Pugh Class 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.

Lenvatinib in recurrent hepatocellular carcinoma after liver transplantation.

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients &lt;60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least &gt;28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H0: ORR = 5%; H1: ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .

First-line therapies in a Latino-rich cohort of US patients (pts) with hepatocellular carcinoma (HCC) and Child Pugh B (CPB) cirrhosis.

453 Background: There are limited prospective clinical trials in patients with both HCC and CPB cirrhosis. As the prevalence of HCC and cirrhosis has been rising among Latinos in South Texas, it is crucial to examine the liver dysfunction within this demographic to understand the contributing factors to treatment patterns. Therefore, we conducted a retrospective analysis of 36 patients with both HCC and Child Pugh B (CPB) cirrhosis. Methods: A dataset of 65 patients with HCC and cirrhosis from 2009 – 2019 was used to identify 36 patients with CPB treated at a Latino-Rich NCI-designated Cancer Center. We further segmented patients of Child Pugh Class B by ALBI grades (1-3) to explore variations in demographics, liver dysfunction, and first-line therapies. Results: Median age overall of the cohort is 59 (50-71). Ethnicity: Latino White (83%), Non-Latino White (14%), Black (3%). Etiology: HCV (78 %) EtOH (50%), NASH (19%), and HBV (3%). ALBI Grade: I (6%), II (50%), III (44%). First line treatment in CPB: Sorafenib (86%), Nivolumab (8%), Lenvatinib (6%). Sorafenib was used across all ALBI grades, while Lenvatinib and Nivolumab were given only in ALBI II (Table). Conclusions: Sorafenib was more often given to patients with CPB cirrhosis, in the first line setting; however, more patients were treated with nivolumab or lenvatinib with ALBI II. Further investigation of survival based on ALBI levels and the trajectory of liver function over time in response to different treatment approaches is underway in a larger cohort who has received newer immunotherapy-based regimens. With more agents approved for HCC, prospective clinical trials are needed in CPB and HCC. [Table: see text]

Study on Red Cell Indices in Chronic Liver Disease in Tertiary Level Hospital

Background: Chronic liver disease (CLD) in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. Liver diseases are frequently associated with hematological abnormalities. Bleeding and defective blood coagulation contributes to the anemia in CLD patients. Other mechanisms of anemia include aplastic anemia secondary to previous hepatitis, or side effects of treatment of hepatitis with chemotherapeutic agent. Other different factors, such as malabsorption, malnutrition or direct toxic effect also contribute to hematological abnormalities. The examination of complete blood count is common, economically cheap and readily available laboratory procedure. Red cell indices are valuable in the evaluation of morphologic characteristic of anaemias or hematological abnormalities in CLD patients. Objectives: To assess the red cell indices in chronic liver disease patients. Materials &amp; method: This descriptive type of cross-sectional study was conducted in Department of Medicine, Dhaka Medical College Hospital, Dhaka, among 75 cases of Chronic liver disease patients. Samples were selected by purposive sampling technique. Detail demographic data were collected from the patients and recorded in structured case report form. Clinical examination and relevant investigation were done meticulously. Data was processed and analysed with the help of computer program SPSS and Microsoft excel. Quantitative data expressed as mean and standard deviation and qualitative data as frequency and percentage. Results was presented by tabulation and graphical presentation in the form of tables, pie chart, graphs, bar diagrams, histogram &amp; charts etc. Result: Maximum number of patients, 37(49.3%) were between 31-40 years of age with mean age of the patient was 37.58 ± 8.23 years. Out of 75 cases 58(77.0%) patients were male and 17(23.0%) were female. Male-female ratio was 3.34:1. Majority of patients belonged to Child Pugh score B. Prevalence of anaemia was 54(72%) in CLD patients. Microcytic anaemia was predominant and Normocytic anaemia was second most common. Hb concentration &amp; MCV decreases with the severity of Child Pugh score. Abnormalities of red cell indices were positively associated with severity of CLD. Conclusion: Present study concluded that chronic liver diseases are associated with hematological abnormalities. Patients with severe hepatocellular disease develop defects of blood coagulation as a consequence of endothelial dysfunction, thrombocytopenia, deficiencies of coagulation factors and various associated disorders. In overall patients, Child Pugh class C cases had significant low hemoglobin in comparison to rest of group. Assessing the severity and type of anaemia by red cell indices is a useful tool for proper treatment, prognosis in patients of CLD for reducing the mortality and morbidity. J MEDICINE 2024; 25: 41-45

Hematological abnormalities in chronic liver disease and their association with severity and types of chronic liver disease

This study aimed to assess the hematological abnormalities in CLD patients and to study the association of hematological abnormalities with type and severity of CLD. This study was conducted as a facility based cross-sectional study at tertiary care centre on confirmed cases of chronic liver disease. Detailed clinical history along with clinical examination findings were recorded. All patients were then subjected to investigations. Mean age of patients with CLD was 48.8±16.9 years and majority of patients were males (76%). Anemia was observed in 71% cases with CLD whereas leukocytopenia and thrombocytopenia were noted in 21% and 56% cases respectively. Mean MCV, MCH, serum bilirubin and iron were significantly higher in cases with alcoholic liver disease whereas TIBC was significantly lower in ALD cases as compared to NALD cases (p&amp;#60;0.05). Mean hemoglobin, platelet levels, MCV, albumin and iron levels were significantly lower in cases with severe liver disease (Child Pugh Class C). However, serum bilirubin, prothrombin time and TIBC levels increased significantly with increase in severity of CLD (p&amp;#60;0.05). Hematological abnormalities particularly normocytic normochromic anemia and thrombocytopenia are common in cases with CLD, which might affect the prognosis of patients with CLD. Assessing the severity and type of anaemia is a useful tool for early initiation of the treatment in patients of CLD for reducing the morbidity and mortality. Early detection and treatment of haematological changes can prevent complications and reduce the mortality in CLD patients.

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Therapeutic Efficacy and Safety of Lenvatinib after Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2-12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months-not reached) and 4.0 months (range, 2.5-6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02-0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003-0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.

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%.

Risk factors analysis of endoscopy and TIPS in the treatment of secondary esophagogastric varicose bleeding with cirrhosis.

To analyse the risk factors of secondary hemorrhage and survival rate in cirrhotic patients with esophagogastric variceal rupture and to compare the efficacy and safety of endoscopic hemostasis and TIPS (transjugular intrahepatic portosystemic shunt). A total of 120 patients with secondary bleeding after endoscopic treatment of esophagogastric varicose bleeding with cirrhosis in our hospital during the past 3 years were retrospectively analysed. There were 65 males and 55 females, ranging in age from 49 to 74 years old, with an average of (59.5 ± 8.4) years old. The etiology, degree of varicose veins, bleeding location, hemostasis method, Infection, ascites, portal vein thrombosis or cancer thrombus, albumin, platelets, prothrombin activity, Child Pugh (Child-Pugh classification is a diagnostic criterion for liver reserve function) grade were compared in each group. The risk factors of treatment failure and analyse the survival time was analysed. There were statistically significant differences in varicosis degree, infection, ascites, portal vein thrombosis or cancer thrombus, child Pugh grade, albumin and prothrombin activity between the failed Endoscopy group and the successful hemostasis group (P< 0.05). There were statistically significant differences in child Pugh grade, albumin and prothrombin activity between the failed TIPS treatment group and successful hemostasis group (P< 0.05). There was no significant difference in 1-year survival between the endoscopy group and the TIPS group. Severe varicose veins, infection, ascites, portal vein thrombosis or cancer thrombus, child pugh classification, albumin, and prothrombin activity were the major risk factors for failed secondary endoscopic therapy, child Pugh classification, albumin and prothrombin activity were the main risk factors for failure TIPS treatment. There is no significant difference in long-term survival between the two methods.

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study.

Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan-Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2-6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7-19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial.

Liver Imaging Reporting and Data System version 2018 for diagnosing hepatocellular carcinoma in alcoholic liver cirrhosis and virus-related cirrhosis

PurposeWe aimed to evaluate and compare the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) v2018 for hepatocellular carcinoma (HCC) ≤ 3.0 cm on gadoxetic acid-enhanced MRI according to the etiology of cirrhosis. MethodsThirty-eight patients with alcoholic liver cirrhosis (ALC) and 37 with hepatitis C virus-related cirrhosis (HCV) who underwent preoperative MRI and subsequent surgical resection or transplantation were included. For comparison groups, patients with hepatitis B virus-related cirrhosis (HBV) were included by 1:1 matching with HCV and ALC groups according to age, lesion size, and Child–Pugh classification. The imaging characteristics of background liver and focal lesions were analyzed. The diagnostic performance of LI-RADS was compared between HCV and HBV groups, and between ALC and HBV groups. ResultsALC group showed significantly higher frequency of hepatic steatosis (25.8 % vs. 6.1 %, p =.04) and lower frequency of nonperipheral washout on portal venous-phase in HCC (63.2 % vs. 97.1 %, p <.001) compared with HBV group. ALC group showed significantly lower sensitivity than HBV group (52.6 % vs. 88.6 %, p<.001). No significant differences in diagnostic performance were found between HCV and HBV groups. In ALC group, hepatobiliary-phase hypointensity provided significantly higher sensitivity (76.3 % vs. 52.6 %, p =.008). ConclusionThe sensitivity of LI-RADS for diagnosing HCC ≤ 3.0 cm was significantly lower in the ALC group than in the HBV group.

Assessment of hepatic fibrosis, portal hemodynamic changes, and disease severity in patients with HCV-related liver cirrhosis after sustained virologic response to direct-acting antiviral drugs (DAAs)

BackgroundRegression of fibrosis and improvement of portal hemodynamics after achievement of sustained viral response (SVR) in patients with chronic hepatitis C (HCV) is a subject of debate in different studies. Some studies reported improvement in the degree of fibrosis, while others did not find significant changes.ObjectiveWe aimed to evaluate changes in liver fibrosis, portal hemodynamics and clinical outcomes in patients with chronic HCV-related liver cirrhosis after the achievement of SVR with direct-acting antiviral drugs (DAAs).Patients and methodsIn our prospective longitudinal study, a total of 100 patients with chronic HCV infection-related liver cirrhosis were recruited, received DAAs, and completed the follow-up period. Clinical evaluation for assessment of liver disease severity using MELD and Child–Pugh class and scores were done. A noninvasive assessment of liver fibrosis using serum biomarkers (APRI index & FIB4 score) and share wave elastography (SWE) was done. Portal hemodynamic evaluation using Doppler ultrasound was done. All were done at baseline and 3 and 12 months after the end of therapy.ResultsA significant reduction in the degree of fibrosis was observed. Share wave elastography (SWE) readings showed 19.79% and 30.45% reduction 3 and 12 months after the end of therapy respectively (P < 0.001). Regarding the FIB4 score, the percentage of score reduction was 19.8% and 26.46% 3 and 12 months after the end of therapy, respectively (P < 0.01). APRI scores showed 22.6% and 41.09% reduction 3 and 12 months after the end of therapy respectively (P < 0.001). Significant improvement in Child–Pugh scores 3 and 12 months after the end of treatment was observed. Doppler ultrasound showed a significant increase in portal vein flow velocity, a significant decrease in time average mean velocity, and cross-section area 12 months after the end of treatment.ConclusionThere was a considerable degree of reduction of liver fibrosis, improvement of portal hemodynamics, and Child–Pugh score in cirrhotic HCV patients who achieved SVR after DAAs.Trial registrationClinicalTrials.gov, ID: NCT03241823. Registered on 08 May 2017.

Role of Stereotactic Body Radiation Therapy in Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma: A Prospective Single Institute Experience

Patients diagnosed with Hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombosis (PVTT) have a limited number of treatment options available and are associated with an overall poor prognosis. With the recent developments in the field of radiation therapy, the role of radiotherapy particularly Stereotactic Body radiotherapy (SBRT) has increased as a loco-regional therapy for HCC. This study was planned to evaluate the role of SBRT in Locally advanced HCC complicated with PVTT and its role as loco-regional therapy. We conducted a prospective study that included patients diagnosed with HCC complicated with PVTT Child-Turcotte Pugh (CTP) Class A/B with a maximum score of 7, diagnosed on triple phase Contrast-Enhanced - MRI unsuitable for other ablative procedures. Patients with Bilirubin levels > 4 mg/dl, active Hepatitis, CTP score >7, normal liver volume <700cc or history of prior radiotherapy were excluded from the study. Patients underwent a contrast enhanced 4D-CT simulation with abdominal compression and were planned for SBRT using VMAT technique. Patients were followed-up as per Institute protocol. CECT or MRI for a radiological response was done for response assessment using mRECIST criteria version 1.1. A baseline MRI was done at one-month post-SBRT to understand any RT changes in the liver and to differentiate from tumor progression during the response assessment at three months. A total of 22 patients with HCC were recruited and received SBRT to PVTT, with a dosage between 30-42 Gy over 6 fractions treated on alternate days. Patients were assessed post-treatment with triphasic CE-MRI every 3 months as per institute protocol. Five patients had achieved Complete response in form of Portal vein recanalization. Three patients had Partial response to the treatment. Seven patients maintained stable disease status whereas six patients had disease progression during the entire course of treatment. The response rate (CR+PR) to treatment was 36.3% at the time of analysis. The Overall Response rate (CR+PR+SD) was 69%. No grade 3 or 4 toxicities were observed and treatment was tolerated well by patients. Kaplan-Meier method was applied to calculate the survival probability at various follow-up intervals. The median time for overall survival was 25 months ((95% CI: 15-35). Out of the 22 subjects included in the study, 6 patients died. There was a 78% survival probability at 12 months and a 68% survival probability at 18 months of follow-up. This prospective single-arm study demonstrated the vital role of SBRT in the treatment of Hepatocellular carcinoma with Portal vein tumor thrombosis and its efficacy in terms of achieving excellent local control with relatively lesser toxicities compared with existing treatment modalities. Patients have shown benefit post-treatment in terms of thrombus reduction and restoration of Portal vein flow making them suitable for further treatment like Resection or TACE.

Biological Response Assessment in Hepatocellular Carcinoma Post Stereotactic Body Radiotherapy

Biological Response in Hepatocellular carcinoma (HCC) is measured in terms of serum alpha-fetoprotein (AFP) which is elevated in nearly 60% HCC patients at baseline and is directly related to the severity of the disease. This biological response is defined as the reduction of more than 50% from the baseline levels and is associated with an increased percentage of tumor necrosis and is directly related to increased loco-regional control. Patients diagnosed with HCC have very limited treatment modalities. With the recent advances in the field of radiation therapy and the development of Stereotactic Body radiotherapy (SBRT), the role of radiotherapy has increased as a loco-regional modality for HCC. In this single-arm prospective study, we evaluated the biological response post-SBRT in patients diagnosed with HCC. We conducted a prospective study that included patients diagnosed with HCC with baseline elevation of serum AFP, Child-Turcotte Pugh (CTP) Class A/B with a maximum score of 7. Patient's serum AFP levels were recorded at baseline, pre-treatment, and post-treatment. The biological response was measured at 3 months post-treatment and compared with the baseline serum AFP levels using Wilcoxon signed rank test. A total of 14 patients with HCC were recruited and received SBRT to the target lesion, with a dose between 30-42 Gy over 6 fractions treated on alternate days. Patients were assessed post-treatment at one month with triphasic CEMRI and serum AFP levels. 12 out of 14 patients (85.71%) had a biological response at 3 months follow-up and levels showed further decline unless a progression was found. The median (IQR) serum AFP level was 1131 ng/ml (359-5668 ng/ml) at baseline. Post-treatment serum AFP levels had a median (IQR) value of 156 ng/ml (15-372 ng/ml) showing a near reduction of 86% from baseline, which was significant. 2/14 pts (14.28%) showed no reduction or even increase in serum AFP levels post-treatment. This prospective single-arm study demonstrated the vital role of SBRT in the treatment of HCC and its importance in achieving a better disease control. The response was achieved in 86% of patients with marked reduction of nearly 90% in serum AFP levels as compared to the baseline and increased median OS and PFS as compared to patients not receiving radiotherapy. Further prospective studies are warranted to confirm our findings.

Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameter

Percutaneous radiofrequency ablation (RFA) is effective for the treatment of small hepatocellular carcinoma (HCC) with a diameter ≤ 3.0 cm. The present study aimed to elucidate the prognostic factors and clarify the indication of treatment for RFA outcomes in patients with HCC with a diameter > 3.0 cm. Among 2188 patients with HCC who underwent RFA, 100 patients with HCC with a diameter > 3.0 cm were enrolled in this study between August, 2000 and August, 2021. We analyzed local therapeutic efficacy, long-term outcomes, and prognostic factors in patients with HCC with a diameter > 3.0 cm. Among all patients, 77 patients achieved complete ablation in one session. There were no treatment-related deaths or major complications. Local tumor recurrence occurred in 48% (n = 48) of the patients, and distant tumor recurrence occurred in 82% (n = 82) of the patients during the study period. The survival rates at 1-, 3-, 5-, 10-, and 15- years were 93.0%, 66.0%, 40.0%, 15.5%, and 10.2%, respectively. Cox proportional hazards regression analysis confirmed that distant tumor recurrence, Child–Pugh class B, and pre-ablation des-γ-carboxy prothrombin (DCP) levels ≥ 200 mAU/mL were independent unfavorable prognostic factors with a hazard ratio of 3.34 (95% CI, 1.57–7.11; P = 0.002), 2.43 (95% CI, 1.35–4.37; P = 0.003), and 1.83 (95% CI, 1.14–2.93; P = 0.012), respectively. In conclusion, patients with HCC with a diameter > 3.0 cm with Child–Pugh class A and DCP levels < 200 mAU/mL might be eligible for RFA treatment.

Vitamin D deficiency exacerbates alcohol-related liver injury via gut barrier disruption and hepatic overload of endotoxin

Endogenous lipopolysaccharide (LPS) that translocates via the disrupted intestinal barrier plays an essential role in the progression of alcohol-related liver disease (ALD). Vitamin D deficiency is observed in ALD, and it participates in regulating gut barrier function. The current study aimed to examine the association between vitamin D deficiency and endotoxemia in patients with ALD-related cirrhosis. Moreover, the effect of vitamin D deficiency on ethanol (EtOH)- and carbon tetrachloride (CCl4)-induced liver injury relevant to gut barrier disruption in mice was investigated.Patients with ALD-related cirrhosis (Child–Pugh Class A/B/C; n=56/15/7) had lower 25(OH)D levels and higher endotoxin activities than non-drinking healthy controls (n=19). The serum 25(OH)D levels were found to be negatively correlated with endotoxin activity (R=−0.481, P<.0001). The EtOH/CCl4-treated mice developed hepatic inflammation and fibrosis, which were significantly enhanced by vitamin D-deficient diet. Vitamin D deficiency enhanced gut hyperpermeability by inhibiting the intestinal expressions of tight junction proteins including ZO-1, occludin, and claudin-2/5/12/15 in the EtOH/CCl4-treated mice. Consequently, it promoted the accumulation of lipid peroxidases, increased the expression of NADPH oxidases, and induced Kupffer cell infiltration and LPS/toll-like receptor 4 signaling-mediated proinflammatory response. Based on the in vitro assay, vitamin D-mediated vitamin D receptor activation inhibited EtOH-stimulated paracellular permeability and the downregulation of tight junction proteins via the upregulation of caudal-type homeobox 1 in Caco-2 cells.Hence, vitamin D deficiency exacerbates the pathogenesis of ALD via gut barrier disruption and hepatic overload of LPS.

The MAPS-CRAFITY score: a novel efficacy predictive tool for unresectable hepatocellular carcinoma treated with targeted therapy plus immunotherapy.

Body composition parameters (BCPs) are associated with mortality in patients with hepatocellular carcinoma (HCC). Our purpose was to develop a practical scoring model by BCP and the CRAFITY score to predict the overall survival (OS) and tumor response of patients with HCC who received targeted therapy plus immunotherapy. This retrospective study included 265 patients with HCC who received targeted therapy plus immunotherapy at 2 centers in China from August 2018 to February 2022. Univariate and multivariate Cox regression analyses were applied to analyze clinical factors and BCP. A scoring model based on independent risk factors was developed to predict OS and tumor response. Moreover, the model's prediction was further validated by an external cohort. A total of 150 patients (55.5 ± 10.8years) and 115 patients (55.0 ± 8.9years) treated with lenvatinib or bevacizumab biosimilar plus anti-programmed death-1 (PD-1) antibody were included in training and validation cohorts, respectively. In the training cohort, independent predictive factors for OS included macrovascular invasion (p = 0.016), Child‒Pugh class (A vs. B, p = 0.001; A vs. C, p < 0.001), sarcopenia (p = 0.034), and the CRAFITY score (p = 0.011). Based on independent risk factors (MAcrovascular invasion, Child‒Pugh class, Sarcopenia, and the CRAFITY score) identified by multivariate analysis, a novel efficacy predictive tool named the MAPS-CRAFITY score was developed to predict OS. In all the training and validation cohorts, the OS differed significantly across the three groups based on the MAPS-CRAFITY score (< 2.1, 2.1-2.3, ≥ 2.4; p < 0.001). Moreover, the C-index of the MAPS-CRAFITY score was 0.720 and 0.761 in the training and validation cohorts, respectively. In both the validation and training cohorts, the MAPS-CRAFITY score was predictive of tumor response and disease control (p < 0.001). The AUCs of the MAPS-CRAFITY score for predicting disease control were 0.752 in the training cohort and 0.836 in the validation cohort. The MAPS-CRAFITY score based on sarcopenia and the CRAFITY score is a reliable and practical tool for predicting the efficacy of targeted therapy plus immunotherapy in patients with unresectable HCC, and may help hepatologists and oncologists in clinical decision-making.

Cytokines in Liver Cirrhosis (Their Importance in Assessing Activity and Decompensation)

Aim: studying the role of pro-inflammatory and anti-inflammatory cytokines in the pathogenesis of liver cirrhosis progression.Materials and methods. The material of the study was the data of clinical-instrumental, biochemical, virological studies of 109 patients with liver cirrhosis of various etiologty, who were hospitalized in the clinic of the Institute of Gastroenterology (Dushanbe, Republic of Tajikistan). The diagnosis of the underlying disease was established according to the clinical recommendations of the Russian Society for the Study of the Liver and the Russian Gastroenterological Association for the diagnosis and treatment of liver fibrosis and cirrhosis and their complications (2021); decompensated liver cirrhosis was established according to the 1996 Child — Pugh classification. The age of the patients ranged from 17 to 79 years (36.9 ± 0.8 years), there were 55 men and 54 women.Results. Among the examined patients, compensated liver cirrhosis (Class A) according to Child — Pugh was detected in 18 persons, subcompensated (Class B) — in 14, decompensated (Class C) — in 77. The study of the content of pro-inflammatory and anti-inflammatory cytokines in the blood serum of patients with Class A liver cirrhosis showed, that levels of tumour necrosis factor alpha (TNF-α), interleukin-2, interleukin-6 were statistically higher compared to healthy individuals, while the concentration of anti-inflammatory interleukin-10 was lower (30.7 ± 4.7 pg/mL) in comparison with the control group. In patients with Class B liver cirrhosis, the level of TNF-α increased to 75.0 ± 4.5 pg/mL (p &lt; 0.001), interleukin-2 — to 328.7 ± 23.9 pg/mL (p &lt; 0.05), and interleukin-6 — to 95.4 ± 7.7 pg/mL (p &lt; 0.001). Serum interleukin-10 decreased compared with the control group (23.1 ± 2.8 pg/mL; p &gt; 0.05). At the decompensated stage of Class C cirrhosis, a huge release of pro-inflammatory cytokines occurs — the content of TNF-α increases by 80 times, of interleukin-2 — by more than 60 times, аs for interleukin-10, its content is progressively reduced.Conclusion. In liver cirrhosis, there is a significant disruption in the synthesis of pro-inflammatory cytokines, which is manifested by a sharp increase in the content of TNF-α, interleukin-2 and interleukin-6. High levels of proinflammatory cytokines in blood serum in liver cirrhosis correlate with the activity and degree of decompensation, which indicates their important role in the pathogenesis and progression of the pathological process.

Nestin, CD44, Ki-67, GS and AQP4 expression in the brain neurogenic niches of deceased patients with liver cirrhosis of different degree

The aim of the study. Immunohistochemical study of Nestin, CD44, Ki-67, GS, AQP4 expression in the subventricular zone of the lateral ventricle and hippocampus of deceased patients with liver cirrhosis depending on the age and Child–Pugh score. Materials and methods. The brains of 90 deceased patients aged 65 ± 3 years with non-alcoholic liver cirrhosis (LC) Child–Pugh class A, B and C were studied, which comprised 3 groups: group “A” – 30 deceased patients with compensated LC; “B” – 30 deceased patients with subcompensated LC (“mild decompensation”); “C” – 30 deceased patients with decompensated LC. Control group included brains of 30 patients died from acute cardiovascular failure and did not have liver disease. Each group was divided into 2 subgroups: patients ≤59 y. o. and patients ≥60 y. o. Grade 1–4 hepatic encephalopathy was detected in 59 out of 90 (65.55 %) patients with LC. The immunohistochemical levels of Nestin, CD44, Ki-67, GS and AQP4 were evaluated in paraffin tissue sections of the subventricular zones (SVZ) of the anterior and lower horns of the brain lateral ventricles, as well as the subgranular zone (SGZ) of the dentate gyrus (DG) and other structures of hippocampus in standardized fields of view of the microscope Scope A1 Carl Zeiss (Germany) using Videotest-Morphology 5.2.0.158 software. Results. In SVZ of control subgroups, Nestin+ astrocyte-like stem cells were localized mainly in subventricular glial nodules (SGN) and to a lesser extent in astrocytic ribbon. In brains of patients with compensated and subcompensated LC, there was increased Nestin expression compared to control (by 61.36 % and 208.74 %, respectively) due to increased numbers of Nestin+ cells in astrocytic ribbons. In the hippocampus of control and cirrhotic patients, Nestin expression was determined mainly in astrocyte-like cells of the fimbria-fornix, “glial plates” around the blood vessels entering the choroid plexus and subpial zone. In the SVZ of patients with subcompensated LC, the expressions of Nestin, CD44, and Ki-67 were maximally increased (by 208.74 %, 37.83 %, and 3 times, respectively), moreover, in the areas of periventricular reparative astrogliosis, in small foci of encephalolysis in the head of caudate nucleus, among GS+ and CD44+ astrocytes clusters of astrocyte-like Nestin+ and CD44+ cells were detected. In patients with decompensated LC, a significant decrease in Nestin and CD44 expression and absence of Ki-67 were observed in the SVZ, with a simultaneous maximum increase in the expression of GS and AQP4. Conclusions. In the neurogenic niches of the lateral ventricles and hippocampus of patients with compensated and subcompensated LC, there are signs of activation of neural stem cells and niche astrocytes with increased expression of Nestin, CD44, and Ki-67, which reaches maximum in subcompensated LC. Clusters of astrocyte-like Nestin+ and CD44+ cells appear in foci of periventricular repair, which probably migrate from active adjacent subventricular niche. In the brains of the patients with decompensated LC and severe Grade 3–4 hepatic encephalopathy, deep astrocytic dysmetabolic dystrophy is associated with substantial decrease in the activity of subventricular stem niche and expected astrocytogenesis.

Significance of Plasma Osteopontin in Diagnosis of Hepatitis C Virus Related Hepatocellular Carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Hepatocellular carcinoma is the sixth most common neoplasm and the third most frequent cause of cancer death. More than 700 000 cases of this malignant disease were diagnosed in 2008, with an age-adjusted worldwide incidence of 16 cases per 100 000 inhabitants. Hepatocellular carcinoma is the leading cause of death among patients with cirrhosis. Aim of the Work The aim of this study is to assess the diagnostic value of plasma OPN in the diagnosis of HCC among hepatitis C virus (HCV)-related LC. Patients and Methods Plasma levels of OPN will be measured in 20 healthy controls and 70 Egyptian patients with HCV-related LC. Patients will be divided into 2 groups: Group 1: 35 HCV patients with liver cirrhosis and HCC. Group 2: 35 HCV patients with liver cirrhosis without HCC. Result There was statistically significant difference between the studied groups as regard sex. There was highly significant difference between the studied groups as regard CBC. As regard HB there was highly significant difference between (control and group 1) and (control and group 2) and significant difference between (group 1 and group 2). As regard INR there was highly significant difference between (control and group 1) and (control and group 2). As regard Platelets there was highly significant difference between (control and group 1) and (control and group 2) and significant difference between (group 1 and group 2). There was highly significant difference between the studied groups as regard Albumin and Total Bilirubin and significant difference as regard ALT and ALP. There was no significant difference between the studied groups as regard Child–Pugh class. There was highly significant difference between the studied groups as regard OPN. Using roc curve, it was shown that OPN level can be used to discriminate between patients and controls at a cutoff level of &amp;gt; 146.9, with 60% sensitivity, 97.14% specificity, 95.5% PPV and 70.8% NPV. Conclusion OPN level can be used to discriminate between patients and controls at a cutoff level of &amp;gt; 146.9, with 60% sensitivity, 97.14% specificity, 95.5% PPV and 70.8% NPV.