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Blood pressure targets in CKD 2021: the never-ending guidelines debacle.
No full textIn 2021, two updated clinical guidelines were published, providing guidance on blood pressure (BP) targets for people with chronic kidney disease (CKD). Kidney Disease: Improving Global Outcomes (KDIGO) updated its 2012 Clinical Practice Guideline for the Management of BP in CKD. Different systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets for CKD (30 mg/g or without pathological albuminuria) were replaced by a single number: an SBP target of <120 mmHg is suggested, when tolerated. This represents a major decrease in the SBP target and the abandonment of DBP targets. The European Society of Cardiology (ESC) also published a 2021 Clinical Guideline on Cardiovascular Disease Prevention in Clinical Practice that updates a prior 2016 guideline on prevention and the 2018 ESC/European Society of Hypertension Clinical Practice Guidelines for the Management of Arterial Hypertension. The 2021 ESC guideline was endorsed by 12 European scientific societies. The recommended office BP targets for people with CKD are <140-130 mmHg SBP (lower SBP is acceptable if tolerated) and <80 mmHg DBP. The question is: What should the practicing physician do now: treat hypertension in people with CKD to an SBP target of <120 mmHg or to a target of <140-130 mmHg? Major guideline bodies are aware of the activities of other major players. There is an urgent need for guideline bodies to establish communication channels, search consensus on major issues that impact the health of hundreds of millions of people worldwide and end individualism in guidelines generation
PD-L1 Testing in Urothelial Carcinoma: Analysis of a Series of 1401 Cases Using Both the 22C3 and SP142 Assays.
No full textImmune checkpoint blockade (ICB) drugs are a novel, effective treatment for advanced urothelial carcinoma. Worldwide, several different ICB drugs are approved, each developed and clinically validated with a specific PD-L1 compound diagnostic assay. As a result, PD-L1 testing workflows in routine practice are complex: requiring multiple assays across two platforms, with each assay having a different method of interpretation. Our service tested 1,401 urothelial carcinoma cases for PD-L1 expression, using both the 22C3 PharmDx assay (required prior to Pembrolizumab therapy) and SP142 assay (required prior to Atezolizumab therapy). Of the 1,401 cases tested, 621 cases (44%) were tested with both the 22C3 PharmDx and SP142 assays, 492 cases (35%) with 22C3 PharmDx only, and 288 cases (21%) with SP142 only. Each assay was used and interpreted according to the manufacturer's guidelines. The rate of positivity we observed was 26% with the 22C3 assay and 31% with the SP142 assay, similar to the pre-licensing studies for both drugs. The discrepancy observed between the assays was 11%, which reinforces the requirement for utilisation of the correct assay for each agent, and limits potential cross-utility of assays. This aspect must be considered when setting up a PD-L1 testing strategy in laboratories where both Pembrolizumab and Atezolizumab are available for the treatment of urothelial carcinoma but also has broader implications for testing of other cancers where multiple ICB drugs and their respective assays are approved
Surgical Correction of Carcinoid Heart Disease Improves Liver Function and 5-Hydroxyindoleacetic Acid Levels.
No full textIntroduction
Carcinoid heart disease (CHD) is a consequence of neuroendocrine tumors releasing 5-hydroxytryptamine (5-HT) into the systemic circulation, affecting right heart valves, causing fibrosis, and eventually right heart failure. The aim of this study was to determine the effect of valve-replacement on kidney function, liver function, and 5-hydroxyindoleacetic acid (5-HIAA) levels.
Methods
A Retrospective study of 17 patients with CHD who had undergone heart-valve replacement surgery between 2010 and 2019, from the Queen Elizabeth Hospital Birmingham. 5-HIAA levels, liver, and kidney function were measured in addition to hepatic inferior vena cava (IVC) diameter and its relationship to carcinoid symptoms.
Results
Eleven patients were male and six were female. At time of surgery, average age was 66.6 ± 8.1 years and average BMI was 25.8 ± 5.5 Kg/cm. Three out of 17 patients had one valve replaced, 13/17 had two replaced (tricuspid and pulmonary), and 1/17 had three replaced (tricuspid, pulmonary and aortic). There was a 31% average decline in 5-HIAA [799.8 (343.6-1078.0) to 555.3 (275.8-817.9), = 0.011], a 35% decline in bilirubin [20 (16-29) to 13 (10-19), = < 0.001], and a 15% reduction in the short and long axes of the IVC after valve-replacement surgery [20.0 (18.0-25.0) and 36.5 (29.0-39.8) to 17.0 (14.5-19.3) and 31.0 (26.5-34.3) respectively, = < 0.001 and 0.002 respectively].
Conclusion
Valve replacement surgery improves 5-HIAA levels alongside improved liver function and hepatic IVC diameter. These findings are consistent with resolution of congestive hepatopathy, and therefore enhanced clearance of 5-HIAA. This suggests that valve-replacement surgery can indirectly have beneficial outcomes on hepatic function and is also associated with a drop in the circulating levels of tumor derived serotonin
Magnetic resonance imaging for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.
No full textBACKGROUND
Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and third in terms of cancer deaths. In clinical practice, magnetic resonance imaging (MRI) is used as a second-line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha-fetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast-enhanced imaging study (computed tomography (CT) or MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is considered valid to diagnose hepatocellular carcinoma. The detection of hepatocellular carcinoma amenable to surgical resection could improve the prognosis. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma may, therefore, be missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of MRI may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of MRI in people with chronic liver disease who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma.
OBJECTIVES
Primary: to assess the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease. Secondary: to assess the diagnostic accuracy of MRI for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease, and to identify potential sources of heterogeneity in the results.
SEARCH METHODS
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test of Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, and three other databases to 9 November 2021. We manually searched articles retrieved, contacted experts, handsearched abstract books from meetings held during the last 10 years, and searched for literature in OpenGrey (9 November 2021). Further information was requested by e-mails, but no additional information was provided. No data was obtained through correspondence with investigators. We applied no language or document-type restrictions.
SELECTION CRITERIA
Studies assessing the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six-month follow-up.
DATA COLLECTION AND ANALYSIS
At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and we tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses.
MAIN RESULTS
We included 34 studies, with 4841 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time interval between the index test and the reference standard was rarely defined. Regarding applicability, we judged 15% (5/34) of studies to be at low concern and 85% (29/34) of studies to be at high concern mostly owing to characteristics of the participants, most of whom were on waiting lists for orthotopic liver transplantation, and due to pathology of the explanted liver being the only reference standard. MRI for hepatocellular carcinoma of any size and stage: sensitivity 84.4% (95% CI 80.1% to 87.9%) and specificity 93.8% (95% CI 90.1% to 96.1%) (34 studies, 4841 participants; low-certainty evidence). MRI for resectable hepatocellular carcinoma: sensitivity 84.3% (95% CI 77.6% to 89.3%) and specificity 92.9% (95% CI 88.3% to 95.9%) (16 studies, 2150 participants; low-certainty evidence). The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results.
AUTHORS' CONCLUSIONS
We found that using MRI as a second-line imaging modality to diagnose hepatocellular carcinoma of any size and stage, 16% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 16% of people with resectable hepatocellular carcinoma would improperly not be resected, while 7% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results
Influence of body composition measures on chyle leak after oesophagectomy.
No full textBackground
Chyle leak (CL) is an infrequent but potentially serious complication of oesophagectomy. Sarcopenia is an increasingly recognised prognostic factor in oesophageal cancer surgery. The aim of this study was to identify the influence of body composition measures on CL following oesophagectomy.
Methods
Patients who developed CL after oesophagectomy between January 2006-December 2020 were identified retrospectively from a prospectively maintained dataset. A control group of patients undergoing oesophagectomy, who did not experience chyle leak during the same time period, was also collected. Relationships between CL and demographics, operative factors and body composition measures were investigated as primary outcomes. Risk factors for severe CL were evaluated as a secondary outcome.
Results
There were 26 patients who developed a CL following an oesophagectomy. On univariate analysis, preoperative body mass index (BMI) (P=0.001), subcutaneous fat index (P=0.001) and total fat index (P=0.004) were significantly associated with CL. On multivariate analysis, a lower preoperative subcutaneous fat index was a significant independent predictor of CL (P=0.003). Sarcopenia, as an overall measure, was not found to be a significant predictor of developing CLs. No significant predictors of severe CL were identified.
Conclusions
A reduced preoperative BMI and body fat composition are risk factors for CL after oesophagectomy. Sarcopenia does not predict either the occurrence or severity of CL. This presents potentially modifiable risk factors for CL after oesophagectomy and emphasises the importance of physiological and nutritional optimisation before oesophagectomy
Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.
No full textIn March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort
Development of the ParaOesophageal hernia SympTom (POST) tool.
No full textBACKGROUND
The aim of this study was to develop a symptom severity instrument (ParaOesophageal hernia SympTom (POST) tool) specific to para-oesophageal hernia (POH).
METHODS
The POST tool was developed in four stages. The first was establishment of a Steering Committee. In the second stage, items were generated through a systematic review and online scoping survey of international experts. In the third stage, a three-round modified Delphi consensus process was conducted with a group of international experts who were asked to rate the importance of candidate items. An a priori threshold for inclusion was set at 80 per cent. The modified Delphi process culminated in a consensus meeting to develop the first iteration of the tool. In the final stage, two international patient workshops were held to assess the content validity and acceptability of the POST tool.
RESULTS
The systematic review and scoping survey generated 64 symptoms, refined to 20 for inclusion in the modified Delphi consensus process. Twenty-six global experts participated in the Delphi consensus process. Five symptoms reached consensus across two rounds: difficulty getting solid foods down, chest pain after meals, difficulty getting liquids down, shortness of breath only after meals, and an early feeling of fullness after eating. The subsequent patient workshops deemed these five symptoms to be relevant and suggested that reflux should be included; these were taken forward to create the final POST tool.
CONCLUSION
The POST tool is the first instrument designed to capture POH-specific symptoms. It will allow clinicians to standardize reporting of symptoms of POH and evaluate the response to surgical intervention
In-situ normothermic regional perfusion versus ex-situ normothermic machine perfusion in liver transplantation from donation after circulatory death.
No full textBACKGROUND
In-situ normothermic regional perfusion (NRP) and ex-situ normothermic machine perfusion (NMP) aim to improve outcomes of liver transplantation (LT) using controlled donation after circulatory death (cDCD). NRP and NMP have not yet been compared directly.
METHODS
In this international observational study, outcomes of LT performed between 2015 and 2019 for organs procured from cDCD donors subjected to NRP or NMP commenced at the donor centre were compared using propensity score matching (PSM).
RESULTS
Of the 224 cDCD donations in the NRP cohort that proceeded to asystole, 193 livers were procured, resulting in 157 transplants. Within the NMP cohort, perfusion was commenced in all 40 cases and resulted in 34 transplants (utilisation rates: 70% vs 85% [p=0.052], respectively). After PSM, 34 NMP liver recipients were matched with 68 NRP liver recipients. The two cohorts were similar for donor functional warm ischemic time (21 min after NRP vs 20 min after NMP; p=0.17), UK-DCD risk score (5 vs 5 points; p=0.38) and lab-MELD scores (12 vs 12 points; p=0.83). The incidence of non-anastomotic biliary strictures (1.5% vs 2.9%; p>0.99), early allograft dysfunction (20.6% vs 8.8%; p=0.13) and 30-day graft loss (4.4% vs 8.8%; p=0.40) were similar, although peak post-transplant AST levels were higher in the NRP cohort (872 vs 344 IU/l; p<0.001). NRP livers were more frequently allocated to recipients suffering from hepatocellular carcinoma (60.3% vs 20.6%; p<0.001). HCC-censored 2-year graft and patient survival were 91.5% vs 88.2% (p=0.52) and 97.9% vs 94.1% (p=0.25) after NRP and NMP, respectively.
CONCLUSION
Both perfusion techniques achieved similar outcomes and appear to match benchmarks expected for DBD livers. This study may inform the design of a definitive trial
Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.
No full textWhether non-selective β-blockers can prevent decompensation of cirrhosis needs clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal-hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in compensated cirrhosis with clinically significant portal hypertension (CSPH).
METHODS
By systematic review we identified RCTs comparing carvedilol vs control therapy (no-active treatment or EVL) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (OLT and death were competing-events) and death (OLT, competing-event). Models were adjusted using propensity score for baseline covariates with the IPTW approach.
RESULTS
Among 125 full-text studies evaluated, 4 RCTs were eligible. The four provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (SHR=0.506, 95%CI=0.289-0.887, P=0.017; I=0.0%, Q-statistic-P=0.880), mainly due to a reduced risk of ascites (SHR=0.491, 95%CI=0.247-0.974, P=0.042; I=0.0%, Q-statistic-P=0.384). The risk of death was also lower with carvedilol (SHR=0.417, 95%CI=0.194-0.896, P=0.025; I=0.0%, Q-statistic-P=0.989).
CONCLUSIONS
Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to start therapy with carvedilol can improve outcomes.
LAY SUMMARY
Portal hypertension is a main determinant of the progression of cirrhosis from compensated to decompensation with the consequent increase in morbidity and worsening of life expectancy. It has been suggested that NSBBs can prevent decompensation, but this has not been clarified. Carvedilol might be particularly useful since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, which is a major mechanism of portal hypertension in compensated cirrhosis. We aimed to investigate such possibility using an individual participant data with competing-risk meta-analysis, to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events. The study shows that carvedilol significantly decreases the risk of decompensation in patients with compensated cirrhosis and CSPH, mainly by reducing the risk of developing ascites. Even more importantly, carvedilol improved survival in these patients. The findings suggest that screening patients with compensated cirrhosis for CSPH to start therapy with carvedilol, can prevent the progression of compensated cirrhosis to decompensation improving survival.
PROSPERO REGISTRATION NUMBER
CRD42019144786
