Systemic Therapies for Hepatocellular Carcinoma in India.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio of ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies such as ramucirumab and bevacizumab and immune-checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care. Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.

Efficacy and safety of pantoprazole and itopride in patients with overlap of gastroesophageal reflux disease and dyspepsia: A prospective, open-label, single-arm pilot study.

Background and Aim: Combining proton pump inhibitors (PPIs) with prokinetics can provide synergistic action in patients with gastroesophageal reflux disease (GERD) and overlapping dyspepsia, but data regarding this is lacking. Methods: This single-center, prospective study evaluated the efficacy and safety of 6-week treatment with fixed-drug combination (FDC) of pantoprazole (PPI) and itopride (prokinetic) in 50 patients with ≥3 month history of GERD and overlapping dyspepsia refractory to pantoprazole. Efficacy was assessed as reduction in GERD symptom assessment scale (GSAS) distress score for 15 symptoms from baseline to week 6. Adverse events (AEs) were monitored up to week 6. Results: Although heartburn was the most common symptom at week 6 (26.8%), its frequency significantly decreased from baseline (84.0%; P <0.01). A similar trend was observed for other symptoms: pressure/discomfort inside chest (19.5%), belching (14.6%), regurgitation (12.2%), bloating (9.8%), flatulence (9.8%), early satiety (7.3%), acidic/sour taste in mouth (7.3%), nausea (7.3%), frequent gurgling in stomach/belly (4.9%), and pressure/lump in throat (2.4%). Mean distress scores of all symptoms markedly decreased at week 6. Three AEs (n = 2) of moderate intensity were reported. Conclusion: The FDC of pantoprazole and itopride showed favorable efficacy and safety in patients with GERD and overlapping dyspepsia refractory to pantoprazole monotherapy. Nevertheless, further studies are warranted.

Myosteatosis for Early Detection of Muscle Disorder in Patients With Liver Cirrhosis.

Background and aims: Muscle disorders in cirrhosis are associated with poor outcome and need early identification. Anthropometric measures lack sensitivity, and CT-based L3-skeletal muscle Index (L3-SMI) may miss early sarcopenia. The study aimed to find if SM-RA can identify more patients with muscle disorder than L3-SMI and anthropometry. Methods: 388 patients with cirrhosis underwent nutritional assessment by anthropometry, short-physical-performance-battery (SPPB) < 9, L3-SMI (<36.5 cm2/m2 (males); <30.2 cm2/m2 (females), and myosteatosis assessment by skeletal muscle radiation attenuation (SM-RA) (<41 HU for body mass index [BMI] <24.9 kg/m2 and <33 HU for ≥25 kg/m2) and results were compared. Results: Sarcopenia based on SPPB was 38.9 % with scores (9 ± 1.48 vs. 10.74 ± 1.25, P = 0.001 in males; and 8.43 ± 1.59 vs. 9.89 ± 1.57, P = 0.001 in females). Mid-arm muscle circumference was lower in sarcopenic males [20.5 ± 2.42 vs. 22.9 ± 2.19 cm, P = 0.001] but not in females [19.4 ± 2.73 vs. 21.1 ± 2.51, P = 0.18]. L3-SMI-based sarcopenia was found in 44.8 % (additional 5.92 %) compared to SPPB, mostly in cryptogenic cirrhosis (19.2 % vs. 35.08 %, δ change +15.9 %). Myosteatosis (71.64 %) identified an additional 26.85 % and 32.74 % of patients with muscle disorder compared to L3SMI and SPPB, respectively, with the majority of new detection in non-alcoholic fatty liver disease (NAFLD) 39.4 % vs. 77.06 %, δ change +37.66 %) CTP-A patients (16.6 % vs. 36.8 %, δ change +20.2 %). Myosteatosis was found in 48.3 % of patients with normal L3-SMI. Conclusion: SM-RA can identify more patients with muscle disorder than L3-SMI and SPPB.

Safety and Efficacy of Atezolizumab-Bevacizumab in Real World: The First Indian Experience.

Background: Atezolizumab-bevacizumab (atezo/bev) combination is a recommended first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). There are no studies from India reporting the safety and efficacy of this drug in real-world settings where most patients present in an advanced stage. Methods: In this retrospective study from two centers in India, we included patients with uHCC who received atezo/bev as first-line systemic therapy. Comparison of overall survival (OS) among the different Child-Turcotte-Pugh (CTP) classes was the primary objective, while progression-free survival (PFS), radiologic response, and adverse events to the therapy were secondary objectives. Results: The median age of the 67 patients who received atezo/bev therapy was 61 (29-82) years, and 86% were males. Nonalcoholic steatohepatitis (55.2%) was the commonest cause of cirrhosis, and most patients belonged to BCLC-C (74.6%%). There were 24 patients in CTP A, 36 in CTP B, and 7 in CTP C. The median OS was 12 (95%CI, 8.16-15.83) months in the cohort. The median OS in CTP class A, B, and C was 21 (95%CI, 0-42.06) months, 9 (95%CI, 5.46-12.53) months, and 4 (95%CI, 2.14-5.85) months, respectively (P < 0.001). The median PFS in the whole cohort was 8 (95%CI, 6.03-9.96) months. The median PFS in Child A, B, and C was 18 (95%CI, 0.16-35.84) months, 8 (95%CI, 6.14-9.85) months, and 2 (95%CI, 1.77-2.23) months (P < 0.001). On mRECIST evaluation, 12.9% had achieved a complete response, 25.8% had a partial response, 27.41% had stable disease, and the rest had progressed. The objective response rate was 38.7%, and the disease control rate was 66.12%. Of the 64% who developed adverse events, 13.43% discontinued the drug. The incidence of grade ≥3 events was significantly higher in CTP C (85.7%) compared to CTP A (12.5%) and CTP B (14%) (P < 0.001). Conclusions: Atezolizumab-bevacizumab is safe and effective in uHCC in real-world settings. Candidate selection is of utmost importance in treating uHCC with atezolizumab-bevacizumab to achieve a good response. Current evidence strongly suggests limited use of atezolizumab-bevacizumab in patients with CTP C, and such individuals should not be considered for this combination therapy.

Presence of pseudo-Kayser-Fleischer rings in patients without Wilson disease: a prospective cohort study.

BACKGROUND AND AIMS: Kayser-Fleischer (KF) rings are due to copper deposition in Descemet membrane of the cornea in Wilson disease. Pseudo-KF ring (PKF), seen in patients with high bilirubin, is often misinterpreted as KF rings. These are bilirubin deposits in posterior corneal stroma. The aim of the study was to prospectively evaluate the presence of KF and PKF rings in Wilson disease and non-Wilsonian liver disease with serum bilirubin >5 mg/dL. METHODS: All patients referred from the hepatology unit with serum bilirubin >5 mg/dL were assessed by slit-lamp examination (SLE) and anterior segment optical coherence tomography at baseline, 3 months, and 6 months for differences in corneal deposits between KF and PKF rings. All other clinical, laboratory, radiological, genetic, and tissue diagnoses by liver biopsy were done as required to confirm the cause of liver disease. RESULTS: Among the 750 patients examined, corneal deposits were present in 13%, KF rings as granular deposits in 31.7%, and PKF as a posterior stromal hue in 68.3% of cases. PKF rings showed regression in 60%, disappearance in 36.6% at 3 months, and in 100% of cases at 6 months. KF ring showed regression in 10.7% and 8.3% until 6 months. Anterior segment optical coherence tomography identified KF ring as a hyperintense line on Descemet membrane in an additional 9.7% of patients compared with a scattered hyperintense hue in PKF rings. CONCLUSIONS: The presence of PKF rings in patients with jaundice is not uncommon and should be differentiated from true KF rings. Serial monitoring is essential to look for resolution, and anterior segment optical coherence tomography may be additionally helpful.

Application of Deep Learning Models to Improve Ulcerative Colitis Endoscopic Disease Activity Scoring Under Multiple Scoring Systems.

BACKGROUND AND AIMS: Lack of clinical validation and inter-observer variability are two limitations of endoscopic assessment and scoring of disease severity in patients with ulcerative colitis [UC]. We developed a deep learning [DL] model to improve, accelerate and automate UC detection, and predict the Mayo Endoscopic Subscore [MES] and the Ulcerative Colitis Endoscopic Index of Severity [UCEIS]. METHODS: A total of 134 prospective videos [1550 030 frames] were collected and those with poor quality were excluded. The frames were labelled by experts based on MES and UCEIS scores. The scored frames were used to create a preprocessing pipeline and train multiple convolutional neural networks [CNNs] with proprietary algorithms in order to filter, detect and assess all frames. These frames served as the input for the DL model, with the output being continuous scores for MES and UCEIS [and its components]. A graphical user interface was developed to support both labelling video sections and displaying the predicted disease severity assessment by the artificial intelligence from endoscopic recordings. RESULTS: Mean absolute error [MAE] and mean bias were used to evaluate the distance of the continuous model's predictions from ground truth, and its possible tendency to over/under-predict were excellent for MES and UCEIS. The quadratic weighted kappa used to compare the inter-rater agreement between experts' labels and the model's predictions showed strong agreement [0.87, 0.88 at frame-level, 0.88, 0.90 at section-level and 0.90, 0.78 at video-level, for MES and UCEIS, respectively]. CONCLUSIONS: We present the first fully automated tool that improves the accuracy of the MES and UCEIS, reduces the time between video collection and review, and improves subsequent quality assurance and scoring.

Post-COVID-19 Cholestasis: A Case Series and Review of Literature.

Background: Coronavirus disease-2019 (COVID-19) cholangiopathy is a recently known entity. There are very few reports of liver transplantation (LT) for COVID-19-induced cholangiopathy. It is well known that vaccines can prevent severe disease and improve outcomes. However, there are no reports on the impact of COVID-19 vaccines on cholestasis. Therefore, we aimed to compare the course and outcome of patients who developed cholestasis following COVID-19 infection among vaccinated and unvaccinated individuals. Methods: Patients diagnosed with post-COVID cholestasis during the pandemic were included in the study after excluding other causes of cholestasis. Results: Eight unvaccinated and seven vaccinated individuals developed cholestasis following COVID-19 infection. Baseline demographics, presentation, severity, and management of COVID-19 were similar in both groups. However, patients in the unvaccinated group had a protracted course. The peak ALP was 312 (239-517) U/L in the vaccinated group and 571.5 (368-1058) U/L in the unvaccinated group (P = 0.02). Similarly, the peak γ-glutamyl transpeptidase values were lower in the vaccinated (325 [237-600] U/L) than in the unvaccinated group (832 [491-1640] U/L; P = 0.004). However, the peak values of total bilirubin, transaminases, and INR were similar in both groups. Five patients developed ascites gradually in the unvaccinated group whereas none in the vaccinated group developed ascites. Plasma exchange was done in five patients, and two were successfully bridged to living donor LT in the unvaccinated group. Only two patients recovered with conservative management in the unvaccinated group, whereas all recovered with conservative management in the vaccinated group. The other four patients in the unvaccinated group were planned for LT. Conclusion: Post-COVID-19 cholestasis is associated with high morbidity and mortality, meriting early identification and appropriate management. Vaccination can modify the course of severe COVID-19 infection and improve outcomes.

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

Evaluation of ultrasound based acoustic radiation force impulse (ARFI) and eSie touch sonoelastography for diagnosis of inflammatory pancreatic diseases.

CONTEXT: Pathology changes the consistency of the tissues. OBJECTIVE: To prospectively assess the accuracy of per-abdominal US elastography in the form of acoustic radiation force impulse--virtual touch tissue quantification (ARFI-VTQ) and eSie touch elasticity imaging in characterizing and differentiating inflammatory pancreatic diseases. PATIENTS: One-hundred and 66 patients from among the patients that visited the Asian Institute of Gastroenterology, Hyderabad, India, during the period April 2009 to December 2010, for master health check-up, blood donation and those with pancreatic pathology. SETTING: Based on the clinical symptomatic criteria and diagnostic imaging findings, the patients were divided into normal, chronic and acute, or acute resolving, pancreatitis group. MAIN OUTCOME MEASURES: The ultrasound based ARFI-VTQ and eSie touch elasticity imaging techniques were applied. DESIGN: Prospective single-center study. RESULTS: The mean ARFI-VTQ values were 1.28 m/s, 1.25 m/s and 3.28 m/s for the normal, chronic and acute pancreas, respectively. The eSie touch gray scale and color elastograms were light gray and purple-greenish, respectively for both normal and chronic pancreas, while for acute pancreas the elastograms were dark black on the gray scale and orange to red on color scale. CONCLUSION: Both the ARFI-VTQ and eSie touch elasticity imaging techniques may be successfully adopted in order to diagnose acute pancreatitis, to assess extent of inflammation (whether focal or diffuse), to assess peripancreatic edema, to identify presence of necrotic areas and early pseudocyst formation, to early diagnose acute recurrent attacks and to monitor patient's response to treatment.