Liver function monitoring in Fontan-procedure patients: audit of current practice across South Wales

The Fontan procedure provides a palliative surgical repair for complex congenital heart disease, but it is associated with many long-term problems, including liver cirrhosis, and hepatocellular carcinoma. The current suggestion from international guidance is that end-organ surveillance should be carried out, with a particular focus on regular blood tests and imaging for liver function.In this study, retrospective analysis was performed on adult patients who had previously had a Fontan operation performed to determine the regularity of end-organ surveillance in regards to their liver function covering the three calendar years from 2016 to 2018, and the first six months of 2019.Eighty-six patients were identified in South Wales monitored by the adult congenital heart disease unit. We found that the number of investigations performed in the first six months of 2019 was comparable to other calendar years in their entirety. Liver function tests had been performed in 57% of patients throughout 2018, with only 8% having had an alpha-fetoprotein taken, and only 9% having had imaging of the liver performed. Over the course of their lifetime, 97% of patients had had a liver function blood test performed at some point, with 17% having had an alpha-fetoprotein taken, and 49% having their liver imaged.In conclusion, end-organ surveillance is an important follow-up for patients with a Fontan circulation, with guidelines proposing yearly blood test and imaging investigations. This study shows the opportunities to improve surveillance in this group of patients to highlight the development of liver cirrhosis, and/or hepatocellular carcinoma.Key words: congenital heart defects, Fontan procedure, healthcare quality assurance, hepatocellular carcinoma, liver disease     

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Amino Surface Modification and Fluorescent Labelling of Porous Hollow Organosilica Particles: Optimization and Characterization

Surface modification of silica nanoparticles with organic functional groups while maintaining colloidal stability remains a synthetic challenge. This work aimed to prepare highly dispersed porous hollow organosilica particles (pHOPs) with amino surface modification. The amino-surface modification of pHOPs was carried out with 3-aminopropyl(diethoxy)methylsilane (APDEMS) under various reaction parameters, and the optimal pHOP-NH₂ sample was selected and labelled with fluorescein isothiocyanate (FITC) to achieve fluorescent pHOPs (F-HOPs). The prepared pHOPs were thoroughly characterized by transmission electron microscopy, dynamic light scattering, FT-IR, UV-Vis and fluorescence spectroscopies, and microfluidic resistive pulse sensing. The optimal amino surface modification of pHOPs with APDEMS was at pH 10.2, at 60 °C temperature with 10 min reaction time. The positive Zeta potential of pHOP-NH₂ in an acidic environment and the appearance of vibrations characteristic to the surface amino groups on the FT-IR spectra prove the successful surface modification. A red-shift in the absorbance spectrum and the appearance of bands characteristic to secondary amines in the FTIR spectrum of F-HOP confirmed the covalent attachment of FITC to pHOP-NH₂. This study provides a step-by-step synthetic optimization and characterization of fluorescently labelled organosilica particles to enhance their optical properties and extend their applications.     

Comparison Evaluation of the Biological Effects of Sterigmatocystin and Aflatoxin B1 Utilizing SOS-Chromotest and a Novel Zebrafish (Danio rerio) Embryo Microinjection Method

Aflatoxin B1 (AFB1) is a potent mycotoxin and natural carcinogen. The primary producers of AFB1 are Aspergillus flavus and A. parasiticus. Sterigmatocystin (STC), another mycotoxin, shares its biosynthetic pathway with aflatoxins. While there are abundant data on the biological effects of AFB1, STC is not well characterised. According to published data, AFB1 is more harmful to biological systems than STC. It has been suggested that STC is about one-tenth as potent a mutagen as AFB1 as measured by the Ames test. In this research, the biological effects of S9 rat liver homogenate-activated and non-activated STC and AFB1 were compared using two different biomonitoring systems, SOS-Chromotest and a recently developed microinjection zebrafish embryo method. When comparing the treatments, activated STC caused the highest mortality and number of DNA strand breaks across all injected volumes. Based on the E. coli SOS-Chromotest, the two toxins exerted the same genotoxicities. Moreover, according to the newly developed zebrafish microinjection method, STC appeared more toxic than AFB1. The scarce information correlating AFB1 and STC toxicity suggests that AFB1 is a more potent genotoxin than STC. Our findings contradict this assumption and illustrate the need for more complex biomonitoring systems for mycotoxin risk assessment.     

Estimating the predictive validity of diabetic animal models in rosiglitazone studies

For therapeutic studies, predictive validity of animal models – arguably the most important feature of animal models in terms of human relevance – can be calculated retrospectively by obtaining data on treatment efficacy from human and animal trials. Using rosiglitazone as a case study, we aim to determine the predictive validity of animal models of diabetes, by analysing which models perform most similarly to humans during rosiglitazone treatment in terms of changes in standard diabetes diagnosis parameters (glycosylated haemoglobin [HbA1c] and fasting glucose levels). A further objective of this paper was to explore the impact of four covariates on the predictive capacity: (i) diabetes induction method; (ii) drug administration route; (iii) sex of animals and (iv) diet during the experiments. Despite the variable consistency of animal species‐based models with the human reference for glucose and HbA1c treatment effects, our results show that glucose and HbA1c treatment effects in rats agreed better with the expected values based on human data than in other species. Induction method was also found to be a substantial factor affecting animal model performance. The study concluded that regular reassessment of animal models can help to identify human relevance of each model and adapt research design for actual research goals.     

The antigen/receptor specificity of antigranulocyte antibodies in patients with SLE

The antigen/receptor specificity of antigranulocyte antibodies (AGAs) detected in the sera of patients with systemic lupus erythematosus (SLE) was investigated by inhibitory immunofluorescence test and Western immunoblotting technique. The interactions of AGAs with antigens of intact normal granulocytes were determined by inhibiting the binding of different myeloid monoclonal antibodies (mAbs). Seven of the studied 12 sera revealed binding to CD15 (X hapten) and/or to CD16 (FcR1o). The specificity investigation of AGAs was completed with Western immunoblotting technique. The binding of AGAs to bands with Mr of about 50-60 kDa and at 30 kDa on unstimulated granulocyte plasma membrane preparation could be demonstrated from 4 out of 6 AGA positive SLE sera. The cause of the disappearance of bands on the phorbol-myristate-acetate (PMA) activated membrane except those of the 50-60 kDa bands is still to be discovered.     

Aortoiliac reconstruction with allograft and kidney transplantation as a one-stage procedure: long term results.

OBJECTIVES: An increasing number of aortoiliac lesions and abdominal aortic aneurysms occur in renal failure patients waiting for renal transplantation. The aim of our study was to assess long term results of simultaneous renal transplantation and surgical repair of aortoiliac lesions with arterial allografts. DESIGN: A retrospective observational study. PATIENTS AND METHODS: From October 1997 to June 2007, we performed simultaneous aortoiliac reconstructions using fresh arterial allografts and kidney transplantation in 14 patients with chronic renal failure (men 9, women 5, mean age 53 years). The indication for vascular reconstruction was an asymptomatic abdominal aneurysm in 6 patients or aortoiliac stenosis/occlusion in 8 patients. The median follow up period for the cohort was 55.5 months (range from 1 to 116 months). RESULTS: Three patients died during the follow up period. In none of them there was an allograft (neither arterial nor renal) related death. No signs of arterial grafts infection or aneurysmal formation and no need for secondary intervention (angioplasty and/or thrombolysis) of any arterial reconstruction was observed during the follow up period in any patient. The renal grafts failed in three patients. CONCLUSIONS: Our experience suggests that it is possible and safe to use arterial allografts in the treatment of arterial occlusive disease or abdominal aortic aneurysm simultaneously with renal transplantation.