Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Pyogenic liver abscesses in liver transplant recipients versus non-transplant population. Outcome and risk factors of patient survival.

Pyogenic liver abscess (PLA) is a life-threatening infection in both liver transplant (LT) and non-LT patients. Several risk factors, such as benign and malignant hepatopancreatobiliary diseases and colorectal tumors have been associated with PLA in the non-LT population, and hepatic artery stricture/thrombosis, biliary stricture, and hepaticojejunostomy in the LT patients. The objective of this study is to compare the outcomes of patients with PLA in LT and non-LT patients and to determine the risk factors associated with patient survival. From January 2000 to November 2020, a total of 296 adult patients were diagnosed of PLA in our institution, of whom 26 patients had previously undergone liver transplantation (LTA group), whereas 263 patients corresponded to the non-LTA population. Seven patients with PLA who had undergone previous kidney transplantation were excluded from this retrospective study. Twenty-six patients out of 1503 LT developed PLA (incidence of 1.7%). Median age was significantly higher in non-LTA patients (p = .001). No significant differences were observed in therapy. PLA recurrence was significantly higher in LTA than in non-LTA (34.6% vs. 14.8%; p = .008). In-hospital mortality was greater in the LT group than in the non-LT group (19.2% vs. 9.1% p = .10) and was identified in multivariable analysis as a risk factor for mortality (p = .027). Mortality rate during follow-up did not show significant differences between the groups: 34.6% in LTA patients versus 26.2% in non-LTA patients (p = .10). The most common causes of mortality during follow-up were malignancies, Covid-19 infection, and neurologic disease. 1-, 3-, and 5-year actuarial patient survival rates were 87.0%, 64.1%, and 50.4%, respectively, in patients of LTA group, and 84.5%, 66.5%, and 51.0%, respectively, in patients with liver abscesses in non-LTA population (p = .53). In conclusion, LT was a risk factor for in hospital mortality, but not during long-term follow-up.

Medium-term outcome of liver recipients from COVID-19 donors

Background: COVID-19 is associated with thrombotic complications and can result in hepatobiliary injury. Excellent early outcomes have been reported in recipients of solid non-lungs organs from SARS-CoV-2-infected donors, however longer follow-up data are lacking. We aimed to describe the medium-term outcome of our liver transplants (LT) from COVID-19 donors. Methods: From 11/2020 to 03/2022, we consecutively enrolled all patients who received a graft from COVID-19 donor in our Centre. Protocol liver biopsy and magnetic resonance cholangiopancreatography (MRCP) after 1-year from LT were reported. Results: In the study period 12/213 (5.6%) adult LT patients received a COVID-19 donor (11 active, 1 resolved COVID-19)1. Eleven patients underwent end-to-end biliary anastomosis and 1 biliodigestive anastomosis. Recipients' and donors' characteristics are reported in table 1. Two recipients tested SARS-CoV-2 RNA positive on nasopharyngeal swab at LT and one was treated with sotrovimab on day-1 after LT. None of the patients developed COVID-19 after LT. One patient underwent hepatic artery thrombectomy at day-1 and died after 320 days for HCC recurrence. Until now: -10 patients underwent protocol MRCP (median time from LT 562 days, IQR 245-614), which showed: 7 no visible abnormalities, 1 donor-recipient's bile duct size discrepancy, 2 caliber changes <50% at the anastomotic level (untreated for the absence of cholestasis);-7 patients underwent protocol liver biopsy (median time from LT 553 days, IQR 311-557) which showed 1 acute cellular rejection (RAI 4/9) successfully treated with steroids;no signs of fibrosis, rejection or biliopathy in the other 6 patients. Conclusions: 11/12 patients who received a LT from COVID-19 donors are alive, without evidence of SARS-CoV-2 transmission. At a median follow-up of 1.5 years, protocol liver biopsy and MRCP did not show biliopathy, supporting the utilization of COVID-19 donors to expand the donor pool and reduce the waiting list mortality.

Evaluation of an Abnormal Liver Panel After Liver Transplantation.

Abnormal liver tests are common after liver transplantation. The differential diagnosis depends on the clinical context, particularly the time course, pattern and degree of elevation, and donor and recipient factors. The perioperative period has distinct causes compared with months and years after transplant, including ischemia-reperfusion injury, vascular thrombosis, and primary graft nonfunction. Etiologies seen beyond the perioperative period include biliary complications, rejection, infection, recurrent disease, and non-transplant-specific causes. The evaluation begins with a liver ultrasound with Doppler as well as appropriate laboratory testing and culminates in a liver biopsy if the imaging and laboratory testing is unrevealing.

Outcome of children on the UK national prioritised paediatric registration tier

P69 Table 1Demographic and transplant data for all 14 prioritised patientsPatient/Sex Centre Age at registration (yrs) Primary liver disease Registered prior to Prioritisation Indication of Prioritization LT Waiting time on prioritised tier/Time on list prior to prioritisation 1/M 1 0 CDG Yes Acute decompensation with presence of encephalopathy Yes/LLS 5/27 2/M 2 1 Cryptogenic Cirrhosis Yes CLD with nodular lesions s/o HCC Yes/LLS 16/48 3/F 1 15 AILD Yes Chronic rejection Yes/whole liver 3/4 4/M 2 0 Biliary Atresia Yes PTLD/HAT/Sepsis Yes/LLS 14/71 5/F 2 4 IFALD No Coagulopathy with active bleeding/Renal impairment Yes/LLS 15/820 6/F 2 0 Biliary Atresia Yes Acute decompensation due to portal hypertension Yes/LLS 37/405 7/M 2 10 NSC Yes Decompensated chronic liver disease/Renal impairment Yes/reduced R lobe 4/7 8/M 3 8 PFIC3 Yes Acute decompensation of Chronic liver disease Yes/LLS 6/51 9/F 1 0 Other (Hepatoblastoma) Intestinal Tx prioritized Acute decompensation of Chronic liver disease Yes/LLS 11/ 10/F 2 0 Biliary atresia Yes Decompensated Chronic Liver Disease with Severe Coagulopathy Yes/LLS 10/120 11/M 1 0 Biliary atresia (Hepatoblastoma) Yes Acute decompensation of Chronic liver disease Yes/LLS 9/4 12/F 3 0 Biliary atresia Yes Acute decompensation of Chronic liver disease Yes/LLS 12/323 13/F 1 17 Hepatic Artery thrombosis Yes Hepatic Artery thrombosis Yes/whole liver 2/ 14/F 2 0 Biliary atresia Yes Acute decompensation of Chronic liver disease Suspended 12/65 PFIC3;Progressive Familial Intrahepatic Cholestasis type 3, LT;Liver transplantation, HCC;Hepatocellular Carcinoma NSC;Neonatal Sclerosing Cholangitis, CDG;Congenital Disorder of Glycosylation, AILD;Autoimmune Liver Disease, IFALD;Intestinal Failure Associated Liver Disease,PTLD;Center 1-Kings;Center2-Birmingham;Center3-Leeds.ConclusionThe national paediatric prioritization tier, introduced during the COVID19 pandemic, has been a pivotal initiative for the UK paediatric LT program, showcasing national collaboration. All patients underwent a LT successfully within a short time from prioritization with 100% patient and graft survival. The intention is to maintain this prioritized paediatric tier beyond the pandemic.

A New Chapter in an Evolving Pandemic: Successful Pediatric Liver Transplantation with COVID+ Donors

Purpose: We report the first two pediatric liver transplants utilizing allografts from COVID+ donors, infected at time of organ procurement, demonstrating a pivotal step toward donor pool maximization amid a viral pandemic with poorly understood transmissibility in the pediatric patient. Method(s): This is a prospective and retrospective review of two pediatric liver transplants and their donors who tested positive for SARS-CoV-2 at time of procurement. Data was obtained through the electronic medical record system and UNet DonorNet platform. Result(s): The first donor is a 3-year-old male succumbing to head trauma. 1 of 5 nasopharyngeal swab RT-PCR tests demonstrated COVID-19 positivity while 1 of 3 bronchoalveolar lavage RT-PCR tests indicated SARS-CoV-2 infection. Preceding procurement in the second donor, a 16-month-old male with unknown etiology of cardiorespiratory arrest, 2 nasopharyngeal swab RT-PCR tests and 1 bronchoalveolar lavage RT-PCR test failed to detect SARS-CoV-2 infection. Diagnosis was not made until the Medical Examiner's office repeated a nasopharyngeal swab RT-PCR and archive plasma RT-PCR which were both positive for SARS-CoV-2. The two 2-yearold pediatric liver recipients underwent transplantation in November 2021. Continued follow-up demonstrates successful transplant void of viral transmission or hepatic artery thrombosis as liver chemistries have anticipatorily normalized with excellent graft function. One recipient experienced early portal vein thrombosis treated by interventional radiology with discharge on postoperative day 20. Conclusion(s): This report is the first to describe successful pediatric liver transplants from COVID+ donors. This data reinforces case reports in the adult transplant population of successful use of COVID + donor organs and further supports the judicious use of COVID+ donors for extrapulmonary pediatric organ transplant. The concern for donor-derived transmission must now be weighed against the realized benefit of successful, life-saving transplantation for end stage liver disease in the pediatric patient. (Figure Presented).

Single organ hepatic artery vasculitis as an unusual cause of epigastric pain: A case report.

BACKGROUND: Single-organ vasculitis (SOV) is characterized by inflammation of a blood vessel, affecting one organ, such as the skin, genitourinary system, or the aorta without systemic features. Gastrointestinal SOV is rare, with hepatic artery involvement reported only in two prior published cases. Herein, we presented a case of isolated hepatic artery vasculitis presenting after Pfizer-BioNTech mRNA corona virus disease 2019 (COVID-19) vaccination. CASE SUMMARY: A 50-year-old woman with hypertension presented to our Emergency Department with recurrent diffuse abdominal pain that localized to the epigastrium and emesis without diarrhea that began eight days after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Blood work revealed an elevated C-reactive protein (CRP) of 19 mg/L (normal < 4.8 mg/L), alkaline phosphatase 150 U/L (normal 25-105 U/L), gamma-glutamyl transferase (GGT) 45 U/L (normal < 43 U/L) and elevated immunoglobulins (Ig) G 18.4 g/L (normal 7-16 g/L) and IgA 4.4 g/L (normal 0.7-4 g/L). An abdominal computed tomography revealed findings in keeping with hepatic artery vasculitis. A detailed review of her history and examination did not reveal infectious or systemic autoimmune causes of her presentation. An extensive autoimmune panel was unremarkable. COVID-19 polymerase chain reaction nasopharyngeal swab, human immunodeficiency virus, viral hepatitis and Heliobacter pylori serology were negative. At six months, the patient's symptoms, and blood work spontaneously normalized. CONCLUSION: High clinical suspicion of SOV is required for diagnosis in patients with acute abdominal pain and dyspepsia.

1-YEAR FOLLOW-UP DATA OF ARTERIAL ABNORMALITIES IDENTIFIED IN KIDNEYS TRANSPLANTED INTO CHILDREN DURING THE FIRST COVID-19 PANDEMIC WAVE

BACKGROUND AND AIMS: Graft artery stenosis can have a significant shortand long-term negative impact on kidney graft function. We previously reported an unusual number of graft-arterial anomalies following kidney transplantation (KTx) in children during the first coronavirus disease (COVID-19) pandemic wave (Berteloot et al.) [1]. We report herein the 1-year follow-up of these patients. METHOD: In this retrospective study, we included all children who received a KTx at our centre from February to July 2020. We compared their outcome to that of paediatric recipients who were transplanted at our centre from 2015 to 2019 and presented an allograft vascular complication ('Historic' group) by querying our local data warehouse. RESULTS: Among the 9 children who received a KTx at our centre between February and July 2020 [8 boys, median age 10 years (3-17)], 8 presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern (Figure 1) after a median delay of 13 days (8-113). For comparison, persistent spectral Doppler arterial anomalies were observed in only 5% of children following KTx at our centre over the previous 5-year period and were all focal anastomotic stenoses. In addition, five children had lymphoceles, which required surgical management as compared to only one patient in the 5 previous years (1%). We retrospectively diagnosed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-20 infection in 6/8 children with arterial stenosis on serologies performed at D0, including one boy with a history of positive real time reverse transcription-polymerase chain reaction (RT-PCR) 120 days before KTx. None of the patients had reported any symptom suggestive of COVID-19. The remaining two patients had received a graft from an asymptomatic deceased adolescent donor with a positive serology at D0. These data led us to suspect immune post-viral graft vasculitis, triggered by SARS-CoV-2. At 1-year post-transplantation, the outcome was favourable in the 8 isolated KTx recipients. A total of 4/8 children had normal blood pressure and 4 had controlled high blood pressure on mono or bi-therapy. Doppler anomalies had resolved in 5/8 and persisted in 3/8 with a trend for improvement of peak systolic velocities and no severe consequences on kidney function and histology. Indeed, the median glomerular filtration rate (GFR) was 91 mL/min/1.73 m2 (65-129), with unspecific and mild lesions on 4/8 protocol kidney biopsies (IFTA 1 or Cpt 1). One liver-kidney graft recipient had persistent hypertension and diffuse irregular inflammatory parietal thickening of the whole vascular graft associated with a parietal thrombus upstream of the birth of the two hepatic arteries (Figure 2);treated with anti-aggregation and prednisone 10 mg/d. CONCLUSION: Our case series suggests a risk of post-viral kidney graft vasculitis in children with recent SARS-CoV-2 infection in the recipient or donor. Pre-transplant vaccination against COVID-19 is mandatory in children > 5 years and their kidney donor candidates at our centre. We also strongly recommend vaccination of all people aged > 5 years in the household. (Figure Presented).