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Epidemiology, natural history and outcomes of primary sclerosing cholangitis: A systematic review of population-based studies.
No full textBACKGROUND
The aim of this study was to quantify the global epidemiology of primary sclerosing cholangitis (PSC), alongside the incidence of liver transplantation, cancer and death, through robust systematic review of population-based data.
METHODS
We searched MEDLINE and EMBASE up to and including June 30 2020 to identify population-based studies reporting the incidence and/or prevalence of PSC. Studies that did not report original data, or of exclusively pediatric-onset disease (diagnosis age <16 years) or exclusively PSC-associated with inflammatory bowel disease were excluded.
RESULTS
Of 4922 published studies, 17 fulfilled inclusion criteria; 16 documenting incidence and 14 prevalence. The highest reported incidence of PSC was reported in Northern Europe (Finland: 1.58 and Norway 1.3 per-100,000 population, respectively) and North America (Minnesota USA, 1.47); with the lowest being observed across the Mediterranean Basin (Italy, 0.1). Prevalence ranged from 31.7 in Finland and 23.99 in Minnesota, to 1.33 in Singapore and 0.0 in Alaska. Of studies reporting temporal occurrence, an increase in disease incidence was observed across North America and Northern Europe (four studies), alongside an increase in prevalence over time (four studies). The incidence and risks for clinical outcomes were presented by nine of the included studies. Median transplant-free survival ranged from 9.7 (USA) to 20.6 years (Netherlands), with standardized mortality ratios of 2.5 and 4.2 compared to the control population. The standardized incidence of cholangiocarcinoma ranged from 235 (Finland) to 398 (Netherlands).
CONCLUSIONS
Estimates of PSC incidence and prevalence vary, with most studies conducted in North America and Western Europe; the latter showing a steady increase in disease occurrence over time. Further research is needed to understand changes in disease epidemiology, including etiological drivers, the implications of rising case burden on healthcare policy, and better appreciation of PSC in the developing world
Azacitidine for the treatment of steroid-refractory chronic graft-versus-host disease: the results of the phase II AZTEC clinical trial.
No full textChronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m days 1-5 per 28-day cycle. Azacitidine was tolerated by 13/14 patients, and 7/14 showed an objective response. Clinical responses were mirrored by improvements in patient-reported cGvHD symptoms and quality of life. AZTEC demonstrates that azacitidine is a safe and promising option for the treatment of cGvHD, and continued evaluation in the second stage of this phase II efficacy study is supported
Outcomes of revision total hip arthroplasty using a vascularised anterior femoral window.
No full textPURPOSE
Extraction of the distal femoral cement mantle and restrictor during revision total hip arthroplasty (rTHA) is challenging and can compromise host bone stock. The aim of this study is to report outcomes of our femoral windowing technique for cement removal.
METHODS
We report on a cohort of 36 patients with an average age of 68.7 years who underwent 40 cemented rTHA between 2011 and 2017 using a vascularised anterior femoral window. Clinical and radiological outcomes were retrospectively reviewed with a mean follow-up of 6.6 years (range, 3.8-10).
RESULTS
Latest mean WOMAC score was 25.4 and all windows achieved radiographic union by a mean of 7.9 weeks. Femoral component survivorship was 100% and 38 out of 40 rTHAs showed no evidence of radiological loosening.
CONCLUSION
The vascularised anterior window to remove the distal femoral cement mantle under direct vision is safe and reproducible with excellent clinical and radiographic results
Prognostic implications of histological organ involvement in retroperitoneal sarcoma.
No full textBACKGROUND
The prognostic significance of histological organ involvement by retroperitoneal sarcoma subtype is unknown. The present study aimed to describe organ involvement across the subtypes, and the implications for survival.
METHODS
Patients undergoing surgery for primary retroperitoneal sarcoma at the Queen Elizabeth Hospital, Birmingham from April 2005 to September 2018 were identified retrospectively. Histological organ involvement was classed as pushing, infiltrative or neither. Univariable and multivariable Cox regression models were produced to analyse the association between histological organ involvement and both overall (OS) and recurrence-free (RFS) survival for the cohort as a whole, and by histological subtype.
RESULTS
Data were available for a total of 197 patients, of whom 171 (86.8 per cent) had at least one organ resected. Infiltrative organ behaviour was seen in 37 patients (18.8 per cent), and pushing behaviour in 67 (34.0 per cent). For the cohort as a whole, infiltration (hazard ratio (HR) 4.32, 95 per cent c.i. 2.35 to 7.93; P < 0.001), but not pushing (HR 1.62, 0.90 to 2.92; P = 0.106), was associated with significantly shorter OS, in comparisons with a group with neither of these behaviours. However, this effect was found to differ significantly by histological subtype (P = 0.009). For patients with dedifferentiated liposarcoma, there was no significant association between tumour behaviour and either OS (P = 0.508) or RFS (P = 0.313). However, in leiomyosarcoma, infiltrative behaviour was associated with shorter OS (P = 0.002), and both infiltrative (P < 0.001) and pushing (P = 0.010) behaviours were associated with shorter RFS, compared with tumours with neither behaviour. Multivariable analyses of both OS and RFS returned similar results.
CONCLUSION
The prognostic implications of organ involvement in retroperitoneal sarcoma vary by histological subtype
Novel detection of specific bacterial quorum sensing molecules in saliva: Potential non-invasive biomarkers for pulmonary Pseudomonas aeruginosa in cystic fibrosis.
No full textPseudomonas aeruginosa produces specific signalling molecules, 2-alkyl-4-quinolones (AQs) that are detectable in the sputum of adults with cystic fibrosis (CF) and who have pulmonary infection with this opportunistic pathogen. This study aimed to determine whether AQs could be detected in saliva of patients with CF and known infection with Pseudomonas aeruginosa. Saliva and sputum samples were obtained from 89 adults with CF and analyzed using liquid chromatography-tandem mass spectrometry. AQs were detected in 39/89 (43.8%) saliva samples and 70/77(90.9%) sputum samples. Salivary AQs had a sensitivity of 50% (95%CI; 37.8; 62.2), specificity of 100% (95%CI; 47.8; 100), when compared to a molecular microbiological measure of P. aeruginosa in sputum as measured using polymerase chain reaction. Specific AQs produced by P. aeruginosa can be detected in the saliva and warrant investigation as potential non-invasive biomarkers of pulmonary P. aeruginosa
Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results.
No full textINTRODUCTION
This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen.
METHODS
Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety.
RESULTS
Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6-11.1) and 5.6 (5.5-8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6-13.8) and 8.0 (5.6-8.3) months in the midgut and panNET cohorts, respectively. Patients' QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort).
CONCLUSIONS
In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies
NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment.
No full textPrimary Sjögren's syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. /NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the /NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 () and its ligand B7/H6 () in pSS salivary gland tissues. Levels of /NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between /NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, /NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory , while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of /NKp30 within the glands
Lung function and breathing patterns in hospitalised COVID-19 survivors: a review of post-COVID-19 Clinics.
No full textINTRODUCTION
There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19.
METHODS
We reviewed lung function and breathing patterns in COVID-19 survivors > 3 months after discharge, comparing patients who had been admitted to the intensive therapy unit (ITU) (n = 47) to those who just received ward treatments (n = 45). Lung function included spirometry and gas transfer and breathing patterns were measured with structured light plethysmography. Continuous data were compared with an independent t-test or Mann Whitney-U test (depending on distribution) and nominal data were compared using a Fisher's exact test (for 2 categories in 2 groups) or a chi-squared test (for > 2 categories in 2 groups). A p-value of < 0.05 was taken to be statistically significant.
RESULTS
We found evidence of pulmonary restriction (reduced vital capacity and/or alveolar volume) in 65.4% of all patients. 36.1% of all patients has a reduced transfer factor (TL) but the majority of these (78.1%) had a preserved/increased transfer coefficient (K), suggesting an extrapulmonary cause. There were no major differences between ITU and ward lung function, although K alone was higher in the ITU patients (p = 0.03). This could be explained partly by obesity, respiratory muscle fatigue, localised microvascular changes, or haemosiderosis from lung damage. Abnormal breathing patterns were observed in 18.8% of subjects, although no consistent pattern of breathing pattern abnormalities was evident.
CONCLUSIONS
An "extrapulmonary restrictive" like pattern appears to be a common phenomenon in previously admitted COVID-19 survivors. Whilst the cause of this is not clear, the effects seem to be similar on patients whether or not they received mechanical ventilation or had ward based respiratory support/supplemental oxygen
Renal haemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularised composite allograft - a preclinical study.
No full textINTRODUCTION
Recent experimental evidence suggests normothermic machine perfusion of the vascularised composite allograft (VCA) results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post-operative period. However, metabolic acidosis is a common feature of VCA perfusion, primarily due to the inability to process metabolic by-products. We evaluated the impact of combined limb-kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model.
METHODS
Ten paired pig forelimbs were used for this study, grouped as either limb-only (LO, n=5) perfusion, or limb-kidney (LK n=5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell-free DNA in the perfusate were recorded.
RESULTS
The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilisation of lactate, bicarbonate, base and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro-inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO.
CONCLUSION
The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis