Single nucleotide insertion in the 5′‐untranslated region of hepatitis C virus with clearance of the viral RNA in a liver transplant recipient during acute hepatitis B virus superinfection

Abstract: Hepatitis C virus (HCV) infection is an important etiology in patients undergoing orthotopic liver transplantation (OLT) world‐wide. Antiviral therapy‐related clearance of HCV RNA may occur both in patients with chronic HCV infection and in transplanted patients for HCV‐related liver cirrhosis, but the role of the 5′‐untranslated region (UTR) of HCV containing the internal ribosome entry site (IRES), which directs the translation of the viral open reading frame has not hitherto been evaluated. We studied the 5′‐UTR in an HCV‐infected recipient of a liver graft that showed spontaneous clearance of HCV RNA during an acute hepatitis B virus (HBV) superinfection. Sequencing of the 5′‐UTR of HCV showed a nucleotide A insertion at position 193 of the IRES.     

The long‐term quality of life and information needs of prostate cancer survivors

What are the quality of life (QoL) and information needs of long‐term prostate cancer survivors? Numbers of prostate cancer survivors are increasing and it is vital that their QoL issues and information needs are understood. The long‐term effects of surviving prostate cancer is poorly understood. Specialist nurses play a key role in their management. A cross‐sectional survey was used. The study questionnaire [(European Organization for Research and Treatment of Cancer‐Quality of Life Questionnaire) EORTC‐QLQ‐30 and EORTC QOL‐INFO25] was posted to 398 prostate cancer survivors attending an Irish centre managed by a clinical nurse specialist and consultant. Completed questionnaires (n = 195) were returned (response rate 49%). Overall, the men demonstrated a Global Health Status/QoL score of 77·6 (SD 20·7), demonstrating a high or healthy level of functioning. Men on hormonal therapy demonstrated inferior physical function in comparison to other treatment options. Fatigue and insomnia were the most frequent symptom experienced, while age was the most significant demographic variable affecting symptom scales. Men undergoing active surveillance for prostate cancer management were least happy with information received (p = 0·019). Comparison with EORTC QLQ‐C30 international reference values suggests that this cohort report a high/healthy QoL. However, a significant proportion of men expressed a need for the receipt of further information, especially men on active surveillance. Specialist nurses are in a unique position to meet the information needs of long‐term prostate cancer patients. However, planning is needed to ensure there are enough specialist nurses to meet the information needs of a growing number of men surviving prostate cancer.     

Hemodynamic spectrum of “dominant” right ventricular infarction in 19 patients

In 19 patients right ventricular infarction was diagnosed on the basis of electrocardiographic features of acute inferior infarction and clinical evidence of elevation of systemic venous pressure and an absence of pulmonary congestion. Right heart catheterization documented elevated right ventricular end-diastolic pressure (mean 15.5 mm Hg) and commensurate right atrial pressure (mean 14.9 mm Hg). In all patients the pulmonary capillary wedge pressure (mean 13.2 mm Hg) was exceeded or equaled by the right ventricular end-diastolic pressure, suggesting a disproportionate reduction in right ventricular compliance or contractile function, or both. Thirteen patients were hypotensive (systolic blood pressure less than 100 mm Hg on admission), including six patients with cardiogenic shock.

Right ventricular infarction is an uncommon and potentially reversible cause of cardiogenic shock;yet, in the experimental model, isolated right ventricular damage is relatively well tolerated. To identify the factors associated with systemic hypotension, data from patients with and without compromised systemic hemodynamic function were compared. In hypotensive patients, the right ventricular end-diastolic pressure was significantly higher (16.8 versus 12.8 mm Hg;p < 0.01) and reflected more extensive right ventricular damage. A pulmonary wedge pressure of 15 mm Hg or more was noted only among the hypotensive patients, and their wedge pressure (mean 14.8 mm Hg) was significantly greater than that of normotensive patients (mean 9.7 mm Hg, p < 0.05). Therefore, in patients with right ventricular infarction, an additional impairment of left ventricular function due to associated infarction of the inferior left ventricle is a significant factor causing hypotension. The elevated wedge pressure may influence right ventricular output by affecting pulmonary arterial diastolic pressure and right ventricular afterload. Right ventricular peak systolic pressure as an index of right ventricular afterload was significantly higher in hypotensive than in normotensive patients (30.5 versus 23.8 mm Hg, p < 0.03), and there was a linear correlation between this pressure and the pulmonary capillary wedge pressure (r = 0.895, p < 0.001).

There was one hospital death (mortality rate 5.3 percent). Clinical management generally consisted of administration of fluids and digitalis and implantation of a temporary pacemaker. This study emphasizes the relatively favorable prognosis of this condition and suggests that aggressive diagnosis and management are appropriate.     

The effect of wheat bran upon bile salt metabolism and upon the lipid composition of bile in gallstone patients

When raw wheat bran was added to the diet of six subjects for 4–6 weeks, chenodeoxycholate (CDC) synthesis increased from 0.46±0.12 to 0.57±0.17 mmol/day (P<0.025), and the CDC pool increased from 1.72±0.47 to 2.19±0.74 mmol (P<0.05). Deoxycholate (DC) pool size diminished from 1.20±0.29 to 0.80±0.16 mmol, but cholate synthesis and pool size were unaffected. Overall, the size of the bile salt pool did not change. In spite of this, when 10 patients with probable cholesterol gallstones took bran supplements for 4–6 weeks, their gallbladder bile aspirated from the duodenum became less saturated with cholesterol. The molar percentage of cholesterol fell from 10.1±3.1% to 8.6±2.7% (P<0.01), and the saturation index of bile fell from 1.49±0.40 to 1.29±0.38 (P<0.005). Bran probably operates primarily on the colon, reducing the formation or absorption of the bacterial metabolite DC, a substance which impairs CDC synthesis.This work was supported by grants from the British Council, the United Bristol Hospitals and the Kellogg Company of Great Britain Limited.     

Treatment continuation in patients receiving biological agents or conventional DMARD therapy

OBJECTIVE: To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure. METHODS: Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases. RESULTS: Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate. CONCLUSIONS: Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.     

Interpretation of somatic POLE mutations in endometrial carcinoma

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (‘POLE-ultramutated’) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.