxicity. The in vivo data using mouse and human NASH samples suggests a potential role for this protein as a noninvasive biomarker for NASH. The in vitro data suggest a role for SLAMF1 as a potential therapeutic target to prevent hepatocyte death in response to lipotoxicity.NEW & NOTEWORTHY This study identified for the first time SLAMF1 as a mediator of hepatocyte death in nonalcoholic fatty liver disease (NASH) and as a marker of NASH in humans. There are no pharmacological treatments available for NASH, and diagnostic tools are limited to invasive liver biopsies. Therefore, since SLAMF1 levels correlate with disease progression and SLAMF1 mediates cytotoxic effects, this protein can be used as a therapeutic target and a clinical biomarker of NASH.

Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma.

BACKGROUND & AIMS: There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. RESULTS: Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33). CONCLUSIONS: In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study.

BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Performance of echocardiography for detection of portopulmonary hypertension among liver transplant candidates: Meta-analysis.

BACKGROUND: Evaluation of pulmonary arterial pressure is crucial among cirrhotic patients, considering that moderate portopulmonary hypertension (POPH) is a contraindication for liver transplantation. Although right heart catheterization (RHC) is the most accurate method to diagnose POPH, it is invasive. OBJECTIVE: The aim of the study is to evaluate the performance of echocardiography in detecting POPH in liver transplant candidates. METHODS: A Literature search was performed, and pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the summary receiver operating curve (AUC) were calculated. Subgroup analyses were performed based on different cutoff values for echocardiography and diagnostic criteria of RHC. RESULTS: Sensitivity, specificity, positive LR, negative LR, and AUC of echocardiography for detection of POPH were 0.86 (0.74, 0.94), 0.87 (0.84, 0.90), 7.17 (3.59, 14.31), 0.22 (0.13, 0.38), and 0.807 while they were 0.82 (0.74, 0.89), 0.81 (0.78, 0.84), 117.75 (16.03, 865.08), 0.28 (0.16, 0.50), and 0.876for detection of moderate POPH, respectively. Performance of echocardiography was not significantly different in the subgroup analyses of stringency of POPH criteria and pulmonary arterial systolic pressure (ePASP) cutoffs. CONCLUSIONS: Our meta-analysis supports utilization of echocardiography for screening of POPH. However, RHC remains essential in highly suspicious cases. Echocardiographic data other than ePASP should be evaluated in future studies.

Biomarkers of rejection in kidney transplantation.

PURPOSE OF REVIEW: To provide an update of the literature on the use of new biomarkers of rejection in kidney transplant recipients. RECENT FINDINGS: The kidney allograft biopsy is currently considered the gold standard for the diagnosis of rejection. However, the kidney biopsy is invasive and could be indeterminate. A significant progress has been made in discovery of new biomarkers of rejection, and some of them have been introduced recently for potential use in clinical practice including measurement of serum donor-derived cell free DNA, allo-specific CD154 + T-cytotoxic memory cells, and gene-expression 'signatures'. The literature supports that these biomarkers provide fair and reliable diagnostic accuracy and may be helpful in clinical decision-making when the kidney biopsy is contraindicated or is inconclusive. SUMMARY: The new biomarkers provide a promising approach to detect acute rejections in a noninvasive way.

Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: Systemic review and meta-analysis.

BACKGROUND AND AIM: There is increasing evidence of non-invasive measurement using elastography such liver stiffness (LS), spleen stiffness (SS), and LS-spleen diameter to platelet ratio score (LSPS) for detection of esophageal varices (EV); however, data regarding comparison between these three parameters are limited. METHODS: We performed a systemic review and meta-analysis of studies evaluating performance of LS, SS, and LSPS for detection of EV and high risk/clinically significant EV (HREV). Pooled sensitivity, specificity, log diagnostic odd ratio (LDOR), and area under the receiver operating characteristic curve (AUC) of LS, SS, and LSPS for detection of EV and HREV were analyzed and compared. Publication bias was assessed by Deeks' funnel plot. RESULTS: SS and LSPS were superior to LS for detection of EV with higher sensitivity (0.90 and 0.91 vs 0.85), specificity (0.73 and 0.76 vs 0.64), LDOR (3.24 and 3.35 vs 2.26), and AUC (0.899 and 0.851 vs 0.817). For HREV, SS had the highest sensitivity (0.87) followed by LS (0.85) and LSPS (0.82); however, SS had the lowest specificity (0.52), LDOR (2.09), and AUC (0.807) whereas LSPS had the highest specificity (0.77), LDOR (2.74), and AUC (0.861). CONCLUSION: For detection of EV, we prefer using LSPS and SS over LS when available, while LS, SS, and LSPS cannot be recommended for detection of HREV due to their moderate sensitivity and specificity.

Kidney outcomes in patients with liver cirrhosis and chronic kidney disease receiving an orthotopic liver transplant alone.

Kidney transplant in patients with liver cirrhosis and nondialysis chronic kidney disease (CKD) is controversial. We report 14 liver cirrhotic patients who had persistently low MDRD-6 estimated glomerular filtration rate (e-GFR) <40 mL/min/1.73 m2 for ≥3 months and underwent either liver transplant alone (LTA; n=9) or simultaneous liver-kidney transplant (SLKT; n=5). Pretransplant, patients with LTA compared with SLKT had lower serum creatinine (2.5±0.73 vs 4.6±0.52 mg/dL, P=.001), higher MDRD-6 e-GFR (21.0±7.2 vs 10.3±2.0 mL/min/1.73 m2 , P=.002), higher 24-hour urine creatinine clearance (34.2±8.8 vs 18.0±2.2 mL/min, P=.002), lower proteinuria (133.2±117.7 vs 663±268.2 mg/24 h, P=.0002), and relatively normal kidney biopsy and ultrasound findings. Post-LTA, the e-GFR (mL/min/1.73 m2 ) increased in all nine patients, with mean e-GFR at 1 month (49.8±8.4), 3 months (49.6±8.7), 6 months (49.8±8.1), 12 months (47.6±9.2), 24 months (47.9±9.1), and 36 months (45.1±7.3) significantly higher compared to pre-LTA e-GFR (P≤.005 at all time points). One patient developed end-stage renal disease 9 years post-LTA and another patient expired 7 years post-LTA. The low e-GFR alone in the absence of other markers or risk factors of CKD should not be an absolute criterion for SLKT in patients with liver cirrhosis.

Single use versus reuse of endoscopy biopsy forceps: A survey of patient preference.

BACKGROUND: Although there are no confirmatory data on this, we suspect that most endoscopy centres in India reuse single-use ('disposable') endoscopic biopsy forceps due to the cost of these forceps and the perceived low risk of infection transmission on reuse. Low-cost single-use biopsy forceps are now available in India, bringing into question the justification for such a practice. We aimed to determine the type of forceps (single-use or reused) patients would prefer during endoscopy for themselves, whether this is dependent on cost, and what cost would be acceptable to them. METHODS: Among patients (conveniently selected from indoor or outdoor) reporting for endoscopy at the division of gastroenterology at a private tertiary-level hospital, we distributed an information sheet about the survey 30-45 minutes before the procedure. After they completed reading the sheet, an endoscopy nurse and/or doctor explained the study. The patient then completed a questionnaire of multiple choices with tick boxes. RESULTS: Of 151 patients approached, 4 declined to participate. Of 147 patients surveyed (age range 16-83 years; 82 men), 127 (86.4%) preferred single-use forceps, 16 (10.9%) preferred reused forceps, and 4 (2.7%) could not decide and left the decision to the physician. When informed that single-use forceps may be available for about ₹1000 (approximately US$ 15), 131 patients (89.1%) preferred these forceps, 11 (7.4%) preferred reused forceps, and 5 (3.4%) could not decide. Forty-four patients (33.1%) stated that an acceptable cost for a forceps for them would be ₹500 (approximately US$ 8), for 65 patients (48.9%) patients it was ₹1000, and for 24 (18.1%) it was ₹1500. CONCLUSION: About 90% of patients in this survey preferred single-use forceps; a cost of ₹1000 for single-use forceps was acceptable to over two-thirds of them.

Regorafenib combined with a PD-1 inhibitor in the second-line setting for unresectable hepatocellular carcinoma in real-world practice.

Background: Most advanced hepatocellular carcinoma (HCC) cases administered molecular targeted agents and/or anti-programmed cell death-1 (PD-1) inhibitors have no response or develop resistance. Moreover, second-line therapies still cannot provide beneficial clinical outcomes. A pilot study assessing combined regorafenib and PD-1 inhibitor as second-line treatment of advanced HCC reported promising effectiveness. Methods: The current single-center, retrospective, real-world study was carried out between January 2019 and July 2021. Advanced HCC cases were administered second-line regorafenib combined with a PD-1 inhibitor or regorafenib alone were assessed. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were determined. Results: Totally 46 HCC cases were analyzed, most of whom underwent previous systemic treatment comprising targeted therapy and immunotherapy. Tumor response was evaluated in 25 and 21 individuals in the regorafenib + PD-1 inhibitor and regorafenib monotherapy groups, respectively: ORRs were 21.7% and 8.7%, and DCRs were 47.8% and 32.6%, respectively. Median PFS was markedly longer in the regorafenib plus PD-1 inhibitor group (11.5 months) compared with the regorafenib monotherapy group (5.1 months, P=0.049). Conclusions: This study suggested regorafenib and a PD-1 inhibitor in combination may provide significant clinical benefits in HCC cases showing progression following first-line treatment. Further analysis in real-world studies with large cohorts is warranted to confirm these findings.

Association of statins with nonalcoholic fatty liver disease in patients with diabetes.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in patients with diabetes; limited data suggested that statins may reduce the risk of NAFLD progression. This study aimed to examine the association between statins and the development or progression of NAFLD in veterans with diabetes. In a new-user negative control design, we conducted a retrospective propensity score (PS)-matched cohort study of patients with diabetes between 2003 and 2015. After excluding patients with other causes of liver disease, we formed PS using 85 characteristics. The primary outcome was a composite NAFLD progression outcome. Primary analysis examined odds of outcome in PS-matched cohort. Post-hoc analysis included a PS-matched cohort of statin users with intensive lowering of low-density lipoprotein-cholesterol (LDL-C) vs low-intensity lowering. We matched 34,102 pairs from 300,739 statin users and 38,038 non-users. The composite outcome occurred in 8.8% of statin users and 8.6% of non-users (odds ratio (OR) 1.02, 95% confidence interval (95% CI) 0.97-1.08). In the post-hoc analysis, intensive lowering of LDL-C compared to low-intensity showed increased NAFLD progression (OR 1.21, 95% CI 1.13-1.30). This study showed that statin use in patients with diabetes was not associated with decreased or increased risk of NAFLD progression. Intensive LDL-C lowering, compared to low-intensity LDL-C lowering, was associated with an increased risk of NAFLD progression.

COVID-19 vaccination-related hemophagocytic lymphohistiocytosis presenting as acute liver failure.

Acute liver failure following COVID-19 infection and/or vaccination is very rare and can be secondary to hemophagocytic lymphohistiocytosis (HLH). Liver injury in such cases appears to be extrinsic and thus treatment hinges on prompt diagnosis and reversal of the primary disease. We describe a patient who developed acute liver failure secondary to HLH after receiving a second dose of the Pfizer COVID-19 vaccine. Persistently elevated liver function tests, fevers, and cytopenia following COVID-19 vaccination should prompt clinicians to calculate an H-score to evaluate for the presence of HLH.

Fibrosing Cholestatic Hepatitis Masquerading Acute Rejection in Hepatitis C Virus-Positive Donor Liver Graft.

Fibrosing cholestatic hepatitis is a rare complication that manifests in patients receiving organ transplantation from seropositive (hepatitis C virus or hepatitis B virus) donors. We report a rare case of such a phenomenon in the immediate post-transplant period.

A Novel Mutation in the ATP7B Gene: A Rare Manifestation of Wilson Disease With Liver Failure.

Wilson disease is a hereditary disorder which involves anomalous copper metabolism. Typically, the presentation is systemic, involving vital organs such as the liver, kidney, and brain, among others. We report a unique case presenting with solitary organ involvement as acute liver failure with novel ATP7B gene mutation, which has never been reported before.

N6-Methyladenosine Modification of ANLN Enhances Hepatocellular Carcinoma Bone Metastasis.

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N6-methyladenosine (m6A) is a prominent modification involved in HCC, but the exact mechanisms on how m6A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m6A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1. The expression of Anillin actin-binding protein (ANLN) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m6A epitranscriptomic regulation by METTL3 and YTHDF1. High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m6A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m6A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.