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.     

Blinded histopathological characterisation of POLE exonuclease domain‐mutant endometrial cancers: sheep in wolf's clothing

Aims

POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE‐mutant ECs.

Methods and results

Fifty‐one POLE‐mutant endometrioid, 67 POLE‐wild‐type endometrioid and 15 POLE‐wild‐type serous ECs were included (total N = 133). An expert gynaecopathologist, blinded to molecular features, evaluated each case (two or more slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, and PMS2. POLE‐mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoral lymphocytes and 59% showed tumour‐infiltrating lymphocytes, as compared with 43% and 28% of POLE‐wild‐type endometrioid ECs, and 27% and 13% of their serous counterparts (P < 0.01, all comparisons). Of POLE‐mutant ECs, 33% contained tumour giant cells; this proportion was significantly higher than that in POLE‐wild‐type endometrioid ECs (10%; P = 0.003), but not significantly different from that in serous ECs (53%). Serous‐like features were as often (focally) present in POLE‐mutant as in POLE‐wild‐type endometrioid ECs (6–24%, depending on the feature). The majority of POLE‐mutant ECs showed wild‐type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%).

Conclusions

A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoral lymphocytes, MLH1, and p53 expression) can assist in prescreening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being detected from 7% to 33%. This facilitates the use of this important prognostic biomarker in routine pathology.     

The Emergence of SARS-CoV-2 within the Dog Population in Croatia: Host Factors and Clinical Outcome

Over a year into the COVID-19 pandemic, there is growing evidence that SARS-CoV-2 infections among dogs are more common than previously thought. In this study, the prevalence of SARS-CoV-2 antibodies was investigated in two dog populations. The first group was comprised of 1069 dogs admitted to the Veterinary Teaching Hospital for any given reason. The second group included dogs that shared households with confirmed COVID-19 cases in humans. This study group numbered 78 dogs. In COVID-19 infected households, 43.9% tested ELISA positive, and neutralising antibodies were detected in 25.64% of dogs. Those data are comparable with the secondary attack rate in the human population. With 14.69% of dogs in the general population testing ELISA positive, there was a surge of SARS-CoV-2 infections within the dog population amid the second wave of the pandemic. Noticeably seroprevalence of SARS-CoV-2 in the dog and the human population did not differ at the end of the study period. Male sex, breed and age were identified as significant risk factors. This study gives strong evidence that while acute dog infections are mostly asymptomatic, they can pose a significant risk to dog health. Due to the retrospective nature of this study, samples for viral isolation and PCR were unavailable. Still, seropositive dogs had a 1.97 times greater risk for developing central nervous symptoms.     

International adoption families: a unique health care journey

The purpose of this study was to identify and describe the health care experiences of families with an internationally adopted child. Content analysis of data from 107 adoptive parents was used to identify themes that characterized health care experiences of the families. Four themes were identified: a) Coming home: Like a lobster thrown into a boiling pot; b) Vigilance: Is my child healthy today? Will my child be healthy tomorrow?; c) Unique health care needs of international adoption families: We are different; and d) Importance of support by health care providers: Do they know or care? Health care providers need to be aware of the unique experiences of the increasing number of international adoption families. The themes identified provide insight into the health care experiences of international adoption families and the crucial role of health care providers in helping international adoption families feel supported on their journey.     

Human-mouse alignments with BLASTZ

The Mouse Genome Analysis Consortium aligned the human and mouse genome sequences for a variety of purposes, using alignment programs that suited the various needs. For investigating issues regarding genome evolution, a particularly sensitive method was needed to permit alignment of a large proportion of the neutrally evolving regions. We selected a program called BLASTZ, an independent implementation of the Gapped BLAST algorithm specifically designed for aligning two long genomic sequences. BLASTZ was subsequently modified, both to attain efficiency adequate for aligning entire mammalian genomes and to increase its sensitivity. This work describes BLASTZ, its modifications, the hardware environment on which we run it, and several empirical studies to validate its results.     

Role of familiarity on effects of caffeine- and glucose-containing soft drinks

Familiarity, through conditioned responses and expectations, may play a significant role in the expression of liking for, and mood and performance effects of, food and drink constituents. The role of familiarity and the effects of caffeine and glucose in Lucozade Energy were investigated by testing this familiar soft drink, and its non-caffeine/non-CHO placebo match, against novel coloured/flavoured full and placebo drinks. Both the familiar drink and its placebo improved alertness, mental energy and mental performance compared to baseline and compared to the novel placebo drink. After repeated exposure, that is, after having gained familiarity with the novel drinks in addition to the already existing familiarity with Lucozade Energy, only the full (caffeine and CHO containing) drinks showed sustained beneficial effects compared to placebo drinks and baseline measures, as well as an increase in liking compared to placebo drinks. Therefore, participants appeared to have learned that beneficial effects were mainly linked to the full products. The results illustrate the restorative combination of caffeine and CHO in the drink, and emphasises the need to implement the appropriate placebo(s) in any study design employing familiar foods or drinks.     

Visit-to-visit lipid variability: Clinical significance,effects of lipid-lowering treatment,and (pharmaco) genetics

In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 × 10^?6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.     

Creating a synergy effect: A cluster randomized controlled trial testing the effect of a tailored multimedia intervention on patient outcomes

Objective

Improving adherence is a challenge and multiple barriers are likely to explain non-adherence. These barriers differ per patient and over course of the regimen. Hence, personalized interventions tailored to the specific barriers are needed. In a theoretical and evidence-based Tailored Multimedia Intervention, technology (online preparatory assessment, text messaging) was used as an add-on to a tailored counseling session (learned during a communication skills training), with the expectation of synergistic effects.