The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.
γ-δ T cells have been found in blood/liver of patients infected with hepatitis C (HCV). CD161+ is a C-type lectin found on the surface of T cells in humans. HCV specific T-cells have been found to express CD161 with enrichment within the liver. The role & function of CD161+ γ-δ cells has not been established in HCV.
Aim
To explore the phenotype and function of CD161+ γ-δ T cells in humans, and to assess the impact on these cells of HCV infection.
Method
Whole blood/Peripheral Blood Mononuclear cell (PBMC) antibody staining with subsequent flow cytometry was performed to assess phenotype. Function was examined by Intracellular Cytokine staining (ICS). Intrahepatic lymhocytes (IHLs) were isolated from patients having liver biopsies for clinical indications with paired blood samples. Cord blood samples were used after ethical approval gained and consent from mothers.
Results
In healthy controls, the CD161 subset encompassed a mean of 82.1 (±12.8)% of γ-δ cells. The CD161 subset expressed more CXCR3/CCR6/IL-18R (p=0.03/0.01 and 0.03 respectively) than the CD161- subset. The CD161+ cells expressed significantly more If-y/TNF-α (p=0.001 respectively) than the negative subset, and more Granzyme A, B and K and perforin in keeping with a Th1 profile. 20% of γ-δ cells from cord blood samples expressed CD161, suggesting it is an innate feature but expanded throughout life. Whole blood γ-δ populations were significantly reduced in HCV compared to healthy donors (70% v 40%, p=0.0031), with the proportion of CD161+ γ-δ T-cells reduced in chronic HCV (82.1% vs 39%, p=0.006). The γ-δ cells in HCV expressed significantly more activation markers (CD38/CD69) and CXCR6 than in healthy controls irrespective of CD161 status. Of the CD161+ γ-δ cells, the predominant subset were Vδ2 in healthy controls blood however in HCV this was significantly reduced (p=0.0173) with the Vδ1 subset dominating. On isolation of IHLs (n=17: 8 HCV, 3 HBV and rest NAFLD/NASH), there was an enrichment of CD3+ γ-δ T-cells in liver tissue compared to blood irrespective of CD161 status. On sub-analysis there were no statistical differences between CD161 status of the γ-δ cell T-cells when comparing viral v non-viral aetiologies.
Conclusion
Our data suggests that HCV infection does directly reduce the γ-δ T-cell population in peripheral blood: mainly the CD161 subset. The virus also causes a reversal in the CD161 γ-δ T-cell population from Vδ2 to Vδ1 in the periphery, however it appears the enrichment of γ-δ T cells to the liver is not specific to CD161+ cells or to HCV infection. The CD161 phenotype present at birth but expanded throughout life. The CD161 subset appears to display a more Th1 profile and unlike their CD8 CD161++ α-β counterparts, CD161 expression by γ-δ T-cells is not tightly linked to a Type-17 differentiation pathway.
Concerns exist regarding increasing use of long term ascitic drains (LTADs) in patients with refractory ascites complicating cirrhosis. Current UK consensus guidelines1 recommend LTAD consideration in non-transplant candidates who are diuretic refractory/intolerant and entering a palliative phase of their illness.1 The REDUCe feasibility study2 demonstrated an increased risk of cellulitis and leakage in those with long term ascitic drains compared to standard paracentesis. Data from our own centre has revealed previously a 50% complication rate.3 Pending the ongoing REDUCe 2 trial results, the aim of this update was to evaluate our LTAD service assessing safety/efficacy of LTADs comparing to previously published data.
Methods
A retrospective case note review was conducted with local QEHB audit approval. Previously published data pertained to 25 LTADs inserted January 2012 to May 2018. 62 further LTAD data was reviewed (May 2018 to December 2022).
Results
62 drains were done in 60 patients (70% M), 29 (47%) had ArLD, 23 (37%) NAFLD. 17 (27%) had concurrent HCC. 13 (21%) had previously documented SBP. 40 (62%) of drains were planned insertions compared to 14 (56%) in our last review. Use prophylactic antibiotics increased from 4 (14%) to 34 (53%). 57 (92%) were referred to palliative care at the time of LTAD compared to 21 (84%) in our previous review. 18 (30%) of patients were alive at 6 months compared to 13 (50%) in our previous review. Please see table 1 for a review of the complications When data amalgamated over a 10-year period (LTADs=91), the overall complication rate for LTADs was 37 (41%). 17 (19%) major and 20 (22%) minor.
Conclusions
Our latest data demonstrates reduced rates of infections compared to our previous data and similar other complications such as leakage. Over a decade experience overall complication rate was 41% (n=37) – the majority minor. In experienced centres, insertion of LTADs remain a good palliative option however patient selection remains key and the patients need to be aware of the complication rates which will be informed by REDUCe2.
References
Macken L, Corrigan M, Prentice W on behalf of the British Association for the Study of the Liver/British Society of Gastroenterology (BASL/BSG) End of Life Special Interest Group, et al. Palliative long-term abdominal drains for the management of refractory ascites due to cirrhosis: a consensus document Frontline Gastroenterology 2022;13:e116-e125. Macken L, Mason L, Evans C, et al. PTU-020 REDUCe study: multi-centre feasibility RCT in cirrhosis-related palliative refractory ascites. participant reported outcomes. Gut 2019;68:A121. Corrigan M, Thomas R, McDonagh J, Speakman J, Abbas N, Bardell S, Thompson F, Holt A, Jones R, Willis A, Karkhanis S. Tunnelled peritoneal drainage catheter placement for the palliative management of refractory ascites in patients with liver cirrhosis. Frontline gastroenterology. 2021 Mar 1;12(2):108–12.
Transjugular Intrahepatic Porto-Systemic Shunts (TIPSS) insufficiency can be addressed with a side placement of another TIPSS beside the original (“parallel” technique) thus improving portosystemic pressure gradient (PPG). There is a paucity of data assessing the efficacy of this technique. The Aim of this study was to assess the efficacy of parallel TIPSS in a large UK tertiary referral centre.
Methods
A retrospective study was performed from patient electronic databases. Parallel TIPSS were performed over a 19 year period.
Results
11 patients (8M:3F) were identified (2% of all TIPSS procedures). Mean age at time of parallel TIPSS was 48.6(+/-13.7). Background aetiology of portal hypertension included: 5 ALD, 2 PSC, 2 PBC, 1 liver graft failure, 1 NCPH. Indications for index TIPSS (5 covered stents) were: 4 Oesophageal variceal (OV) haemorrhage, 3 gastric variceal (GV) haemorrhage, 1 stromal variceal haemorrhage and 3 for refractory ascites. At time of 1st TIPSS, documented mean PPG was 16.6(+/-7.71) and post TIPSS 10.8(+/-7.35) mmHg. Median time between index TIPSS and parallel TIPSS insertion was 72 days (IQR 4–1122 days). Prior to parallel stent placement, 7 patients had dilatation of the index TIPSS. At parallel TIPSS, the mean initial PPG was 16.0 (+/-7.40)/post procedure 6 (+/-2.28) mmHg. 63% had covered stent as the parallel TIPSS. One patient had transient encephalopathy, but no other complications were encountered. Nine patients had a resolution in symptoms. One patient had ongoing GV bleeding requiring Thrombin injection and 1 patient had ascites with no flow in parallel TIPSS 4 days post-procedure. Secondary patency was 82% with a median number of interventions of 1.5 (IQR 1–3). Median follow-up was 30 months (range 0.5–120). 92% patients were alive at 1 month with 86% 1 year survival. Two patients were transplanted during follow-up.
Conclusion
Parallel TIPSS is a safe and effective method to treat TIPSS insufficiency. The majority of patients not only had a good haemodynamic result, but also resolution of symptoms.
Self expanding metallic stent (SEMS) placement effectively palliates malignant dysphagia, most commonly due to oesophageal cancer. Typically stents are placed under fluoroscopic guidance, but some centres use direct vision endoscopy as an alternative.1 There are however little data comparing the two techniques. At our 2-hospital institution, all patients presenting to Stoke Mandeville Hospital undergo radiologically guided stent placement, while patients at Wycombe Hospital undergo endoscopic placement without fluoroscopy. We describe our experience over a three year period.
Methods
A retrospective observational study of all patients who underwent SEMS placement at our two hospitals over a three year period (2009–2012) was performed. 41 patients were included in the study, with placement of 48 SEMS. Improvement in dysphagia, survival and complication rates were the main outcome measures.
Results
21 patients underwent radiologically guided placement, 20 for oesophageal cancer, 14 male, median age 78 years. 20 patients underwent endoscopically guided placement, 17 for oesophageal cancer, 8 male, median age 80.5 years. Disease stage was similar in both groups, with metastases in 11/21 of the radiology group, and 10/20 of the endoscopy group. More patients in the radiology group had received prior radiotherapy (13 vs 8). Significant improvement in dysphagia was similar in both groups (14/21 radiology vs 14/20 endoscopy, p = 0.82). There was no significant difference in median survival after stenting (135 vs 116 days, p = 0.98), or major 30 day complications defined as perforation, recurrent dysphagia or death (5 in both groups).
Conclusion
Direct vision endoscopic SEMS placement was as effective as radiological guidance for dysphagia palliation at our institution, with a similar mortality and complication rate. This provides further evidence for the role of direct vision endoscopic SEMS placement in palliation of malignant dysphagia.
Reference
Wilkes EA et al. Insertion of expandable metallic stents in esophageal cancer without fluoroscopy is safe and effective: a 5 year experience. Gastrointest Endosc. 2007 May;65:923–9
Background and aims Cirrhosis increases perioperative and postoperative mortality in nonhepatic surgery. Transjugular intrahepatic portosystemic shunt (TIPSS), by reducing portal pressure, may reduce intraoperative bleeding and postoperative decompensation. We report our experience of prophylactic TIPSS in nonhepatic surgery. Methods Patients who underwent prophylactic TIPSS before nonhepatic surgery were identified from database with retrospective data collection via an e-patient record system. Primary outcome was discharged without hepatic decompensation after a planned surgery. Results Twenty-one patients [age (median, range): 55, 33–76 years, Child’s score: 6, 5–9] who underwent prophylactic TIPSS before nonhepatic surgery over a period of 9 years were included. All patients underwent successful TIPSS with a reduction in portal pressure gradient from 21.5 (11–35) to 16 (7–25) mmHg ( P < 0.001). Immediate post-TIPSS complications were seen in 7 (33%) patients including hepatic encephalopathy in four. Eighteen patients (86%) underwent planned surgical intervention. Significant postoperative complications included hepatic encephalopathy (3), sepsis (2) and bleed (1). Two patients died postoperatively with multi-organ failure. The primary outcome was achieved in 12 (57%) patients. Post-TIPSS portal pressure gradient was significantly higher in patients with the adverse primary outcome. Over a follow-up period of 11 (1–78) months; 1-, 6- and 12-months’ survival was 90, 80 and 76%, respectively. Conclusion Prophylactic TIPSS is associated with complications in up to one-third of patients, with 57% achieving the primary outcome. Careful patient selection in a multidisciplinary team setting is essential. Multicentre studies are necessary before the universal recommendation of prophylactic TIPSS.
Objective The incidence of hepatocellular carcinoma (HCC) continues to rise dramatically in the UK. Liver transplantation offers a potential cure and there is a large body of evidence demonstrating good outcomes. However, there is a paucity of data on the assessment, acceptance rates, and reasons for turning down liver transplantation in HCC. Methods We undertook an analysis of all patients with HCC referred for liver transplant assessment to a tertiary liver centre between January 2015 and January 2020. Patient and tumour demographics, assessment outcomes and overall survival were analysed. Multivariate analysis was performed on factors affecting listing decisions. To evaluate the impact of the COVID-19 pandemic, data collection was extended from March 2020 to March 2021. Results Of 263 patients with HCC who completed liver transplant assessment, 168 (64%) were accepted for listing. The most common factors associated with a decision not to list a patient were medical comorbidities (n=50, 56.2% of those not listed) and rapid tumour progression (n=25, 26.3%). Of patients who were listed, 145 (86.4%) received a liver transplant. Five year survival from the time of transplant assessment was 68% with transplant and 12% without. The pandemic resulted in more patients progressing out of criteria after listing. Prepandemic median dropout per annum was 2% (0%–9%), compared with 25% during the pandemic study period. Conclusion This study provides outcomes on patients with HCC referred for transplant assessment, identifying factors for non-listing and confirming the negative impact of decreased transplant activity during the pandemic on waiting list dropouts for HCC patients.
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