What is the appropriate management of nonfunctioning pancreatic neuroendocrine tumours disclosed on screening in adult patients with multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterised by a predisposition to the development of endocrine tumours of the parathyroid glands, pituitary and pancreas: 30%‐80% of patients with MEN1 develop pancreatic neuroendocrine tumours (pNETs), with metastatic tumours and/or their sequelae contributing to increased morbidity and early mortality. The optimal management of nonfunctioning (NF) pNETs in MEN1 remains controversial. Whilst pancreatic resection is widely recommended for tumours >2 cm, for smaller tumours (≤2 cm) a well‐established consensus guiding the indications for surgical intervention does not exist. Although total pancreatectomy may be curative for some patients, both short‐ and long‐term complications make this an unsatisfactory option for many patients. For small (<2 cm) MEN1 NF‐pNETs, some clinicians advocate surveillance based largely on retrospective data that suggest 50%‐80% of these lesions are stable over time and infrequently exhibit accelerated growth rates. It is increasingly recognised, however, that NF‐pNETs exhibit unpredictable malignant behaviour that is not determined by tumour size alone, thereby prompting other clinicians to advocate surgery for all MEN1 NF‐pNETs, irrespective of size. Such uncertainty poses clinical management challenges with regards to the timing and extent of surgery, which is further hindered by the inability to stratify patients based on predicted tumour behaviour. It is therefore critical that future MEN1 research initiatives include: (a) the discovery of biomarkers that better predict tumour behaviour; (b) the evaluation of medical therapies that may delay, or even prevent, the need for pancreatic surgery; and, ultimately, (c) improvement in the quality of life for individuals with MEN1. Here, based on the published literature, we address the Clinical Question, ‘What is the management of NF‐pNETs disclosed on screening in adult patients with MEN1?’.     

Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study

Aims Cell‐mediated immunity and pro‐inflammatory cytokines are implicated in the pathogenesis of Type 1 diabetes. The aim of this study was to investigate whether circulating chemokines involved in T‐helper 1 (CXCL10) and T‐helper 2 (CCL2) autoimmunity are increased in children with Type 1 diabetes at onset and follow‐up. Methods Serum CXCL10 and CCL2 were measured in 96 children with newly diagnosed Type 1 diabetes, 59 age‐matched first‐degree relatives of diabetic children and 40 age‐matched non‐diabetic children with no family history of diabetes. In the diabetic children, an additional serum sample was obtained a median of 16 months after diagnosis. Results Serum CXCL10 levels were significantly higher in Type 1 children than in relatives or control children (P < 0.001); 44.7% of patients had a serum CXCL10 level ≥ 2 standard deviation above the mean value of the control group vs. 3.4% of relatives (P < 0.0001). In contrast, serum CCL2 levels were similar in patients, relatives and control subjects. In the Type 1 diabetic patients at follow‐up, CXCL10 was significantly reduced vs. baseline (P = 0.01), while CCL2 did not change. Conclusions In children with newly diagnosed Type 1 diabetes, raised serum CXCL10 and normal CCL2 concentrations signal a predominant T‐helper 1‐driven autoimmune process, which shifts toward T‐helper 2 immunity over the first 1–2 years from diagnosis.     

Immune effector mechanisms in malaria: An update focusing on human immunity

The past decade has witnessed dramatic decreases in malaria‐associated mortality and morbidity around the world. This progress has largely been due to intensified malaria control measures, implementation of rapid diagnostics and establishing a network to anticipate and mitigate antimalarial drug resistance. However, the ultimate tool for malaria prevention is the development and implementation of an effective vaccine. To date, malaria vaccine efforts have focused on determining which of the thousands of antigens expressed by Plasmodium falciparum are instrumental targets of protective immunity. The antigenic variation and antigenic polymorphisms arising in parasite genes under immune selection present a daunting challenge for target antigen selection and prioritization, and is a given caveat when interpreting immune recall responses or results from monovalent vaccine trials. Other immune evasion strategies executed by the parasite highlight the myriad of ways in which it can become a recurrent infection. This review provides an update on immune effector mechanisms in malaria and focuses on our improved ability to interrogate the complexity of human immune system, accelerated by recent methodological advances. Appreciating how the human immune landscape influences the effectiveness and longevity of antimalarial immunity will help explain which conditions are necessary for immune effector mechanisms to prevail.     

Leishmania tarentolae expressing CXCL‐10 as an efficient immunotherapy approach against Leishmania major‐infected BALB/c mice

Recent findings have demonstrated the suitability of interferon‐gamma‐induced protein 10 (IP‐10) or CXCL‐10 as an immunotherapy tool in treatment of leishmaniasis. This chemokine can overcome Leishmania (L.) infection through inducing nitric oxide (NO) production for parasite elimination. This study was undertaken to investigate the therapeutic effects of recombinant Leishmania tarentolae expressing CXCL‐10 and an expression vector encoding CXCL‐10 (pcDNA‐CXCL‐10‐EGFP) in a model of BALB/c mice susceptible to infection by Leishmania major. The outcome of intervention was examined at 3 weeks post‐treatment by evaluating the parameters of parasite burden (PB), arginase activity, NO and various cytokines such as IFN‐γ, IL‐4, IL‐6 and IL‐10. The results have shown that despite the efficacy of CXCL‐10 expression vector as gene therapy, the live therapy strategy using L. tarentolae expressing CXCL‐10 was more effective in terms of decreasing PB. Nitric oxide production increased, especially in the live therapy approaches. Arginase activity also decreased in all regimens, which demonstrates the potency of the treatment. The overall cytokine production shifted in favour of Th1 responses in the treated mice. Altogether, recombinant L. tarentolae expressing CXCL‐10 represents a promising therapeutic strategy to improve treatment of cutaneous leishmaniasis.     

Artificial intelligence in pancreaticobiliary endoscopy

Artificial intelligence (AI) applications in health care have exponentially increased in recent years, and a few of these are related to pancreatobiliary disorders. AI‐based methods were applied to extract information, in prognostication, to guide clinical treatment decisions and in pancreatobiliary endoscopy to characterize lesions. AI applications in endoscopy are expected to reduce inter‐operator variability, improve the accuracy of diagnosis, and assist in therapeutic decision‐making in real time. AI‐based literature must however be interpreted with caution given the limited external validation. A multidisciplinary approach combining clinical and imaging or endoscopy data will better utilize AI‐based technologies to further improve patient care.     

Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes

Objective—To discriminate between chronic inflammation and acute activation of the plaque immune response in culprit lesions of patients with acute coronary syndromes.Design—Retrospective study.Setting—Tertiary referral centre.Subjects—71 patients having coronary atherectomy were classified according to their ischaemic syndrome: stable angina (n = 23); stabilised unstable angina (n = 18); refractory unstable angina (n = 11); and acute myocardial infarction (n = 19).Main outcome measures—Immunohistochemical measurement of interleukin 2 receptor (IL-2R) (CD25) positive cells expressed as a percentage of the total amount of (CD3 positive) T lymphocytes in frozen sections of atherectomy specimens.Results—The number of lesions containing IL-2R (CD25) positive T cells increased with severity of the ischaemic coronary syndrome (stable angina, 52%; stabilised unstable angina, 77.8%; refractory unstable angina, 90.9%; acute myocardial infarction, 89.4%). The percentage of activated T cells (CD25/CD3 ratios ×100) increased in lesions associated with refractory unstable angina (7.8%) and acute myocardial infarction (18.5%), compared with those in lesions associated with either chronic stable angina (2.2%) or stabilised unstable angina (3.3%).Conclusions—An increase in the percentage of IL-2R positive T lymphocytes in culprit lesions of patients with acute coronary syndromes indicates recent activation and amplification of the immune response within plaques. This may result in a burst of inflammatory products with tissue degrading and vasoactive properties and, hence, could initiate or accelerate the onset of an acute coronary event.     

Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study

Background—Standard treatment of inoperable hepatocellular carcinoma has not been established. Somatostatin has been shown to possess antimitotic activity against a variety of non-endocrine tumours. Aims—To assess the presence of somatostatin receptors in human liver and to treat advanced hepatocellular carcinoma with the somatostatin analogue, octreotide. Methods—Somatostatin receptors were measured in liver tissue homogenates from patients with acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Fifty eight patients with advanced hepatocellular carcinoma were randomised to receive either subcutaneous octreotide 250 µg twice daily, or no treatment. Groups were comparable with respect to age, sex, Okuda classification, presence of cirrhosis, and liver biochemistry and virology. Results—Various amounts of somatostatin receptors were identified in liver tissue of all patients including those with hepatocellular carcinoma. Treated patients had an increased median survival (13 months versus four months, p=0.002, log rank test) and an increased cumulative survival rate at six and 12 months (75% versus 37%, and 56% versus 13% respectively). Octreotide administration significantly reduced α fetoprotein levels at six months. When a multivariable Cox''s proportional hazards model was fitted, variables associated with increased survival were: treatment administration, absence of cirrhosis, increased serum albumin, and small tumours. Treated patients clearly had a lower hazard (0.383) in the multivariate analysis. Conclusions—Octreotide administration significantly improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma.     

Radiofrequency ablation of a fascicular tachycardia after orthotopic cardiac transplantation

A 51 year old male received an orthotopic transplant because of end stage ischaemic heart disease. The donor was a healthy male teenager with no history of arrhythmias or other cardiac conditions. The patient presented with haemodynamically stable tachycardia and dyspnoea five weeks post-transplant. The ECG showed a regular tachycardia of 140 beats/min with a right bundle branch block morphology, left axis deviation, and a QRS duration of 135 ms. There were independent P waves, capture, and fusion beats confirming the diagnosis of ventricular tachycardia. Endomyocardial biopsy showed moderate focal rejection that was thought to be responsible for the arrhythmia. During the following six months the patient had recurrent tachyarrhythmias; on each occasion the ECG morphology was the same and there was no cellular rejection. The patient continued to have frequent hospital admissions with ventricular tachycardia requiring DC cardioversion despite the empirical use of amiodarone, sotalol, disopyramide, and procainamide. Eighteen months after transplantation the diagnosis of fascicular tachycardia was suspected by ECG morphology and supported by successful termination with intravenous verapamil. The arrhythmia was successfully managed by radiofrequency ablation. This patient shows that arrhythmias following transplantation are not always related to rejection, and that other potentially reversible causes should be considered, particularly when the ECG during arrhythmia conforms to a classic configuration.     

Risk of hepatitis B virus reactivation in hepatitis B virus + hepatitis C virus‐co‐infected patients with compensated liver cirrhosis treated with ombitasvir,paritaprevir/r + dasabuvir + ribavirin

Hepatitis B virus may reactivate in patients with chronic hepatitis C treated with direct‐acting antivirals. The aim of this study was to investigate the risk of hepatitis B virus (HBV) reactivation in HBV + hepatitis C virus (HCV)‐co‐infected patients with compensated liver cirrhosis treated with paritaprevir/ombitasvir/ritonavir, dasabuvir with ribavirin. We reviewed prospectively gathered data from a national cohort of 2070 hepatitis C virus patients with compensated liver cirrhosis who received reimbursed paritaprevir/ombitasvir/r, dasabuvir with ribavirin for 12 weeks from the Romanian National Health Agency during 2015‐2016. Twenty‐five patients in this cohort were HBs antigen positive (1.2%); 15 untreated with nucleotide analogues agreed to enter the study. These patients were followed up: ALT monthly, serology for HBV and DNA viral load at baseline, EOT and SVR at 12 weeks. Hepatitis B virus (HBV)‐co‐infected patients were all genotype 1b and 52% females, with a median age of 60 years (51 ÷ 74); 76% were pretreated with peginterferon + ribavirin; 72% were with severe necroinflammatory activity on FibroMax assessment; 40% presented comorbidities; and all were HBe antigen negative. Hepatitis C virus (HCV) SVR response rate was 100%. Hepatitis B virus (HBV)‐DNA viral load was undetectable in 7/15 (47%) before therapy, and for the other 8 patients, it varied between below 20 and 867 IU/mL. Five patients (33%) presented virological reactivation (>2 log increase in HBV‐DNA levels) during therapy. One patient presented with hepatitis associated with HBV reactivation, and two started anti‐HBV therapy with entecavir. Hepatitis B virus (HBV) virological reactivation was present in 33% in our patients. Generally, HBV‐DNA elevations were mild (<20 000 IU/mL); however, we report one case of hepatitis associated with HBV reactivation.     

Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients

Objective—To examine the reproducibility and responsiveness to change of a six minute walk test and a quality of life measure in elderly patients with heart failure.Design—Longitudinal within patient study.Subjects—60 patients with heart failure (mean age 82 years) attending a geriatric outpatient clinic, 45 of whom underwent a repeat assessment three to eight weeks later.Main outcome measures—Subjects underwent a standardised six minute walk test and completed the chronic heart failure questionnaire (CHQ), a heart failure specific quality of life questionnaire. Intraclass correlation coefficients (ICC) were calculated using a random effects one way analysis of variance as a measure of reproducibility. Guyatt''s responsiveness coefficient and effect sizes were calculated as measures of responsiveness to change.Results—24 patients reported no major change in cardiac status, while seven had deteriorated and 14 had improved between the two clinic visits. Reproducibility was satisfactory (ICC > 0.75) for the six minute walk test, for the total CHQ score, and for the dyspnoea, fatigue, and emotion domains of the CHQ. Effect sizes for all measures were large (> 0.8), and responsiveness coefficients were very satisfactory (> 0.7). Effect sizes for detecting deterioration were greater than those for detecting improvement.Conclusions—Quality of life assessment and a six minute walk test are reproducible and responsive measures of cardiac status in frail, very elderly patients with heart failure.     

Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve

Aims—To determine whether mitral annular calcification and aortic valve calcification, with or without stenosis, are expressions of atherosclerotic disease.Methods—The incidence of atherosclerotic risk factors was analysed in patients with mitral annular calcification and aortic valve calcification and in control patients from a prospective echocardiographic database of 8160 consecutive patients; 657 patients (8%) were identified with mitral annular calcification and 815 (9%) with a calcified aortic valve, of whom 515 (6.3%) had stenosis with a minimal aortic valve gradient of 16 mm Hg. In these patients, cardiac and vascular risk factors were compared with 568 control patients using multiple logistic regression analysis.Results—Age (odds ratio (OR) varying from 5.78 to 104, depending on age class), female sex (OR 1.75), hypertension (OR 2.38), diabetes mellitus (OR 2.85), and hypercholesterolaemia (OR 2.95) were strongly and significantly associated with aortic valve calcification without stenosis, as were age (OR varying from 8.82 to 67, depending on age class), female sex (OR 2.22), hypertension (OR 2.72), diabetes mellitus (OR 2.49), and hypercholesterolaemia (OR 2.86) with mitral annular calcification. Age (OR varying from 1.11 to 7.7), hypertension (OR 1.91), and hypercholesterolaemia (OR 2.55) were strongly and significantly associated with stenotic aortic valve calcification.Conclusions—Mitral annular calcification and stenotic or non-stenotic aortic valve calcification have a high incidence of atherosclerotic risk factors, suggesting they should be considered as manifestations of generalised atherosclerosis.     

Dietary determinants of ischaemic heart disease in health conscious individuals

Objective—To investigate dietary determinants of ischaemic heart disease (IHD) in health conscious individuals to explain the reduced risk in vegetarians, and to examine the relation between IHD and body mass index (BMI) within the normal range.Design—Prospective observation of vegetarians, semi-vegetarians, and meat eaters for whom baseline dietary data, reported weight and height information, social class, and smoking habits were recorded.Subjects—10 802 men and women in the UK aged between 16 and 79, mean duration of follow up 13.3 years.Main outcome measures—Death rate ratios for IHD and total mortality in relation to dietary and other characteristics recorded at recruitment (reference category death rate = 100).Results—IHD mortality was less than half that expected from the experience reported for all of England and Wales. An increase in mortality for IHD was observed with increasing intakes of total and saturated animal fat and dietary cholesterol—death rate ratios in the third tertile compared with the first tertile: 329, 95% confidence interval (CI) 150 to 721; 277, 95% CI 125 to 613; 353, 95% CI 157 to 796, respectively. No protective effects were observed for dietary fibre, fish or alcohol. Within the study, death rate ratios were increased among those in the upper half of the normal BMI range (22.5 to < 25) and those who were overweight (BMI ? 25) compared with those with BMI 20 to < 22.5.Conclusions—In these relatively health conscious individuals the deleterious effects of saturated animal fat and dietary cholesterol appear to be more important in the aetiology of IHD than the protective effect of dietary fibre. Reduced intakes of saturated animal fat and cholesterol may explain the lower rates of IHD among vegetarians compared with meat eaters. Increasing BMI within the normal range is associated with increased risk of IHD. The results have important public health implications.     

Clinical suppression of bradycardia dependent premature ventricular contractions by the potassium channel opener nicorandil

Objective—To assess the clinical antiarrhythmic effect of nicorandil, a potassium channel opener, on premature ventricular contractions.Design and patients—The effect of oral nicorandil (15 to 60 mg daily for four weeks) on premature ventricular contractions was investigated in 20 patients (11 female, nine male, mean (SD) age 63 (17) years) who underwent 24 hour ambulatory ECG. Patients were classified into two groups based on the relation between the frequency of premature ventricular contractions and heart rate: (1) those with a positive correlation (n = 9); and (2) those with a bidirectional correlation (n = 11), characterised by an increased frequency of premature contractions at low heart rates and a decreased frequency at high heart rates.Results—Nicorandil reduced the frequency of premature ventricular contractions by 75% in five patients in group 2, but was not effective in any patient in group 1. The heart rate at which the frequency of premature ventricular contractions peaked was significantly lower in the five responders in group 2 than in the six non-responders (63.2 (3.7) v 76.3 (12.4) beats/min, p < 0.05).Conclusions—Nicorandil may suppress premature ventricular contractions when they occur mainly at a low heart rate.     

A normal electrocardiogram precludes the need for left ventriculography in the assessment of coronary artery disease

Objective—To assess whether a normal electrocardiogram can identify good left ventricular function and obviate the need for routine left ventriculography in patients undergoing cardiac catheterisation for suspected coronary artery disease.Design—A prospective study of patients undergoing cardiac catheterisation.Setting—A regional cardiac centre.Patients—The electrocardiograms, coronary angiograms, and left ventriculograms of 391 consecutive patients undergoing investigations for suspected coronary artery disease were entered into the study. Patients with arrhythmias and cardiac pathologies other than coronary artery disease were excluded.Main outcome measures—The electrocardiogram was assessed using a 29 point QRS scoring system, and classified by two cardiologists and a trainee cardiologist as normal or abnormal. Left ventricular function was assessed by digital ventriculography.Results—The sensitivity, specificity, and negative predictive value of a QRS score of 0 (normal QRS complexes) for discriminating good left ventricular function (ejection fraction ? 50%) were 92.6%, 41.5%, and 97.2%, respectively. The figures for a normal electrocardiogram as assessed by a doctor were 96.3%, 40.4%, and 98.6% for cardiologist A; 96.3%, 37.4%, and 98.4% for cardiologist B; and 94.4%, 49.6%, and 98.2% for the cardiology trainee.Conclusions—If a cardiologist judges the ECG to be normal, left ventriculography is unnecessary and a formal QRS score does not improve reliability of this clinical judgment. Adopting this strategy would save £30-40 000 in consumables and 65-87 hours of catheter laboratory and staff time for a department catheterising 3000 patients with suspected coronary artery disease annually.