Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma

Background

Oral squamous cell carcinomas are often heavily infiltrated by immune cells. The organization of B-cells, follicular dendritic cells, T-cells and high-endothelial venules into structures termed tertiary lymphoid structures have been detected in various types of cancer, where their presence is found to predict favourable outcome. The purpose of the present study was to evaluate the incidence of tertiary lymphoid structures in oral squamous cell carcinomas, and if present, analyse whether they were associated with clinical outcome.

Methods

Tumour samples from 80 patients with oral squamous cell carcinoma were immunohistochemically stained for B-cells, follicular dendritic cells, T-cells, germinal centre B-cells and high-endothelial venules. Some samples were sectioned at multiple levels to assess whether the presence of tertiary lymphoid structures varied within the tumour.

Results

Tumour-associated tertiary lymphoid structures were detected in 21 % of the tumours and were associated with lower disease-specific death. The presence of tertiary lymphoid structures varied within different levels of a tissue block.

Conclusions

Tertiary lymphoid structure formation was found to be a positive prognostic factor for patients with oral squamous cell carcinoma. Increased knowledge about tertiary lymphoid structure formation in oral squamous cell carcinoma might help to develop and guide immune-modulatory cancer treatments.

     

A randomized controlled trial: the efficacy of eluoride rinse combined with calcium pre-rinse to increase overnight salivary fluoride

Background. Previous studies have shown that a calcium (Ca) pre-rinse given before a 228 ppm fluoride (F) rinse greatly increased salivary fluoride. Objectives. The aim of this randomized controlled trial is to examine if Ca pre-rinse could increase the fluoride concentration in the overnight unstimulated saliva after a 905 ppm F-rinse. Materials and methods. Pre-rinses containing 150 mM, 75 mM or 0 mM Ca-lactate prepared by a validated pharmaceutical cGPM procedure were tested by nine subjects in a randomized order immediately followed by a 905 ppm F-rinse. The fluoride concentration was measured in unstimulated saliva collected 10 h later. Results and conclusions. The Ca pre-treatment significantly increased F level in overnight saliva following the 905 ppm fluoride rinse by 1.7× relative to the 905 ppm F-rinse alone; however, a significant effect was only observed with the highest (150 mM) Ca concentration as pre-rinse. Clinical relevance. High concentration F rinses (905 ppm) are commonly recommended for patients at high-risk of caries. A pre-treatment with high levels of Ca may further improve the cariostatic effect of this ion.     

Bisphenol A replacement chemicals,BPF and BPS,induce protumorigenic changes in human mammary gland organoid morphology and proteome

Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.

Bisphenols, of which the most prevalent is bisphenol A (BPA), are environmental chemicals that are used as plasticizers in a variety of goods, including plastic bottles, children''s toys, eyeglass lenses, food containers, and some types of thermal paper (e.g., cash register receipts). They leach from these products, contaminating humans (and animals) either directly or indirectly via other environmental media, such as household dust. Thus, in most adults, BPA is detected in serum, tissues, and urine (1, 2). Children (ages 6 to 11) have the highest concentrations of urinary BPA (3, 4). This chemical has structural similarities to estrogen (17-β-estradiol [E2]) and as a result, weakly mimics its activity (5). Hormones and growth factors play an important role in controlling prenatal mammary gland development and later on, the morphologic and functional alterations that occur during puberty, pregnancy, and eventually, menopause. Due to this plasticity, the mammary gland is particularly susceptible to the actions of endocrine-disrupting chemicals (EDCs), such as BPA (6–8). In vivo and in vitro studies have consistently shown that exposures to BPA at crucial developmental stages impair mammary gland development and increase neoplastic transformation (9–12). Treating rats with BPA results in mammary epithelial hyperplasia and enhances proliferation (13), common features of precancerous lesions. Additionally, BPA induces cell cycle progression and increases proliferation of human breast cancer cells in vitro via the up-regulated expression of estrogen-dependent genes (14).Based on these and other data, BPA has been removed from many commercial products. Most commonly, this chemical of concern is replaced by bisphenol S (BPS) and bisphenol F (BPF) compounds that share close structural similarities with BPA. However, little is known about their endocrine effects and more broadly, their biological activities. Marketing a product as “BPA free” suggests to the consumer that a product is safer, but research shows that replacement bisphenols have adverse effects similar to, or even greater than, BPA. For example, studies in zebrafish, rodents, and human cell culture models show that BPS and BPF have endocrine-disrupting activities. In zebrafish, despite species-specific differences in estrogen receptor (ER) affinity and specificity, BPF and BPS have estrogenic activities similar to BPA (15–17). In rats, exposure to BPF induces uterine growth, which suggests estrogenic effects (18). BPA, BPF, and BPS promote estrogen-dependent cell cycle progression, proliferation, and migration of human MCF-7 breast cancer cells along with epigenetic changes (19, 20). BPS exposure of pregnant and lactating mice limits milk production, suggesting alterations in mammary gland composition (21). In addition to estrogen signaling, BPF affects other endocrine pathways; in rats, oral administration of this compound alters thyroid hormone levels (22).Current research on bisphenol actions is mainly focused on endocrine effects. It is less well understood whether these chemicals have additional protumorigenic effects independent of their endocrine-disrupting activity. Moreover, tumor development is a multistep process involving heterogeneous cell types and numerous factors, including the potential roles of a variety of environmental chemicals (23, 24). Recapitulating this complexity in an experimental setup is challenging. In this context, tissue organoids are valuable models for understanding the early steps of carcinogenesis. They can be derived from nonmalignant primary tissues ex vivo. When grown for short periods of time in vitro, they maintain many of the genetic and epigenetic features of their normal cognates. Also, organoids have the added advantage of consisting of multiple cell types that are representative of the complexity of the tissue from which they are derived (25, 26).In this study, we exploited the strengths of the human mammary gland organoid culture system to understand the impact of the BPA replacements, BPF and BPS. Organoids established from nonmalignant human mammary gland tissues were exposed to one of the bisphenols, E2, or the vehicle control. The results showed that BPA replacements, in particular BPS, disrupted organoid architecture, enhanced branching, and caused compound-specific proteomic alterations—effects that were mostly E2 independent. Together, these observations suggested that the mammary gland effects of BPA substitutes should be equally or more concerning than those of the compound they are replacing.     

Social and emotional factors as predictors of poor outcomes following cardiac surgery

 Open in a separate windowOBJECTIVESExisting risk prediction models in cardiac surgery stratify individuals based on their predicted risk, including only medical and physiological factors. However, the complex nature of risk assessment and the lack of parameters representing non-medical aspects of patients’ lives point towards the need for a broader paradigm in cardiac surgery. Objectives were to evaluate the predictive value of emotional and social factors on 4 outcomes; death within 90 days, prolonged stay in intensive care (≥72 h), prolonged hospital admission (≥10 days) and readmission within 90 days following cardiac surgery, as a supplement to traditional risk assessment by European System for Cardiac Operative Risk Evaluation (EuroSCORE).METHODSThe study included adults undergoing cardiac surgery in Denmark 2014–2017 including information on register-based socio-economic factors, and, in a nested subsample, self-reported symptoms of anxiety and depression. Logistic regression analyses were conducted, adjusted for EuroSCORE, of variables reflecting social and emotional factors.RESULTSAmongst 7874 included patients, lower educational level (odds ratio 1.33; 95% confidence interval 1.17–1.51) and living alone (1.25; 1.14–1.38) were associated with prolonged hospital admission after adjustment for EuroSCORE. Lower educational level was also associated with prolonged intensive care unit stay (1.27; 1.00–1.63). Having a high income was associated with decreased odds of prolonged hospital admission (0.78; 0.70–0.87). No associations or predictive value for symptoms of anxiety or depression were found on any outcomes.CONCLUSIONSSocial disparity is predictive of poor outcomes following cardiac surgery. Symptoms of anxiety and depression are frequent especially amongst patients with a high-risk profile according to EuroSCORE.Subj collection105, 123     

Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression

Background The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation.Methods Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy.Results ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15).Conclusions These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.Subject terms: Tumour biomarkers, Biomarkers     

Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.     

Diagnostic and Therapeutic Implications of Type 2 Myocardial Infarction: Review and Commentary

The Task Force for the Universal Definition of Myocardial Infarction recently published updated guidelines for the clinical and research diagnosis of myocardial infarction under a variety of circumstances and in a variety of categories. A type 1 myocardial infarction (MI) is usually the result of atherosclerotic coronary artery disease with thrombotic coronary arterial obstruction secondary to atherosclerotic plaque rupture, ulceration, fissuring, or dissection, causing coronary arterial obstruction with resultant myocardial ischemia and necrosis. Patients with a type 2 MI do not have atherosclerotic plaque rupture. In this latter group of patients, myocardial necrosis occurs because of an increase in myocardial oxygen demand or a decrease in myocardial blood flow. Type 2 MI has been the subject of considerable clinical discussion and confusion. This review by knowledgeable members of the Task Force seeks to help clinicians resolve the confusion surrounding type 2 MI.