Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as ‘multiple-classifier’ ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

An unusual ECG pattern in restrictive cardimyopathy

Restrictive cardiomyopathy is the least common type of primary cardiomyopathies. Electrocardiographic recording is abnormal in 99% of patients with RCM. Biatrial enlargement, obliquely elevated ST segment with notched or biphasic late peaking T waves are considered characteristic ECG finding. Significant ST depression with T inversion mimicking subendocardial ischemia has also been reported in patients with RCM and is even suggested as a predictor of sudden cardiac death. We noted a similar ECG pattern in a 16 yr girl with Idiopathic restrictive cardiomyopathy. Coronaries were normal, stress perfusion imaging did not show any perfusion defect. This diffuse resting ST depression with T inversion in precordial & inferior leads along with ST elevation in aVR was persistent for more than six months.     

Prognostic Utility of the IPS 3 Score for Predicting Outcomes in Advanced Hodgkin Lymphoma

Background

The International Prognostic Scoring System (IPSS) consisting of 7 parameters (IPS7) has been the standard prognostic model used in advanced Hodgkin lymphoma (aHL). However, recent studies have questioned its discriminatory power. For retrospective analyses, its utility might be limited by missing parameters. A recent study has shown that the IPSS consisting of only 3 high-risk features (IPS3; stage IV, age 45 years or older, and hemoglobin <105 g/L) is a simple predictor of survival in aHL. However, there are limited data validating the IPS3.

‘Brain attacks’ and acute stroke in childhood: a practical approach in a time of proposed thrombolysis

Sudden focal neurological symptoms or ‘brain attacks’ in children are a common scenario for acute paediatric care givers. A small proportion will have had a vascular stroke. Suspected stroke in adults, signalled by FAST (Face, Arms, Speech, Time) test positivity, is an accepted medical emergency. Children are rarely dealt with urgently unless there is coma. Barriers to stroke recognition and response in children are multifactorial. Childhood stroke is rare and may be ‘FAST negative’. Overall, there is low awareness, low clinical suspicion and many logistic obstacles to timely detection and aspired treatment delivery. Yet stroke continues to affect hundreds of children in the UK each year, causing life-changing disability and, in some, death. This article highlights current key recommendations for the diagnosis and management of acute stroke set out in the 2017 Royal College of Paediatrics and Child Health (RCPCH) Stroke in childhood guideline. Evidence and rationale are discussed, and important practice points offered. There is focus on arterial ischaemic stroke in light of the proposed hyperacute management pathway, which includes thrombolysis. Ongoing challenges on the ground and how these may be overcome are considered.