Real world experience of drug-drug interactions for HCV patients receiving pan-genotypic direct-acting antivirals in the era of COVID-19 pandemic

Background and Aims: The treatment of chronic hepatitis C (CHC) has evolved from genotype-specific to pan-genotypic direct acting antivirals (DAAs) with high efficacy and safety. However, drug-drug interactions (DDIs) must be avoided when used in combination with other medications, especially with the possible concomitant use of COVID-19 infection antivirals during the COVID-19 pandemic. This study aimed to access the potential DDIs of concomitant drugs with pan-genotypic DAAs and COVID-19 infection antivirals, and actual incidence of DDIs in real-world experience. Method(s): From January 2022 to October 2022, consecutive 116 HCV patients receiving pan-genotypic DAAs were retrospectively enrolled in Taipei Veterans General Hospital. The number of comedications and their potential DDIs with three pan-genotypic DAA regimens and three COVID-19 infection antivirals were analyzed. The actual incidence of DDIs during DAAs treatment were also investigated. Result(s): The mean age was 60.9 years old, with male predominant (55.2%). Of them, 12 (10.3%) patients had cirrhosis, and 24 (20.7%) patients had diabetes mellitus. Most patients were within Child-Pugh class A (109/116, 94.0%). The distribution of HCV genotypes was 8.6% in GT 1a, 36.2% in GT 1b, 39.7% in GT 2, 6.9% in GT 6, and 8.6% in indeterminate genotype, respectively. Of them, 43 (37.1%) patients received GLE/PIB, 69 (59.5%) received SOF/VEL 7plusmn;RBV, and 4 (3.4%) received SOF/VEL/VOX as DAAs regimen. Noteworthy, four patients had COVID-19 infection during DAAs treatment course. The rates of ETVR and SVR12 were 97.6% and 95.3%. The mean number of concomitant medications was 2.01. The distribution of concomitant drugs was 64.7% with no concomitant drug, 11.2% with 1-3 drugs, 11.2% with 4-6 drugs, 9.5% with 7-9 drugs, and 3.4% had more than 9 drugs, respectively. In potential contraindicated (red) DDI class, GLE/PIB was the most prevalent (7.3%), followed by SOF/VEL/VOX (6.4%), and SOF/VEL (1.8%) for non-cirrhosis and compensated cirrhosis patients;and no red DDI occurred in decompensated cirrhosis patients. In addition, the percentage of patients without potential DDIs was higher with SOF/VEL (79.8%) than with the other regimens. The potential red DDIs were predominantly with lipid-lowering agents for DAAs. For potential red DDI class with COVID-19 infection antivirals, Nirmatrelvir/Ritonavir was the most prevalent (6%), followed by Remdesivir (0.9%), and no potential DDIs with Molnupiravir. For COVID-19 antivirals, the potential red DDIs was mainly with central nervous system drugs. Finally, the actual incidence of DDIs during DAAs treatment showed no red DDI occurred for all patients, and GLE/PIB was the most prevalent (93%) of no potential DDIs. Conclusion(s): The potential DDIs between these comedications differed, with the most potential DDIs occurring with GLE/PIB and Nirmatrelvir/Ritonavir. After careful assessment of comedications and their potential DDIs, the actual incidence of DDIs could be reduced, and optimize safety in real-world practice.

Ablation for hepatocellular carcinoma (HCC)

Ablation includes ethanol injection, radiofrequency ablation (RFA), microwave ablation (MWA), etc. Ablation can be potentially curative, minimally invasive and easily repeatable for recurrence. RFA has been the most widely used ablation technique for liver tumors. The new-generation MWA system incorporating antenna cooling and high-power generation has attracted attention. It can create a more predictable ablation zone and a larger ablation volume in a shorter procedure time. Many high-volume centers have introduced new-generation MWA in Japan. However, many studies failed to show that new-generation MWA is superior to RFA in terms of local control and overall survival. In MWA, clinical data have been insufficient compared with those of RFA. There has been keen competition between surgical resection and ablation for almost 40 years since the era of ethanol injection. In 2021, SURF trial revealed that overall survival and recurrence-free survival were not significantly different between surgical resection and RFA. SURF trial was a multicenter randomized controlled trial in which 49 major centers in Japan enrolled patients with good hepatic function (Child-Pugh scores <= 7) and primary HCC of largest diameter <= 3 cm, and <= 3 nodules during the 6-year period of 2009-2015. The registered patients were followed for at least 5 years. As the result of SURF trial and other comparative studies, the revised Japanese clinical practice guidelines in 2021 treats hepatic resection and ablation equally for patients with <= 3 lesions, <= 3 cm in diameter. Recently, the combination of systemic and locoregional therapies has been attracting much attention. Systemic therapy using molecular targeted agents or immune checkpoint inhibitors is used for advanced HCC which cannot be treated by surgery or ablation. On the other hand, some locoregional therapies, such as hepatectomy and ablation, are potentially curative, but they cannot be indicated for advanced HCC. Combination of both therapies is an approach to improve the prognosis of advanced HCC, which is not indicated for curative treatment. Systemic therapy is used to shrink the tumor, and then locoregional therapies are performed to eradicate it. The combination may build a new strategy for advanced HCC. Ablation is highly operator-dependent. The skills and outcomes are very different from operator to operator. Before the pandemic of COVID-19, we held domestic and international training programs for intermediate and advanced doctors and hands-on seminars for young doctors. These were activities to exchange knowledge and experience and standardize the procedure. During the pandemic, we cannot get together. Since August 2020, we have conducted Japan Ablation Webinar 8 times with a total of 1,566 participants. We have also conducted International Ablation Webinar 4 times with a total of 1,272 participated doctors. Education is important to acquire skills and knowledge for successful ablation. We have established Japan Academy of Tumor Ablation (JATA) this year. There are two triggers. One is that SURF trial revealed that there is no difference between hepatectomy and ablation. The other is that ablation for lung, bone and soft tissue and kidney cancers has become reimbursed with health insurance since this September.

Pre-existing chronic liver disease is associated with poor outcome in patients with SARS-CoV2 infection

COVID-19 is characterized by predominant respiratory and gastrointestinal symptoms. Liver enzymes derangement is seen in 15-55% of the patients. Cirrhosis is characterized by immune dysregulation, leading to concerns that these patients may be at increased risk of complications following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with metabolic dysfunction-associated fatty liver (MAFLD) had shown a 4-sixfold increase in severity of COVID-19, and its severity and mortality increased in patients with higher fibrosis scores. Patients with chronic liver disease had shown that cirrhosis is an independent predictor of severity of COVID-19 with increased hospitalization and mortality. An international European registry study included 756 patients with chronic liver disease from 29 countries reports high mortality in patients with cirrhosis (32%). Data of 228 patients collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19 (APCOLIS study) showed that SARSCoV- 2 infection produces acute liver injury in 43% of CLD patients without cirrhosis. Additionally, 20% of compensated cirrhosis patients develop either ACLF or acute decompensation. In decompensated cirrhotics, the liver injury was progressive in 57% of patients, with 43% mortality. Patients with CLD and associated diabetes and obesity had a worse outcome. Liver related complications were seen in nearly half of the decompensated cirrhotics, which were of greater severity and with higher mortality. Increase in Child Turcotte Pugh (CTP) score and model for end-stage liver disease (MELD) score increases the mortality in these patients. In a subsequent study of 532 patients from 17 Asian countries was obtained with 121 cases of cirrhosis. An APCOLIS risk score was developed, which included presence of comorbidity, low platelet count, AKI, HE and respiratory failure predicts poor outcome and an APCOLIS score of 34 gave a sensitivity and specificity of 79.3%, PPV of 54.8% and NPV of 92.4% and predicted higher mortality (54.8% vs 7.6%, OR = 14.3 [95 CI 5.3-41.2], p<0.001) in cirrhosis patients with Covid-19. The APCOLIS score is helpful in triaging and prognostication of cirrhotics with Coivd-19. The impact of COVID-19 on patients with cirrhosis due to non-alcoholic fatty liver disease (NASH-CLD) was separately studied in 177 NASH-CLD patients. Obese patients with diabetes and hypertension had a higher prevalence of symptomatic COVID. Presence of diabetes [HR 2.27], fraility [HR 2.68], leucocyte counts [HR 1.69] and COVID-19 were independent predictors of worsening liver functions in patients with NASH-CLD. Severity of Covid in Cirrhosis could also be assessed by measuring ICAM1 the Intercellular Adhesion Molecule, an indicator of Endothelial Injury Marker. in Cirrhosis with Covid 19 Immunosuppression should be reduced prophylactically in patients with autoimmune liver disease and post-transplantation with no COVID-19. Hydroxychloroquine and remdesivir are found to be safe in limited studies in a patient with cirrhosis and COVID-19. And is safe in cirrhosis patients. However, flare of AIH has been reported in AIH patients. For hepatologists, cirrhosis with COVID-19 is a pertinent issue as the present pandemic cause severe disease in patients with chronic liver disease leading to more hospitalization and decompensation.

Final results of a phase 1b/2 study of tivozanib in combination with durvalumab in patients with advanced hepatocellular carcinoma in both previously untreated patients and patients progressing on atezolizumab and bevacizumab

Background: The approval of atezolizumab + bevacizumab for untreated advanced HCC was a significant benefit for patients, but with an increased risk of potentially severe bleeding complications. Tivozanib (a selective VEGFR 1, 2, & 3 tyrosine kinase inhibitor [TKI]) has been combined with durvalumab in the DEDUCTIVE study;preliminary results presented in January 2022 showed that this combination was well tolerated with comparable efficacy to other immune checkpoint and VEGF containing regimens in patients with previously untreated HCC (J Clin Oncol 40, no. 4 suppl 462-462). We now report the final results of this cohort (cohort A) of patients as well as those with previously treated HCC, including safety results for all the patients. Method(s): Major eligibility criteria included age .18 yrs with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, and creatinine clearance .40 ml/min. Major exclusion criteria included co-infection with HBV and HCV and significant organ dysfunction. Patients were treated with 0.89 mg tivozanib p.o., 21 days on followed by 7 days off and 1500 mg durvalumab i.v. every 28 days. The primary objective was to determine the safety and tolerability of this combination in patients with advanced HCC;secondary objectives included assessing objective response rate (ORR), progression free survival, and overall survival (OS). The study was amended in 2021 to include a cohort of patients previously treated with atezolizumab and bevacizumab (cohort B). Result(s): 21 patients were enrolled in cohort A and 6 in cohort B;the median age was 67, 88% of patients were male, and 24% were Asian. The median followup time was 13.2 mos and 3.4 mos for cohorts A and B, respectively. Data were available for 25 of the 27 patients enrolled. For cohort A, the ORR was 25% (5/20) and 1-year OS was 76%. For safety analysis, 24 (96%) patients had at least 1 treatment-emergent adverse event (TEAE);92% were attributed possibly to either tivozanib or durvalumab;32% were serious TEAEs and there was 1 TEAE leading to death (unrelated). Of the 8 (32%) serious TEAE, 2 were coronavirus infection. 2 patients had serious (grade 3) treatment-related AEs: 1 pneumonitis and 1 with gastrointestinal hemorrhage and anemia. There were no grade 4 or 5 treatment-related AEs. Conclusion(s): Treatment with the combination of tivozanib and durvalumab in patients with either untreated advanced HCC or those previously treated with atezolizumab and bevacizumab was well tolerated;no severe bleeding events occurred in this study. Efficacy outcomes were comparable to other IO-TKI combinations in HCC. Data for PDL1 status, HBV/HCV status was collected and will be presented along with final safety and efficacy results for both cohorts.

Response assessment and clinical efficacy of 188Re-NDEDC/ Lipiodol trans-arterial Radionuclide therapy (TART) in patients with Hepatocellular carcinoma: A prospective single center study

Aim/Introduction: Inoperable HCC patients with multifocal lesions and malignant portal vein thrombosis (PVT) have poorer prognosis with limited treatment options. 188Re-N-DEDC lipiodol is an emerging agent for such cases due to its simple and on-site labelling procedure, cost-effectiveness and least radiation induced side effects. We aimed to explore the response assessment, safety and efficacy of 188Re-N-DEDC-lipiodol in multifocal HCC with/without PVT. Material(s) and Method(s): Radiologically and biochemically confirmed HCC patients with/without PVT having ECOG performance status <=2 and Child Pugh score A /B were recruited. Baseline serum alpha-fetoprotein (AFP) was obtained for biochemical correlation and follow-up. After lipiodol labelling & QC checks, therapeutic activity of 188Re-N-DEDC/lipiodol were injected under fluoroscopic guidance through femoral branch in super-selective artery of tumor. Post-therapy planar and SPECT/CT imaging were performed at 2, 6, 12, 24, 48 and 72hrs to see tumoral retension. Response was assessed at 2 months post-therapy by mRECIST criteria and S. AFP level. Clinical & biochemical toxicities were graded by CTCAE v5.0. Result(s): Thirty-One (31) patients (27 male;4 female) with mean age 55.9 +/- 9.78 years have been recruited for therapy. Overall mean injected activity of 188Re-N-DEDC lipiodol was 2.9+/-0.9GBq (78.4+/-24.2mCi). The median follow-up period was of 6 months. One patient was lost to follow-up due to prevailing COVID situations and 3 patient died before follow-up due to internal variceal bleeding, so radiological and biochemical response were assessed only in 27/31 patients by mRECIST criteria and serum AFP tumor marker level respectively. Radiologically, objective response rate was seen in 12/27 patients (~45%) and disease control rate was seen in 20/27 patients (~74%). 6/27 patients had non-AFP producing tumor i.e. serum AFP were normal at baseline and follow-ups while in remaining 21 patients, biochemical objective response rate was seen in 11/21 patients (~52%) and disease control rate was 14/21 patients (~67%). Post-therapy clinical toxicities (Nausea, Vomiting, Fever, abdominal pain) were observed in most of the patients for 2-3 days and were treated symptomatically. One patient showed grade 3 liver toxicity & progressive worsening of LFT, 20 patients showed grade 1 derangements in liver enzymes & 6 patients showed grade 2 derangements in liver enzymes. Hematological toxicities were seen in 4 patients (<=Grade 2 in 2 patients & grade 3 in two patients). Conclusion(s): In patients of HCC with/without PVT, trans-arterial Re188-N-DEDC/lipiodol therapy proved to be safe and effective with good disease control.

Predictors of Bradycardia with Dexmedetomidine Use

INTRODUCTION: Although dexmedetomidine is a widely used sedative in the ICU, risk factors for bradycardia associated with dexmedetomidine use are not well characterized. Identifying factors that place a patient at increased risk for bradycardia with dexmedetomidine use may help guide interventions or limit complications associated with the medication's negative chronotropic effects. The aim of this analysis is to determine risk factors for development of bradycardia with dexmedetomidine use. METHOD(S): This single center, retrospective nested casecontrol included adult patients in cardiac and non-cardiac intensive care units with an intravenous dexmedetomidine duration of at least 1 hour. A univariate analysis was used to compare patients with and without bradycardia with dexmedetomidine use, and a predictive model was used to evaluate factors associated with bradycardia. Step-down backward variable selection was used based on Akaike's Information Criterion (AIC) and Bayesian Information Criteria (BIC) to identify the final model. The discriminatory power and absolute predictive ability of the final model was evaluated by the concordance index (c-index), which was internal validated by bootstrapping. Multiple imputation was performed before model selection to fill in missing values in pulse at initiation and Child Pugh Score before modeling. RESULT(S): Of the 1,838 patients receiving dexmedetomidine, 110 patients (6.0%) developed bradycardia within 72 hours of initiation. In patients that experienced bradycardia, 31 (28.1%) required an intervention. The initial full predictive model for bradycardia included age, sex, BMI, COVID19 positive test, hypothermia, pulse at initiation, ICU location (Cardiac vs non-cardiac), Child Pugh Score, use of fentanyl and propofol. Step-down backward variable selection identified 4 predictors in the final model, including COVID positive test, hypothermia, pulse at initiation, and ICU location. The final model achieved a good performance in discriminatory capability (c-index: 0.758, 95%CI 0.713-0.806) using the smallest number of predictors. CONCLUSION(S): Patients with COVID-19, hypothermia, non-cardiac ICU locations and lower pulse at initiation are at increased odds of developing bradycardia. Recognition of risk may be used to guide monitoring or alternative sedation strategies.

Safety and efficacy of atezolizumab (Atezo) + bevacizumab (Bev) in Japanese patients (pts) with unresectable hepatocellular carcinoma (uHCC): A prospective, multicenter, observational study (ELIXIR) - A preliminary analysis

Background: Atezo + Bev has been approved as first-line treatment in pts with uHCC based on a global phase 3 study (IMbrave 150). However, there is a lack of real-world data worldwide. Thus, we conducted the ELIXIR study to evaluate the safety and efficacy of Atezo + Bev prospectively in 500 real-world Japanese pts. Here, we report the first pre-planned safety assessment in 105 initially registered pts out of 500 pts. Method(s): In this prospective, multicenter, observational study, 500 systemic treatment-naive pts with uHCC and Child-Pugh A received Atezo 1200 mg IV q3w + Bev 15 mg/kg IV q3w. The primary endpoint was adverse events of special interest (AESI). Efficacy outcomes including progression-free survival (PFS) and objective response rate (ORR) were assessed in this analysis. Result(s): A total of 500 pts were enrolled between Apr 2021 and Feb 2022. One hundred and five initially registered pts finished enrollment by Aug 2021 and the median follow-up time was 6.4 mo. A total of 49 AESIs and 35 AESIs Grade >=3 were observed in these pts (Table). Median PFS was 6.0 mo (95% CI, 5.1, 6.7) per RECIST 1.1 and 6.5 mo (95% CI, 5.2, 8.0) per modified RECIST (mRECIST). ORR was 23.8% (95% CI, 16.0, 33.1) per RECIST 1.1 and 34.3% (95% CI, 25.3, 44.2) per mRECIST. [Formula presented]. Conclusion(s): In this analysis, additional safety signals were not observed in Japanese pts. Efficacy data could be underestimated at this time. The ELIXIR study showed that Atezo + Bev is a promising first-line treatment for Japanese pts with uHCC in the real world. Clinical trial identification: UMIN000043463. Editorial acknowledgement: Medical writing assistance for this was provided by Tetsuji Asao, PhD, of SunFlare Co., Ltd. Legal entity responsible for the study: Chugai Pharmaceutical Co., Ltd. Funding(s): Chugai Pharmaceutical Co., Ltd. Disclosure: M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Ono, Takeda, GlaxoSmithKline;Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, NIHON SERVIER, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, NIHON SERVIER, Takeda;Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, NIHON SERVIER, Delta-Fly Pharma, Syneos Health, Merus.N.V. N. Kato: Financial Interests, Personal, Invited Speaker: Gilead Sciences Inc., AbbVie G.K., Ohtsuka Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Olympus Corporation, Eisai Co., Ltd., Aska Pharmaceutical Co., Ltd., Tsumura & Co., Mochida Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Covidien Japan Inc., Eli Lilly Japan K.K., Nobelpharma Co., Ltd., Kowa Company, Ltd., Incyte Biosciences Japan GK, Yakult Honsha Co.,Ltd., Olympus Marketing, Inc., Taisho Pharmaceutical Co.,Ltd., Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Research Grant: AbbVie G.K., Ohtsuka Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Tsumura & Co., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd., Kowa Company, Ltd. T. Kagawa: Financial Interests, Personal, Invited Speaker: AbbVie, Eisai, Chugai, Sumitomo Pharma, Gilead, EA Pharma, Asuka, Takeda, Miyarisan, Otsuka, Eli Lilly, Kowa, Bayer;Financial Interests, Personal, Funding: AbbVie, Chugai, Sumitomo Pharma, Diichi Sankyo, Tanabe Mitsubishi, Takeda, MSD, Eisai, Shionogi, EA Pharma, Otsuka, Kyowa Kirin, Sanofi, Teijin, Eli Lilly. T. Yamashita: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Lilly, Bayer;inancial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, MSD, Ono. M. Moriguchi: Financial Interests, Personal, Invited Speaker: Eisai Co., Ltd., Bayer Yakuhin, Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd.;Financial Interests, Personal, Advisory Board: Eisai Co., Ltd., Bayer Yakuhin, Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd.;Financial Interests, Institutional, Funding: MSD K.K. Eisai Co., Ltd., Bristol Myers Squibb K.K., Bayer Yakuhin, Ltd. H. Iijima: Financial Interests, Institutional, Funding: Canon Medical systems, GE healthcare. K. Ohkawa: Financial Interests, Personal, Invited Speaker: Gilead, Eisai, Century Medical, Takeda;Financial Interests, Personal, Research Grant: Towa, Sumitomo Chemical. R. Sugimoto: Financial Interests, Personal, Invited Speaker, Speaker and moderator fees: Eisai Co, Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd.;Financial Interests, Personal, Invited Speaker, Speaker fees: Gilead Sciences, Chugai Pharmaceutical Co., Ltd.;Financial Interests, Personal, Invited Speaker, Speaker fees: Bayer Yakuhin Ltd, Nobelpharma Co., Ltd., Takeda Pharmaceutical Company Limited. T. Takehara: Financial Interests, Personal, Invited Speaker: Chugai;Financial Interests, Institutional, Research Grant: Chugai. M. Kudo: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Eli Lilly, Bayer, Takeda, MSD;Financial Interests, Institutional, Research Grant: Otsuka, Sumitomo Dainippon Pharma, EA Pharma, Taiho, Eisai, AbbVie, Gilead Sciences, Takeda, GE Healthcare, Chugai. K. Yamamoto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, CMIC holdings, Johokiko, Triceps, Kanagawa Medical Practitioners Association;Financial Interests, Personal, Other, Statistical analysis: Otsuka Pharmaceutical;Financial Interests, Personal, Other, Statistical consultation: J-Pharma, Craif, Kanagawa Prefectural Hospital Organization;Financial Interests, Institutional, Other, unlimited grant: Taiho Pharmaceutical;Financial Interests, Institutional, Other, Unlimited grant: Boehringer Ingelheim, Ono Pharmaceutical, Takeda Pharmaceutical, Bayer Yakuhin, Daiichi-Sankyo, Astellas, Kyowa Kirin, Data Vehicle Inc., EP Croit. All other authors have declared no conflicts of interest. Copyright © 2022

Clinical assessment of coagulation hemostasis in liver cirrhosis associated with COVID-19

Background: Since the beginning of the pandemic, our understanding of the hepatic repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection and the resulting coronavirus disease 2019 has significantly progressed. Aim(s): The primary objective of this study was to characterize coagulation hemostasis in patients with COVID-19- associated liver cirrhosis. Method(s): Our study involved 200 patients (confirmed COVID-19 ) with liver cirrhosis, decompensation stage, Child-Pugh class V as the objects of study. I group consisted of 50 patients with liver cirrhosis of HBV etiology, II group 30 patients with HBV + HDV liver cirrhosis, III groups 50 patients with cirrhosis of unknown etiology. The control group consisted of 20 healthy individuals. All patients were tested for coagulogram. Result(s): In group I, activated partial thromboplastin time was 18.4 +/- 2.3 c, prothrombin time was 9.5 +/- 0.6 c, prothrombin index was 126 +/- 6.4, and MNO was 0.79 +/- 0.03. In group II, activated partial thromboplastin time was 15.2 +/- 1.1 c, prothrombin time was 8.2 +/- 0.4 c, prothrombin index was 146 +/- 8.2, and the international normalized ratio was 0.68 +/- 0.02. In group III, was 12.2 +/- 0.8 c, prothrombin time was 7.9 +/- 0.4 c, prothrombin index was 152 +/- 10.4, and the international normalized ratio was 0.66 +/- 0.02. In the control group, activated partial thromboplastin time was 32 +/- 1.8 c, prothrombin time was 12.1 +/- 0.2 c, prothrombin index was 99 +/- 3.7, and the international normalized ratio was 1.01 +/- 0.06. Conclusion(s): To summarize, our findings demonstrate that severe COVID-19 infection is associated with coagulopathy, which is associated with a bad prognosis. COVID-19 coagulopathy, on the other hand, does not appear to be a form of disseminated intravascular coagulation. Additional research is required to elucidate additional probable mechanisms of this coagulopathy, including a thorough examination of the fibrinolytic system.

FXR INHIBITION AS A NEW STRATEGY AGAINST COVID19 T Brevini1, M Maes2, GJ Webb3, CD Fuchs4, G Buescher5

Introduction: Vaccines revolutionised the management of COVID19. Nevertheless, they lack efficacy in high-risk or vulnerable groups (e.g., immunosuppressed patients), who may not mount an appropriate immune response. Monoclonal antibodies represent the gold-standard agents for such cases;but they are limited by availability, need for parenteral administration and the risk for viral escape because of spike protein mutations. Therefore, there is a pressing need for new prophylactic agents less prone to resistance.The viral receptor ACE2 represents an ideal target as it is essential for viral entry and transmission and because being a host protein it is not affected by viral mutations. However, the regulation of ACE2 remains elusive, due to the lack of appropriatein vitromodels. Cholangiocytes show one of the highest ACE2 expression levels in the body, representing an ideal platform for these studies. Here, we use cholangiocyte organoids as proof-of-principleto identify that the bile acid receptor FXR regulates ACE2 expression and SARS-CoV-2 infectionin vitro. We validate these findings in lung and gut organoids, animal models, human organs perfusedex situand patient cohorts. Aims & Methods: 1. Identify pathways controlling the transcriptional regulation of ACE2 2. Identify drugs modulating these pathways as novel prophylactic and therapeutic agents for COVID19. Organoids were propagated using established protocols. Marker expression was assessed using single-cell RNA sequencing, QPCR, and immunofluorescence. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Syrian golden hamsters were infected via direct inoculation and QPCR on oral swab, nasal turbinate and lung samples was used to measure SARS-CoV-2 infection. Human livers and lungs not used for transplantation were perfusedex-situusing normothermic perfusion. Nasopharyngeal swabs were used to measure ACE2 expression in nasal epithelial cells of healthy individuals taking UDCA at the standard therapeutic dose of 15 mg/kg/day. Patient registry data were compared using propensity score matching for sex, age, diabetes, NAFLD and Child- Turcotte-Pugh score. Result(s): We identified that FXR directly regulates ACE2 transcription in cholangiocyte organoids, while FXR inhibition with the approved drug ursodeoxycholic acid (UDCA), reduced ACE2 expression and SARS-CoV-2 infectionin vitro. We confirmed this mechanism in organoids from other COVID19-affected tissues, including the respiratory and intestinal systems. We validated our findingsin vivoin Syrian golden hamsters, showing that treatment with UDCA downregulates ACE2 and prevents SARS-CoV-2 infection. We confirmed that UDCA reduces ACE2 and SARS-CoV-2 infection in human lungs and livers perfusedex-situ. We performed a clinical study demonstrating that UDCA lowers ACE2 levels in the nasal epithelium of 6 healthy volunteers. Finally, we identified a correlation between UDCA and better clinical outcomes (hospitalisation, ICU admission and death) in COVID19 patients receiving UDCA for cholestatic diseases using the COVID-Hep and SECURELiver registry data. Conclusion(s): We identified FXR as a novel regulator of ACE2 expression. Using a bench-to-bedside approach combining in vitroand in vivomodels, exsituperfused human organs and clinical data we showed that FXR inhibition prevents or reduces SARS-CoV-2 infection and identified UDCA as an approved, cost-effective drug which could be repurposed for COVID19, paving the road for future clinical trials.

Impact of the Covid-19 Pandemic in the Diagnosis and Therapy of Single Hepatocellular Carcinoma Less Than 3 Cm in a Western Country

Introduction: The aim of a cancer screening program is to reduce cancerrelated mortality. For that reason patients with liver cirrhosis are enrolled into surveillance through biannual ultrasonography plus AFP to detect single hepatocellular carcinomas (HCC) less than 3 cm, best candidates to apply therapies with curative intent. This study evaluates the impact of the COVID-19 pandemic in the time between detection, diagnosis, and treatment in patients with uninodular HCC < = 3 cm. The secondary objective is to assess the number and sequence of tests needed to achieve the final diagnosis. Aims & Methods: Retrospective inclusion of consecutive patients with final diagnosis of single HCC <= 3 cmat ourcentre. Baseline clinical and analytical variables, date of detection, diagnosis, treatment / entry on the transplant waiting list and the sequence of tests performed (CT, MRI, biopsy) were recorded. Time to diagnosis (period from detection to diagnosis), time to treatment (from diagnosis to date of treatment/entry on the waiting list) and overall time (the sum of the above) were defined. The results were analyzed globally and divided into two periods: pre-COVID (Jan-15 to Feb-2020) and COVID (Mar-20 to the present). Result(s): From Jan 27th2015 to Dec 27th2021, 128 patients of 685 had a final diagnosis of single HCC <= 3 cm, 18% in the pre-COVID era and 22% in the COVID era. Baseline characteristics: median age 64 years old, 84% males, aetiology: alcohol 46%, hepatitis C 39%, fatty liver disease 5%. Child-Pugh class A 86%, BCLC-0 29%, BCLC-A 71%. Median size 20.5 mm, median AFP 5 ng/mL. Only 74% were diagnosed within the screening program. Thermal ablation was applied in 58 patients, liver transplantation in 29, surgical resection in 21 and intraarterial therapy in 16. Twelve patients were left in natural history. Diagnosis was reached by non-invasive criteria (imaging) in 112 patients and by biopsy in 16.The tests performed are shown in the TABLE 1. No statistically significant differences were found in the diagnostic capacity between multiphasic CT (67.6%) and dynamic MRI (73.3%), p-value 0.113. There were no differences in the diagnostic method (imaging versus biopsy) according to the size of the nodule (21.43 mm vs. 21.13 mm), p-value 0.199;nor in the number of studies performed according to the sequence (CT-MR-Biopsy vs MR-CT-Biopsy vs others), p-value 0.746. There were no significant differences neither in the proportion of tumors diagnosed between 10-20 mm and 21-30 mm on the pre-COVID vs COVID era, p-value 0.80, nor in the therapy applied (surgical versus loco-regional, p-value 0.639). Time to diagnosis, time to treatment, and overall time are shown in TABLE 2. Significant differences were found in the time to treatment between the pre-COVID and COVID eras:8 weeks vs 11 weeks, p-value 0.038. Conclusion(s): The COVID pandemic did not affected the proportion of single HCC <=3 cm diagnosed, but it increased the median time from diagnosis to treatment.

Evaluation of the Immune Response against Sars-Cov-2 after Two and Three Doses of Mrna Vaccination in Patients with Liver Cirrhosis

Introduction: Liver cirrhosis entails elevated risk of COVID-19-associated mortality. This study determined T cell-mediated and antibody reactivity against the spike 1 (S1) protein of SARS-CoV-2 among 48 cirrhotic patients and 39 healthy controls after two and three doses of mRNA COVID-19 vaccination. Aims & Methods: SARS-CoV-2-specific T cell reactivity was measured by induced level of T cell-derived interferon-gamma (IFN-gamma) in blood cells stimulated ex vivo with multimeric peptides spanning the N-terminal portion of S1. S1-induced IFN-gamma was quantified before and after the 1st and 2nd vaccination (BNT162b2, Pfizer-BioNTech or mRNA-1273, Moderna), while serum IgG against the receptor-binding domain (RBD) within S1 (anti-RBD-S1 IgG) were quantified after the 1st, 2nd and third dose of the vaccine. Result(s): T cell reactivity against S1 was reduced in cirrhotic patients after the 1st (P<0.001 vs controls) and 2nd (P<0.001) vaccination. Sixty-eight % of patients lacked detectable S1-specific T cell reactivity after the 1st vaccination vs. 19% in controls (OR 0.11, HR 0.03-0.48, P=0.003) and 36% remained devoid of reactivity after the 2nd vaccination vs. 6% in controls (OR 0.12, HR 0.03-0.59, P=0.009). T cell reactivity in cirrhosis remained significantly impaired after correction for potential confounders in multivariable analysis. Advanced cirrhosis (Child-Pugh class B) was associated with absent or lower T cell responses (P<0.05 vs. Child-Pugh class A). The deficiency of T cell reactivity was paralleled by lower levels of anti-RBD-S1 IgG after the 1st (P<0.001 vs. controls) and 2nd (P<0.05) vaccination. Anti-RBD IgG levels were increased significantly after the 3rd compared to the 2nd dose (median 944 vs. 563 BAU/ml, p=0.002). Hybrid immunity, i.e., the combined effect of vaccination and naturally acquired COVID-19, was associated with significantly higher antibody levels (>5680 (821->5680) vs 944 (5-5675)) BAU/ml, p=0.0001) as compared to antibody levels achieved through 3 doses of vaccination alone. The time elapsed between vaccination to blood draw after the 3rd dose of the vaccine was significantly longer than after the 2nd dose (90 vs 118 days, p < 0.001). Conclusion(s): Cirrhotic patients show deficient T cell reactivity against SARS-CoV-2 antigens along with diminished levels of anti-RBD-S1 IgG after dual COVID-19 vaccination. Nevertheless, a third dose of mRNA COVID-19 vaccine generally results in high antibody levels, and hybrid immunity following naturally acquired infection elicits further augmented levels in patients with cirrhosis. As immune waning is of concern with regards to COVID-19, continued vigilance as well as iterated booster vaccine doses for these vulnerable patients is likely prudent.

The Elevated De Ritis Ratio on Admission Is Independently Associated with Mortality in COVID-19 Patients.

Liver damage in COVID-19 patients was documented as increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels or an elevated AST/ALT ratio, known as the De Ritis ratio. However, the prognostic value of the elevated De Ritis ratio in COVID-19 patients is still unknown. The aim of our study was to evaluate the prognostic value of the De Ritis ratio compared to other abnormal laboratory parameters and its relation to mortality. We selected 322 COVID-19 patients in this retrospective study conducted between November 2020 and March 2021. The laboratory parameters were measured on admission and followed till patient discharge or death. Of the 322 COVID-19 patients, 57 (17.7%) had gastrointestinal symptoms on admission. The multivariate analysis showed that the De Ritis ratio was an independent risk factor for mortality, with an OR of 29.967 (95% CI 5.266-170.514). In ROC analysis, the AUC value of the the De Ritis ratio was 0.85 (95% CI 0.777-0.923, p < 0.05) with sensitivity and specificity of 80.6% and 75.2%, respectively. A De Ritis ratio ≥1.218 was significantly associated with patient mortality, disease severity, higher AST and IL-6 levels, and a lower ALT level. An elevated De Ritis ratio on admission is independently associated with mortality in COVID-19 patients, indicating liver injury and cytokine release syndrome.

The Course of Alcoholic Cirrhosis of The Liver in a Patient with COVID-19

This article presents the features of the course of liver cirrhosis (LC) in a patient with a new coronavirus infection. The patient had no specific respiratory symptoms of COVID-19 (CoronaVirus Disease 2019), and the reason for outpatient examination for SARS-CoV-2 (severe acute respiratory syndrome coronavirus) RNA was the presence of these symptoms in relatives. Previously, patient E. had been undergoing in-patient examination and treatment for abdomen volume build-up against the background of prolonged alcoholization, and was diagnosed with alcoholic class B LC according to Child-Pugh classification. Conservative therapy was administered, and the patient was discharged with regression of ascites. Within a week after SARS-CoV-2 identification, patient E. showed signs of LC decompensation in the form of increasing abdominal volume, which required repeated inpatient treatment, during which portal vein thrombosis (PVT) and progression of chronic liver disease (CLD) in the post-coid period were revealed. Literature data on 30-day mortality in patients with LC against COVID-19 background are presented, as well as my own observations on the example of 580 case histories. Complications of new coronavirus infection in patients with CLD, methods of their correction are considered here. This observation demonstrates the social significance of the problem of COVID-19 incidence in patients with LC, the necessity for screening for COVID-19 in case of the presence of decompensation episodes, as well as active prevention of infection in these patients.

A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL

Background: Trans-arterial chemoembolization (TACE) is the gold-standard for intermediate stage HCC. We hypothesised the ischemic and cytotoxic effect of TACE to boost anti-cancer immunity and to synergise with the anti PD-1 pembrolizumab (pembro). We designed a phase Ib study to test the safety and preliminary efficacy of pembro after TACE in intermediate HCC. Methods: PETAL study will enroll up to 32 patients with intermediate HCC to receive pembro 200 mg every 3 weeks for up to 1 year or until disease progression or unacceptable toxicity. The first safety-run-in phase includes 6 patients: if no dose limiting toxicities (DLTs) emerge over a 21-day window after first pembro, the others are enrolled in the expansion phase. Pembro is given within 30 days after 1 or 2 TACEs. The first phase includes 1 patient scoring Child-Pugh (CP)-B7 and the remaining have to be CP-A. Safety is the primary endpoint and is measured as the incidence of treatment-related adverse events (TRAEs), graded according to NCI CTCAEv4. Efficacy is the secondary endpoint and is evaluated as progression free survival (PFS) from first TACE, according to mRECIST criteria. Survival is estimated using Kaplan-Meier method. All the patients who have received at least one dose of pembro are evaluable for safety. Results: At the time of data cut-off, on the 14th of January 2022, 14 patients had received at least one dose of pembro. The median age was 72 (IQR: 63.3-74.6), 79% were male, 71% were cirrhotic, 29% had viral hepatis and 43% ECOG PS 1. One patient had Child-Pugh (CP) class B7 and 13 had A. The median number of nodules was 1.5 (IQR:1-2.8), and 4.1 cm (IQR: 3.7-4.5) the median diameter. Overall, 5 patients received 2 TACEs and 9 had 1. Patients received a median of 4.5 cycles (IQR: 2.3-6.5) of pembro. No DLTs emerged in the first phase. Treatment-related adverse events (TRAE) of any grade (G) were reported in 86% of participants, 21% of participants experienced G3 TRAEs, and there were no G4 or G5 TRAEs. Specific skin-related toxicity was the most frequently reported (35%) TRAE. No patients had treatment-related liver toxicity. Causes of treatment discontinuation were PD (n=7), TRAEs (n=1), clinical deterioration in the CP B patient (n=1), COVID pandemic (n=2) and withdrawal of consent (n=1);at the time of data cut-off, mPFS from first TACE was 10.8 months (95%CI: 6.63-14.97). Conclusions: Adjuvant pembro following TACE is manageable and tolerable with signs of activity. These results prompt the investigation in larger trials.

Inner Branch Endovascular Repair in Complex Secondary Aortic Intervention in Case of Abdominal and Thoraco-Abdominal Aneurysmal Progression: An Early Single Centre experience

Introduction: Aortic aneurysmal disease is an evolving pathology: when treating an aortic aneurysm, we must consider the possibility of a thoraco-abdominal evolution aneurysm, which might lead to further treatments. In case of challenging anatomies (narrow aortic lumen at the level of visceral arteries, aortic wall thrombus, true lumen in an aortic dissected aneurysm, and focal aortic narrow diameter), unfavourable both for fenestrated endovascular aneurysm repair (FEVAR) and branched endovascular aneurysm repair (BEVAR), an inner branched custom made device could represent a potential feasible solution. Inner branched endografts have a typical configuration that combines the advantageous characteristics of both fenestrated and side branched endografts, thus showing advantages over other custom made grafts. Our study aimed to investigate the potential role of this technique in a broad variety of aortic anatomies unfavourable for FEVAR and BEVAR, in patients who received different previous aortic treatments. Methods: In our institution, between July 2018 and July 2020, 20 consecutive patients underwent a FEVAR/BEVAR procedure to treat complex abdominal aortic aneurysm or thoracic aortic aneurysm. Nine patients who were deemed untreatable with a fenestrated/branched graft due to aortic anatomy and/or previous treatments were treated with a custom made, four inner branch E-xtra design endograft (I BEVAR). All patients were treated for a complex aortic abdominal and thoraco-abdominal aneurysm: two patients were previously treated with frozen elephant trunk and TEVAR;three patients were previously treated with TEVAR;and one with TEVAR + abdominal aortic surgical treatment. Two patients received abdominal aortic surgical treatment only. The last patient was previously treated with EVAR, which was then complicated with a type 1A endoleak (EL). Five of six TEVARs were placed before BEVAR as staged procedures, to decrease spinal cord ischaemia risk. All patients had a lumbar cerebrospinal fluid drainage during the BEVAR procedure. In total, the bridging stents placed included 43 balloon expandable and four self-expandable stents. Results: In our experience, all cases were treated with a four inner branch endograft with a total revascularisation of 36 target vessels. Technical success was achieved in all nine cases (100%), with precise deployment of the inner branched endograft and effective engagement and bridging of all branches. Major clinical complications occurred in three (33%) patients: one case of continuous veno-venous haemofiltration treatment for a transient acute renal failure in a chronic renal disease;one case of hepatic decompensation in patient with a chronic cirrhosis, which led to liver failure (Child Pugh C10, MELD 19, still under medical treatment);and one patient with a pulmonary infection disease (COVID-19 related), which then resolved. No patient suffered spinal cord ischaemia. The mean follow up was 12.8 months ± 6.79 months, with an estimated one year survival rate of 89%. One patient with a thrombophilic disorder died on postoperative day 48 as a result of multiple organ failure after acute four inner branches simultaneous occlusion. During follow up, the target vessel primary patency rate was 89%, associated with four (11%) bridging stent ELs. At 30 days, computed tomography angiography detected five BS ELs in four patients: one type III BS EL (2.7%), and four type I BS ELs (11%). Re-intervention was needed in one patient (11%) with a type III and I BS EL associated with an aneurysm sac enlargement treated with bridging stent relining in the left renal artery and superior mesenteric artery. Conclusion: Our experience shows the feasibility of treating complex aortic anatomies with an inner branched graft in patients which were anatomically unfit for FEVAR/BEVAR treatment, allowing complex visceral vessels recanalisation and an adequate sealing. When a re-intervention is needed, we have to consider that previous surgical and endovascular treatments modify the aortic anatomy, and the graft deploy ent may be tougher, with a higher risk of malrotation. Inner branched endograft could be a valid option in case of complex anatomies, but long term follow up is needed.

The prevalence and prognostic significance of vitamin C deficiency in patients with cirrhosis: a prospective observational cohort study

Background and aims: Malnutrition is a common comorbidity in cirrhotic patients and confers a poorer prognosis. Vitamin C (VC) is a micronutrient essential for human health. Vitamin C deficiency (VCD) can lead to scurvy and may impair immune and liver functions. Although previously thought to be rare in developed countries, VCD is now well described in patients with pneumonia, COVID19 and upper gastrointestinal bleeding (UGIB). The prevalence and clinical significance of VCD in cirrhosis remains poorly studied. Method: Patients with cirrhosis admitted to 3 metropolitan tertiary centres in Australia were prospectively included over a 10-month period in 2021. Fasting VC levels were collected on admission and we recorded demographic data and clinical outcomes. The primary outcomes were the prevalence of VCD (defined as VC level <23 mcmol/L) and severe VCD (SVCD), defined as <11 mcmol/L. Secondary outcomes included mortality, intensive care admission, length of stay (LOS) and rate of infection. Results: 117 patients were included. Mean age was 57.1 ± 13.9 years, 59.0% were male and 23.9% belonged to the lowest socioeconomic decile. The most common aetiologies of cirrhosis were alcohol (62.4%), viral hepatitis (24.0%) and non-alcoholic fatty liver disease (18.8%). Median MELD scorewas 29 (IQR 22–36) and Child Pugh (CP) grades were 12.8% A, 46.2% B and 41.0% C. Most patients (74.4%) were hospitalised with complications of decompensated cirrhosis, including ascites (59.0%), encephalopathy (31.6%) and variceal bleeding (11.1%). Median VC level was 34mcmol/L (IQR 16–55) and did not differ with age, gender, or aetiology of cirrhosis. Increasing CP grade correlated with significantly lower median VC levels (CP-A 46.0 mcmol/L vs. CPB 36.5 mcmol/L and CP-C 20.5 mcmol/L, p = 0.026). The prevalence of VCD and SVCD were 39.3% and 17.1% respectively. SVCD was more prevalent in patients with a body mass index <25 (28.3% vs 13.0%, p = 0.036). In-hospital mortality was 12.8% and did not differ by VCD status, however in the subgroup of patients presenting with UGIB, SVCD correlated with significantly higher mortality (50% vs 4.1%, p = 0.045). Bacteraemia was more frequent in patients with VCD (13.3% vs. 1.4%, p = 0.014) and SVCD (26.3% vs 2.1%, p < 0.001), which remained significant at multivariate analysis (OR for every 1mcmol/L increase in VC, 0.91 (95% CI: 0.83–0.99), p = 0.037). Overall infection rateswere higher in patients with SVCD (40.0% vs. 27.8%) although thiswas nonsignificant (p = 0.279). Median hospital LOS was 10 (IQR 6–18) days and did not differ by VCD status. (Figure Presented) Conclusion: VCD is common in hospitalised cirrhotic patients and prevalence increases with severity of liver disease. VCD increases the risk of infective complications and higher mortality was observed in patients with UGIB and SVCD. Further studies are required to assess the significance of VCD in cirrhosis and the impacts of VC replacement.

A study evaluating outcomes of a virtual specialist liver cirrhosis clinic

Background and aims: Managing patients in a specialist cirrhosis clinic improves survival. The COVID-19 pandemic necessitated the transition to virtual clinics (VC). We aimed to evaluate the clinical impact of VC on survival, admission and decompensation rates in cirrhotic patients managed in a specialist service. Method: We retrospectively analysed cirrhotic patients who had a specialised VC from March to June 2020. Clinical parameters were collected at baseline and 6 months and compared with a cohort of patients reviewed face to face (F2F) in the same specialist cirrhosis clinics from March to June 2019. Patients with COVID-19 were excluded. Results: 143 patients attended for VC, 129 for F2F review. Groups were matched for age, sex, aetiology, and Child Pugh grade (CP). There was no difference at 6 months in survival, change in MELD/UKELD, decompensation or need for ambulatory reviewin all cirrhosis grades combined or CP BandC subgroup alone (p > 0.05) (Table 1). Fewer patients were admitted in the VC vs the F2F group (p = 0.01) but this was not validated in CP BandC subgroup (p = 0.28). Fewer blood tests were ordered for the VC group (p = 0.0001). The VC group had longer delays for ultrasound HCC surveillance (<0.0001) without an increase in new HCC cases.Table: Baseline Patient Demographics and 6 months’ outcome (*p < 0.05, **p < 0.01)(Table Presented)Conclusion: VC have not resulted in poorer clinical outcomes, even in patients with decompensated cirrhosis. Access to ambulatory care was still required. Fewer blood tests ordered and completed in the VC group did not result in adverse outcomes and this raises the possibility of cost-saving. urther studies need to confirm the longterm clinical impact and cost-effectiveness of specialist VC in management of cirrhotic patients.

Unusual presentation of hepatocellular carcinoma-cannonball pulmonary metastasis

Objectives: Cannonball metastasis refers to well-circumscribed, spherical nodules scattered over both lungs, usually occur due to hematogenous spread of tumor, classically seen in germ cell tumor, renal cell carcinoma, choriocarcinoma, endometrial cancer but it is a rare and an unusual phenomenon in hepatocellular carcinoma. Materials and Methods: Case description: Results: We report a case of hepatocellular carcinoma with unusual presentation of pulmonary cannonball lesions. A 41-year-old Chinese man who attended to ED on 8.10.2021 with one month duration of abdominal discomfort and progressive dyspnea. He has past history of chronic hepatitis B infection since the age of 16 years but he did not receive any treatment. He denied fever and no history of TB contact. His oxygen saturation was 89% on room air. On examination, he was dyspneic, tachypneic, few crepitations in both lungs, hepatomegaly was noted. Covid PCR test was negative. Imaging tests revealed cannonball lesions were seen in both CXR and CECT chest (Figure-1) and infiltrative type of hepatocellular carcinoma both lobes of liver with portal vein thrombosis detected in CECT Liver (Figure-1). Blood tests showed elevated bilirubin (3.5 g/dl), AST 122, ALT 30, hypoalbuminemia (3.2), AFP 8421, HBeAg negative, antiHBeAb negative, qHBsAg 2793 IU/ml. His Child Pugh stage B (score 9), MELDNa 12 and BCLC stage C. Therefore, we diagnosed him to have advanced hepatocellular carcinoma with cannonball pulmonary metastasis with underlying chronic hepatitis B infection, for which we started Tenofovir (TDF) 300 mg OD and Lenvatinib 4 mg OD. Unfortunately, he expired on 17.10.2021. Conclusion: Hepatocellular carcinoma is one of the commonest cancers in the world with chronic hepatitis B and C infection. Extrahepatic spread to lung is common and about one third of these patients developed pulmonary metastasis. However, cannonball pulmonary metastasis is rare and is an unusual presentation in hepatocellular carcinoma. Moreover, prognosis of these patients is poor and survival is usually only days. (Figure Presented).

BICEPS another score for the assessment of severity of liver cirrhosis

Background and Aim: The clinical assessments using the Child-Turcotte-Pugh (CTP) and model for end-stage liver disease-sodium (MELD-Na) scores are heterogeneous. The present study aims to collate most relevant markers of chronic liver disease as a new score BICEPS (Bilirubin, INR, Creatinine, Encephalopathy, Platelet and Sodium) an alternate to CTP and MELD-Na in patients diagnosed with liver cirrhosis. Methods: From January 2019 till December 2021, patients who were admitted with a diagnosis of liver cirrhosis were included. Patients were classified as per the CTP, MELD-Na and BICEPS scoring systems using a proforma. The BICEPS score is created by the authors and study intended to validate clinically. Results: In 211 patients, were evaluated during the study period including COVID pandemic period. The mean MELD-Na score was 23.49 ± 8.42, ranging 7 to 42, while CTP score ranged from 5 to 15, with a mean value of 9.65 ± 2.76. We classified patients as per scoring to 16%, 32% and 52% as Grade A, B and C on CTP respectively and 6%, 54% and 40% as Grade A, B and C on BICEPS respectively. We observed moderate level of agreement between BICEPS and CTP [Cohen’s kappa = 0.57, 95% confidence interval (CI) 0.45 to 0.69, p value < 0.01]. BICEPS correlated strongly with both MELD-Na [Pearson’s correlation coefficient (r) = 0.84, p value < 0.01] and CTP (r = 0.83, p value < 0.01). Conclusions: BICEPS yet another clinical scoring that has a moderate level of agreement with CTP and significant correlation with both CTP and MELD Na. Being a clinical scoring helps bedside estimation easy and includes all the 6 critical markers of CLD and is comparable to MELD Na without a calculator. Further studies are required with more number of patients for validating the BICEPS score.