Precision cut liver slices (PCLSs) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two‐dimensional mono‐ or ...co‐cultures. The aim of this study was to develop a bioreactor system to increase the healthy life span of PCLSs and model fibrogenesis. PCLSs were generated from normal rat or human liver, or fibrotic rat liver, and cultured in our bioreactor. PCLS function was quantified by albumin enzyme‐linked immunosorbent assay (ELISA). Fibrosis was induced in PCLSs by transforming growth factor beta 1 (TGFβ1) and platelet‐derived growth factor (PDGFββ) stimulation ± therapy. Fibrosis was assessed by gene expression, picrosirius red, and α‐smooth muscle actin staining, hydroxyproline assay, and soluble ELISAs. Bioreactor‐cultured PCLSs are viable, maintaining tissue structure, metabolic activity, and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell‐cultured PCLSs rapidly deteriorate, and albumin secretion is significantly impaired by 48 hours. TGFβ1/PDGFββ stimulation of rat or human PCLSs induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts, and histological fibrosis. Fibrogenesis slowly progresses over 6 days in cultured fibrotic rat PCLSs without exogenous challenge. Activin receptor‐like kinase 5 (Alk5) inhibitor (Alk5i), nintedanib, and obeticholic acid therapy limited fibrogenesis in TGFβ1/PDGFββ‐stimulated PCLSs, and Alk5i blunted progression of fibrosis in fibrotic PCLS. Conclusion: We describe a bioreactor technology that maintains functional PCLS cultures for 6 days. Bioreactor‐cultured PCLSs can be successfully used to model fibrogenesis and demonstrate efficacy of antifibrotic therapies.
Background
Major urological complications (MUCs) after kidney transplantation contribute to patient morbidity and compromise graft function. The majority arise from the vesicoureteric anastomosis and ...present early after transplantation. Ureteric stents have been successfully used to treat such complications. A number of centres have adopted a policy of universal prophylactic stenting, at the time of graft implantation, to reduce the incidence of urine leaks and ureteric stenosis. Stents are associated with specific complications and some centres advocate a policy of only stenting selected anastomoses.
Objectives
To examine the benefits and harms of routine ureteric stenting to prevent urological complications in kidney transplant recipients.
Search methods
We searched the Cochrane Renal Group's Specialised Register (up to 8 January 2013) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
Selection criteria
All RCTs and quasi‐RCTs were included in our meta‐analysis.
Data collection and analysis
Four reviewers assessed the studies for quality against four criteria (allocation concealment, blinding, intention‐to‐treat and completeness of follow‐up). The primary outcome was the incidence of MUCs. Further outcomes of interest were graft and patient survival and the incidence of adverse events (urinary tract infection (UTI), haematuria, irritative symptoms, pain and stent migration). Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI).
Main results
Seven RCTs (1154 patients) of low or moderate quality were identified. The incidence of MUCs was significantly reduced (RR 0.24, 95% CI 0.07 to 0.77, P = 0.02, NNT 13) by universal prophylactic stenting. This was dependent on whether the same surgeon performed, or was in attendance, during the operations. Two patients lost their grafts to infective urinary tract complications in the stented group. UTIs, in general, were more common in stented patients (RR 1.49, 95% CI 1.04 to 2.15) unless the patients were prescribed cotrimoxazole 480 mg/d: in which case the incidence was equivalent (RR 0.97, 95% CI 0.71 to 1.33). Stents appeared generally well tolerated, although studies using longer stents (≥ 20 cm) for longer periods (> 6 weeks) had more problems with encrustation and migration.
Authors' conclusions
Routine prophylactic stenting reduces the incidence of MUCs. Studies comparing selective stenting and universal prophylactic stenting, whilst difficult to design and analyse, would address the unresolved quality of life and economic issues.
To investigate the null hypothesis that an objective, noninvasive technique of measuring cardiorespiratory reserve, does not improve the preoperative assessment of patient risk of postoperative ...complications, when compared with a standard questionnaire-based assessment of functional capacity.
Postoperative complications may be increased in patients with reduced cardiorespiratory function. Activity questionnaires are subjective, whereas cardiopulmonary exercise testing (CPET) provides an objective definition of cardiorespiratory reserve. The use of preoperative CPET to predict postoperative complications is not fully defined.
CPET and an algorithm-based activity assessment (Veterans Activity Questionnaire Index VASI) were performed on consecutive patients (n = 171) with low subjective functional capacity (metabolic equivalent score METS < 7), being assessed for major surgery. A morbidity survey determined postoperative day 7 complications. Logistic regression defined independent predictors of complication group. Receiver-operating curve (ROC) analysis defined the predictive value of CPET to outcome. P < 0.05 value demonstrated significance.
Objective cardiorespiratory reserve did not differ between operated (n = 116) and nonoperated patients (n = 55). Median complication rate on postoperative day 7 was 1. Patients with >1 complication had an increase in hospital LOS compared to the group with < or =1 complication (26 vs. 10 days; P < 0.001). Anaerobic threshold (AT) was higher in the group with < or =1 complication (11.9 vs. 9.1 mL/kg/min; P = 0.001) and demonstrated high accuracy (AUC = 0.85), sensitivity (88%), and specificity (79%), at an optimum AT of 10.1 mL/kg/min (defined by the furthest left point on the ROC curve). AT, VASI, and surgical reintervention were independent predictors of complication group. Preoperative AT significantly improved outcome prediction when compared with the use of VASI alone.
An objective measure of cardiorespiratory reserve was an independent predictor of a major surgical group with increased postoperative complications and hospital LOS. AT measurement significantly improved outcome prediction compared with an algorithm-based activity assessment.
Background & Aims Hepatocellular cancer (HCC) commonly complicates chronic liver disease and increases in incidence have been reported despite falling prevalences of viral hepatitis. Methods ...Following the introduction of centralised specialist teams to manage patients with cancer in England, we characterised the demographics of patients with HCC referred to the Newcastle-upon-Tyne Hospitals NHS Foundation Trust between 2000 and 2010. Regional HCC mortality data was from Public Health England. Results HCC related mortality in the region rose 1.8 fold in 10 years, from 2.0 to 3.7 per 100,000. 632 cases were reviewed centrally, with 2–3 fold increases in referrals of patients with associated hepatitis C, alcoholic liver disease or no chronic liver disease and a >10 fold increase in HCC associated with non-alcoholic fatty liver disease (NAFLD). By 2010 NAFLD accounted for 41/118 (34.8%) cases. Irrespective of associated etiologies, metabolic risk factors were present in 78/118 (66.1%) cases in 2010, associated with regional increases in obesity and diabetes. Median overall survival was just 10.7 months. Although patients with NAFLD associated HCC were older (71.3 yr vs. 67.1 yr; p <0.001) and their cancers less often detected by surveillance, their survival was similar to other etiologies. This was attributed to significantly higher incidental presentation (38.2%) and lower prevalence of cirrhosis (77.2%). Conclusions HCC related mortality is increasing, with typical patients being elderly with metabolic risk factors. The prognosis for most of the cases is poor, but older patients with co-morbidities can do well, managed, within a specialist multidisciplinary team if their cancer is detected pre-symptomatically.
Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and death; ...however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory‐confirmed SARS‐CoV‐2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow‐up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case‐mix. One hundred ninety‐seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS‐CoV‐2. Mortality after testing positive for SARS‐CoV‐2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS‐CoV‐2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS‐CoV‐2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.
The authors link national datasets in England and compare waitlisted patients and transplant recipients on the incidence of SARS‐CoV‐2 infection and subsequent mortality to inform risk/benefit decisions during the COVID‐19 pandemic.
Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and ...<10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how ‘resectable’ disease is defined – molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.
OBJECTIVE:This study aimed to define the relationship between cardiorespiratory fitness and age in the context of postsurgery mortality and morbidity in older people.
BACKGROUND:Postsurgery mortality ...and morbidity increase with age. Cardiorespiratory fitness also declines with age, and the independent and linked associations between cardiorespiratory fitness and age on postsurgical mortality and morbidity remain to be determined.
METHODS:An unselected consecutive group of 389 adults with a mean age of 66 years (range 26–86 years) underwent cardiorespiratory exercise testing before major hepatobiliary surgery at a single center. Mortality and critical care unit and hospital lengths of stay were collected from patient records. Primary outcomes were in-hospital all-cause mortality after surgery and hospital and critical care lengths of stay.
RESULTS:Anaerobic threshold was the most significant independent predictor for postoperative mortality (P = 0.003; β = −0.657 and odds ratio = 0.52) in 18 of 389 (4.6%) patients who died during their in-hospital stay. Age was not a significant predictor in this model. Older people with normal cardiorespiratory fitness spent the same number of days in the hospital or critical care unit as younger people with similar cardiorespiratory fitness (13 vs 12; P = 0.08 and 1 vs 1; P = 0.103). Patients older than 75 years with low cardiorespiratory fitness spent a median of 11 days longer in hospital (23 vs 12; P < 0.0001) and 2 days longer in critical care (2.9 vs 0.9; P < 0.0001) when compared with patients with adequate cardiorespiratory fitness.
CONCLUSIONS:Cardiorespiratory fitness is an independent predictor of mortality and length of hospital stay and provides significantly more accurate prognostic information than age alone. Clinicians should consider both the prognostic value of cardiorespiratory testing and techniques to preserve cardiorespiratory function before elective surgery in older people.
The role of adjuvant therapy for biliary tract cancer is not clearly defined with conflicting results demonstrated across nonrandomized and randomized studies. We report a systematic review and ...meta-analysis to delineate the effect of AT on overall survival.
Eligible studies were identified from MEDLINE, EMBASE, Cochrane and PubMed. Studies comparing adjuvant chemotherapy or chemoradiotherapy after curative-intent surgery with curative surgery only for biliary tract cancer were included. Data pertaining to tumours of the gallbladder and bile ducts were included. The primary outcome assessed was overall survival. Random-effects meta-analysis was performed, as well as pooling of unadjusted Kaplan-Meier curve data.
35 studies involving 42,917 patients were analysed. There was a significant improvement in overall survival with any adjuvant therapy after surgery compared with surgery only (HR 0.74; 95% CI, 0.67 to 0.83; P < 0.001). There was a significant benefit for adjuvant therapy in those with margin positive surgery (RR, 0.83; 95% CI, 0.77 to 0.91; P < 0.001) and node-positive disease (RR 0.82; 95% CI 0.76 to 0.89; P < 0.001)
Our review advocates the use of adjuvant therapy in bile duct cancer after curative intent resection. Further prospective studies are needed to determine the optimal regime and timing of an adjuvant approach.
•Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data: KR, GS, DM, HM, ZH.•Drafting the article or revising it critically for important intellectual content: KR, GS, DM, HM, ZH.•Final approval of the version to be published: KR, GS, DM, HM, ZH.
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