The Association of Incidental Radiation Dose to the Heart Base with Overall Survival and Cardiac Events after Curative-intent Radiotherapy for Non-small Cell Lung Cancer: Results from the NI-HEART Study.

AIMS: Cardiac disease is a dose-limiting toxicity in non-small cell lung cancer radiotherapy. The dose to the heart base has been associated with poor survival in multiple institutional and clinical trial datasets using unsupervised, voxel-based analysis. Validation has not been undertaken in a cohort with individual patient delineations of the cardiac base or for the endpoint of cardiac events. The purpose of this study was to assess the association of heart base radiation dose with overall survival and the risk of cardiac events with individual heart base contours. MATERIALS AND METHODS: Patients treated between 2015 and 2020 were reviewed for baseline patient, tumour and cardiac details and both cancer and cardiac outcomes as part of the NI-HEART study. Three cardiologists verified cardiac events including atrial fibrillation, heart failure and acute coronary syndrome. Cardiac substructure delineations were completed using a validated deep learning-based autosegmentation tool and a composite cardiac base structure was generated. Cox and Fine-Gray regressions were undertaken for the risk of death and cardiac events. RESULTS: Of 478 eligible patients, most received 55 Gy/20 fractions (96%) without chemotherapy (58%), planned with intensity-modulated radiotherapy (71%). Pre-existing cardiovascular morbidity was common (78% two or more risk factors, 46% one or more established disease). The median follow-up was 21.1 months. Dichotomised at the median, a higher heart base Dmax was associated with poorer survival on Kaplan-Meier analysis (20.2 months versus 28.3 months; hazard ratio 1.40, 95% confidence interval 1.14-1.75, P = 0.0017) and statistical significance was retained in multivariate analyses. Furthermore, heart base Dmax was associated with pooled cardiac events in a multivariate analysis (hazard ratio 1.75, 95% confidence interval 1.03-2.97, P = 0.04). CONCLUSIONS: Heart base Dmax was associated with the rate of death and cardiac events after adjusting for patient, tumour and cardiovascular factors in the NI-HEART study. This validates the findings from previous unsupervised analytical approaches. The heart base could be considered as a potential sub-organ at risk towards reducing radiation cardiotoxicity.

A low-cost alternative for nasolaryngoscopy simulation training equipment: a randomised controlled trial.

OBJECTIVES: Flexible nasolaryngoscopy is a key diagnostic procedure used in many specialities. Simulation-based teaching is beneficial for endoscopy training, but it is expensive. This study assessed whether an inexpensive simulation model is an effective training method for flexible nasolaryngoscopy. METHODS: A three-armed, randomised, controlled trial was performed. One group received no simulation training, while two others were trained with either a high-cost or a low-cost model. All candidates then performed flexible nasolaryngoscopy on a volunteer. Their ability to perform this task was assessed by the patient discomfort score and time taken by a blinded expert. RESULTS: Simulation-based teaching reduced patient discomfort and improved candidate skill level. Low-cost model training did not have a negative effect when compared with high-cost model training. CONCLUSION: Simulated flexible nasolaryngoscopy training may be more accessible with the use of an effective low-cost model.

Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.

BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years). CONCLUSIONS: PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.

An investigation of ring and dicentric chromosomes found in three Turner's syndrome patients using DNA analysis and in situ hybridisation with X and Y chromosome specific probes.

We have studied three patients with features of Turner's syndrome, two with a 45,X/46,X,r(?) and the third with a 45,X/46,X,dic?(Y) karyotype. Because Turner's syndrome patients with a mosaic karyotype containing a Y chromosome are known to have a high risk of developing gonadal tumours, we used DNA analysis and in situ hybridisation with X and Y specific probes to identify the chromosomal origin of the rings and dicentric chromosomes in the three index patients. Both ring chromosomes were shown to be of X origin, while the dicentric was composed of Y chromosome material. We discuss the importance of using a combination of molecular and cytogenetic analyses in such cases.

Café-au-lait spots in schoolchildren.

This paper reports a study of café-au-lait spots of a minimum diameter of 1 cm in 732 white schoolchildren. Three groups were identified, according to the number of café-au-lait spots on each child: (1) those with none (74%), (2) those with fewer than 5 (25%), and (3) those with at least 5 (5 children, 2 considered to be normal, and 3 siblings each presumed to have neurofibromatosis, one having died from leukaemia). Excluding the last group, the number of café-au-lait spots in the sample was not significantly related to age or sex. Some support is given for using the number of café-au-lait spots as an empirical threshold to diagnose neurofibromatosis.

Gut-hormone profile in coeliac disease.

Patients with coeliac disease have a highly significant reduction in the release of secretin and gastric inhibitory polypeptide from the upper small intestine, but a greatly increased release of enteroglucagon, and also of neurotensin, from the lower part of the small intestine. The release of gastrin and pancreatic polypeptide, from the antrum and pancreas respectively, is, however, normal. Thus the pattern of hormone release reflects the location of the mucosal lesion. The gut-hormone profile may also help to characterise other gastrointestinal diseases.

Spontaneous perforation of common bile duct in infants.

Two infants with spontaneous perforation of the common bile duct are described. One presented with mild jaundice, dark urine, acholic stools, and hydroceles, the other with bilateral inguinal hernia. In both the diagnosis was unsuspected until bile-stained ascites was discovered. Both eventually developed bile-staining of the scrotum. Neither was acutely ill. The 131I-Rose Bengal faecal excretion test showed reduced faecal excretion at 8% and 12% of the injected dose with 16-5 and 17%/dl of the dose being recovered in the ascitic fluid 48 hours after intravenous injection. The ascitic:plasma ratio of isotope at that time was 32:1 and 28:1. Operative cholangiography in both showed a perforation at the junction of the cystic duct and common bile duct with no contrast entering the duodenum. Cholecystenterostomy using a Roux-en-Y loop of jejunum produced a rapid sustained recovery and is suggested as the treatment of choice. This condition should be considered in the differential diagnosis of obstructive jaundice in infancy since early surgical correction is necessary.

Serum alpha-fetoprotein levels in extrahepatic biliary atresia, idiopathic neonatal hepatitis and alpha-1-antitrypsin deficiency (PiZ).

Serum alpha-fetoprotein levels were measured using a sensitive radioimmunoassay in 77 infants presenting with persistent conjugated hyperbilirubinaemia. A breed range of alpha-fetoprotein concentrations occurred in both the 23 infants with extrahepatic biliary atresia and the 35 with idiopathic neonatal hepatitis but the 13 with alpha-1-antitrypsin deficiency had uniformly low levels. High alpha-fetoprotein concentrations (above 10 000 mug/1) favoured the diagnosis of neonatal hepatitis especially in the first ten weeks of life, but the overlap between neonatal hepatitis and extrahepatic biliary atresia was large and alpha-fetoprotein determination cannot be recommended as a reliable method for distinguishing the two conditions. Serial alpha-fetoprotein values showed no consistent relationship with standard liver function tests and gave no guide to prognosis. There was an association between alpha-fetoprotein production and needle biopsy evidence of hepatic giant cell transformation. The uniformly low alpha-fetoprotein levels in alpha-1-antitrypsin deficient infants with neonatal hepatitis is a new observation and possible mechanisms for disordered glycoprotein release are discussed.