Abstract Cellular senescence is a fundamental, complex mechanism with an important protective role present from embryogenesis to late life across all species. It limits the proliferative potential of ...damaged cells thus protecting against malignant change, but at the expense of substantial alterations to the microenvironment and tissue homeostasis, driving inflammation, fibrosis and paradoxically, malignant disease if the process is sustained. Cellular senescence has attracted considerable recent interest with recognition of pathways linking aging, malignancy and insulin resistance and the current focus on therapeutic interventions to extend health-span. There are major implications for Hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells and immune cells has been implicated in chronic liver disease progression. This review focuses on cellular senescence in chronic liver disease and explores therapeutic opportunities.
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•Most patients with single HCC ≤3 cm treated by RFA will eventually develop recurrent HCC distant to the ablation site.•Many patients treated with HCC will recur beyond the Milan ...criteria despite close post-RFA surveillance.•Patients with tumors >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond Milan criteria.
Radiofrequency ablation (RFA) is an effective treatment for single hepatocellular carcinoma (HCC) ≤3 cm. Disease recurrence is common, and in some patients will occur outside transplant criteria. We aimed to assess the incidence and risk factors for recurrence beyond Milan criteria in potentially transplantable patients treated with RFA as first-line therapy.
We performed a retrospective cohort study of potentially transplantable patients with new diagnoses of unifocal HCC ≤3 cm that underwent RFA as first-line therapy between 2000-2015. We defined potentially transplantable patients as those aged <70 years without any comorbidities that would preclude transplant surgery. Incidence of recurrence beyond Milan criteria was compared across 2 groups according to HCC diameter at the time of ablation: (HCC ≤2 cm vs. HCC >2 cm). Competing risks Cox regression was used to identify predictors of recurrence beyond Milan criteria.
We included 301 patients (167 HCC ≤2 cm and 134 HCC >2 cm). Recurrence beyond Milan criteria occurred in 36 (21.6%) and 47 (35.1%) patients in the HCC ≤2 cm and the HCC >2 cm groups, respectively (p = 0.01). The 1-, 3- and 5-year actuarial survival rates after RFA were 98.2%, 86.2% and 79.0% in the HCC ≤2 cm group vs. 93.3%, 77.6% and 70.9% in the HCC >2 cm group (p = 0.01). Tumor size >2 cm (hazard ratio 1.94; 95%CI 1.25–3.02) and alpha-fetoprotein levels at the time of ablation (100–1,000 ng/ml: hazard ratio 2.05; 95%CI 1.10–3.83) were found to be predictors of post-RFA recurrence outside Milan criteria.
RFA for single HCC ≤3 cm provides excellent short- to medium-term survival. However, we identified patients at higher risk of recurrence beyond Milan criteria. For these patients, liver transplantation should be considered immediately after the first HCC recurrence following RFA.
Radiofrequency ablation and liver transplantation are treatment options for early stages of hepatocellular carcinoma (HCC). After ablation some patients will experience recurrence or metastatic spread of the initial tumor or may develop new tumors within the liver. Despite close follow-up, these recurrences can progress rapidly and exceed transplant criteria, preventing the patient from receiving a transplant. We identified that patients with HCC >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond the transplant criteria. These data suggest that liver transplantation should be considered immediately after the first HCC recurrence for these patients.
Donor outcomes in anonymous live liver donation Goldaracena, Nicolas; Jung, Judy; Aravinthan, Aloysious D. ...
Journal of hepatology,
November 2019, 2019-11-00, 20191101, Letnik:
71, Številka:
5
Journal Article
Recenzirano
Odprti dostop
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•Anonymous liver donors can successfully contribute to the donor organ pool.•Social media can be used to educate communities about this opportunity.•Anonymous donors are motivated by ...their values and beliefs and are very satisfied with their experience.
Death rates on liver transplant waiting lists range from 5%–25%. Herein, we report a unique experience with 50 anonymous individuals who volunteered to address this gap by offering to donate part of their liver to a recipient with whom they had no biological connection or prior relationship, so called anonymous live liver donation (A-LLD).
Candidates were screened to confirm excellent physical, mental, social, and financial health. Demographics and surgical outcomes were analyzed. Qualitative interviews after donation examined motivation and experiences. Validated self-reported questionnaires assessed personality traits and psychological impact.
A total of 50 A-LLD liver transplants were performed between 2005 and 2017. Most donors had a university education, a middle-class income, and a history of prior altruism. Half were women. Median age was 38.5 years (range 20–59). Thirty-three (70%) learned about this opportunity through public or social media. Saving a life, helping others, generativity, and reciprocity for past generosity were motivators. Social, financial, healthcare, and legal support in Canada were identified as facilitators. A-LLD identified most with the personality traits of agreeableness and conscientiousness. The median hospital stay was 6 days. One donor experienced a Dindo-Clavien Grade 3 complication that completely resolved. One-year recipient survival was 91% in 22 adults and 97% in 28 children. No A-LLD reported regretting their decision.
This is the first and only report of the characteristics, motivations and facilitators of A-LLD in a large cohort. With rigorous protocols, outcomes are excellent. A-LLD has significant potential to reduce the gap between transplant organ demand and availability.
We report a unique experience with 50 living donors who volunteered to donate to a recipient with whom they had no biological connection or prior relationship (anonymous living donors). This report is the first to discuss motivations, strategies and facilitators that may mitigate physical, social and ethical risk factors in this patient population. With rigorous protocols, anonymous liver donation and recipient outcomes are excellent; with appropriate clinical expertise and system facilitators in place, our experience suggests that other centers may consider the procedure for its significant potential to reduce the gap between transplant organ demand and availability.
Biliary drainage with ERCP is successful in only 80% to 90% of cases of extrahepatic cholangiocarcinoma and pancreatic cancer. We present the results of a multicenter prospective study assessing the ...safety, feasibility, and quality of life of patients after EUS-guided biliary drainage (EUS-BD) with lumen-apposing metal stents after failed ERCP.
All consecutive adults with a dilated common bile duct (CBD) ≥14 mm secondary to inoperable malignant distal CBD stricture and failed ERCP biliary drainage were screened and recruited from 3 tertiary UK centers. Technical success of EUS-BD using lumen-apposing metal stents was the primary endpoint. Improvement in serum bilirubin level, 30-day mortality, procedure-related adverse events, and quality of life were secondary endpoints. Improvement in quality of life was measured using a validated questionnaire (EORTC QLQ-BIL21).
Twenty patients were included in the analysis. EUS-BD was technically successful in all patients and the clinical success rate was 95% (19 of 20) at day 7 (>50% reduction in bilirubin level) and 92.3% (12 of 13) at day 30 (bilirubin <50 μmol/L). There were significant improvements in overall quality of life score (49 vs 42, P = .03) at day 30. All-cause 30-day mortality was 20% and the moderate adverse event rate was 10% (1 cholangitis and 1 stent migration).
EUS-BD has acceptable technical success and safety as a second-line palliative treatment for inoperable malignant distal CBD strictures. Randomized controlled studies comparing EUS-BD with percutaneous transhepatic biliary drainage are needed to determine their effectiveness in clinical practice. (ISCRTN registration number: ISRCTN13196704.)
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Historically, bleeding was thought to be a frequent and fatal complication of liver disease. However, thrombosis due to coagulation disorders in cirrhosis remains a real risk. We aim to ...systematically analyse published articles to evaluate epidemiology of venous thromboembolism (VTE) in chronic liver disease (CLD).
Electronic search was conducted on Ovid Medline, EMBASE and Scopus from inception to November 2021 to identify studies presenting epidemiology VTE (deep vein thrombosis and pulmonary embolism) in CLD in inpatients and/or community settings. Random-effects meta-analysis was performed to determine pooled per-year cumulative incidence, incidence rate and prevalence. Heterogeneity was measured by I2 test, and, potential sources of heterogeneity by meta-regression and sensitivity analysis. PROSPERO registration-CRD42021239117.
Twenty-nine studies comprising 19,157,018 participants were included, of which 15,2049 (0.79%) had VTE. None of the included studies were done in the community. In hospitalised patients with CLD: pooled cumulative incidence of VTE was 1.07% (95% CI 0.80,1.38) per-year, incidence rate was 157.15 (95% CI 14.74,445.29) per 10,000 person-years, and period prevalence was 1.10% (95% CI 0.85,1.38) per year. There was significant heterogeneity and publication bias. Pooled relative risk (RR) of studies reporting incidence rate was 2.11 (95% CI 1.35,3.31). CLD patients (n = 1644), who did not receive pharmacological prophylaxis were at 2.78 times (95% CI 1.11, 6.98) increased risk of VTE compared to those receiving prophylaxis.
Hospitalised patients with CLD may be at an increased risk of VTE. For every 1000 hospitalised patients with CLD ten have new, and eleven have pre-existing diagnoses of VTE per-year.
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Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject ...of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.
The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A ...multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.
Abstract
Background and study aims Pancreatic cysts are common incidental findings, with an estimated prevalence of 13% to 15% in imaging done for other reasons. Diagnosis often relies on collection ...of cyst fluid, but tissue sampling using micro-forceps may allow for a more reliable diagnosis and higher yield of DNA for next-generation sequencing (NGS). The primary aim was to assess the performance of NGS in identifying mucinous cyst. The secondary aims were to assess DNA yield between the cyst fluid and cyst wall tissue, complication rate and performance of conventional investigations.
Patients and methods Twenty-four patients referred for endoscopic ultrasound were recruited. Biopsies were taken using micro-forceps and the AmpliSeq Cancer Hotspot panel was used for NGS, a polymerase chain reaction assay targeting several hotspots within 50 genes, including GNAS, KRAS and VHL.
Results The concentration of DNA extracted from 24 cyst wall samples was significantly higher than in the nine of 24 available matched cyst fluid samples. The sensitivity, specificity, and diagnostic accuracy of NGS for diagnosing mucinous cyst were 93%, 50% and 84%; for standard of care, they were -66.6%, 50% and 63.1%; and for standard of care with NGS, they were 100%, 50%, and 89.4% respectively. Cyst wall biopsy was able to diagnose 19 of 24 cysts (4 high risk, 7 intraductal papillary mucinous neoplasms, 4 cysts of mucinous origin, and 4 benign).
Conclusions NGS data correlate well with histology and may aid in diagnosis and risk stratification of pancreatic cysts. Cyst wall biopsy performs well in diagnosing cysts but was inadequate in five of 24 patients.
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