Ontogenetic patterns in human frontal sinus shape: A longitudinal study using elliptical Fourier analysis.

Frontal sinus morphology is highly variable across individuals, but little is known regarding how or at what age that variation is reached. Existing ontogenetic studies are conflicting and often cross-sectional in nature, limiting understanding of individualistic growth. Studies investigating sinus growth with longitudinal series often focus on lateral cephalograms and consequently do not capture the sinus morphological features that are most relevant to clinical and medicolegal settings (e.g., arcade/scalloping, width-to-height dimensions, asymmetry). Longitudinal analysis of sinus morphology from frontal radiographs is important to understand when sinus morphology stabilizes. The purpose of this study was to investigate at what age the frontal sinus attains its final shape, and whether sex-based differences in ontogeny are evident, using a longitudinal sample of posterior-anterior (PA) frontal radiographs from the AAOF Legacy Collection. Frontal sinus outlines were manually traced in 935 radiographs from 111 individuals (55F/56M) spanning 8-29 years of age. Outlines were subjected to elliptical Fourier analysis (EFA) and underwent principal components analysis (PCA). PC1 (51.02% of variation) appears to represent the relative height and breadth of the sinus, PC2 (11.73%) and PC3 (10.03%) captures the degree of relative complexity in the outlines. Individual PC scores were plotted against age-in-months with individual Loess growth curves. Overall, younger individuals typically display relatively shorter, flatter sinuses, increasing in vertical complexity with age. Mixed-effect models on PC1 indicate significant effects for the repeated measure of years (p < 0.001). Within individuals, Euclidean distances of PCs between each sinus outline and their oldest-age outline (i.e., final morphology) were calculated and plotted against age-in-months with Loess growth curves. The results indicate that final frontal sinus morphology is mostly attained by 20 yoa regardless of sex. There is sexual dimorphism in ontogenetic trajectories: females attain frontal sinus shape earlier than males. Specifically, Loess growth curves of the Euclidean distances to final sinus shape indicate that female shape shows decreased development at 14-16 yoa, with males approaching stabilization at 18-20 yoa. These trends were supported by paired t-tests on PC1 between each year and the oldest age, whereby significant differences end for females starting at 15 and 18 yoa for males. The timing of shape-stabilization in the current study closely aligns with previous studies on linear and size dimensions, indicating a close relationship between the ontogeny of frontal sinus shape and size. This research has several implications in diverse fields. Documenting ontogenetic patterns in modern humans could lead to more accurate interpretations of frontal sinus variation in hominin lineages. Understanding the age at which frontal sinus shape and size stabilizes in pediatric populations has important clinical implications, with future studies needed to investigate if/how sinus development directly relates to sinonasal disease susceptibility (e.g., sinusitis), surgical complications, and/or expected trauma patterns. For forensic practitioners utilizing frontal sinus comparisons for decedent identifications, it is important to know at what age these features stabilize to understand how much change may be expected between antemortem and postmortem radiographs.

Expression of the immune checkpoint receptor TIGIT in seminoma.

A characteristic feature of testicular seminoma is the abundance of immune cells in the tumor microenvironment, raising the possibility that immune checkpoint inhibitors may serve as a therapeutic option in these types of tumors. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor in analogy to PD-1, and drugs targeting TIGIT are currently being investigated in clinical trials. Little is known about the expression of these proteins in testicular seminomas. Therefore the present study performed immunohistochemical analysis to determine the relative abundance of TIGIT and PD-1 in relation to the total CD3+ immune cell infiltration in a tissue microarray (TMA) constructed from 78 seminoma patients. The fraction of TIGIT+ and PD-1+ lymphocytes was highly variable in individual cancers and ranged from 2.3 to 69.4% (mean: 32.2±14.7%) for TIGIT and from 0.8 to 56.5% (mean: 21.6±13.2%) for PD-1. The same high degree of variability was also identified for the ratio of PD-1 to TIGIT positive cells, which varied from a dominance of TIGIT (PD-1: TIGIT ratio=0.02) in 74% of patients, to a predominance of PD-1 (PD-1: TIGIT ratio=12.5) in 23% of patients. In summary, the immune checkpoint receptors TIGIT and PD-1 are abundantly expressed in human seminomas. Once available, anti-TIGIT antibodies, possibly in combination with anti-PD-1 drugs, may be a reasonable therapeutic strategy for this type of cancer.

Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer.

TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.

Expression of the immune checkpoint receptor TIGIT in Hodgkin's lymphoma.

Hodgkin's lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immunotherapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin's lymphoma lymph nodes (n = 40) and normal human tonsil (n = 2). The ME-TMA was stained by brightfield and fluorescence multiplex immunohistochemistry (IHC) to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD3, CD8, CD4, FOXP3) in the lymphocytic background. All analyzed cases of HL contained 9-99% (median: 86%) of TIGIT+ lymphoid cells. In general, TIGIT localized to the same cells as PD-1. Strikingly, expression levels of TIGIT and PD-1 were highly variable among the analyzed samples. Highest levels of TIGIT and PD-1 were found in one sample of nodular lymphocytic-predominant HL (NLPHL). In conclusion, TIGIT expression is highly variable between patients with Hodgkin's lymphoma. Our results encourage further studies evaluating the role of TIGIT as a target for immunotherapies in Hodgkin's lymphoma.

Complaints to the Norwegian System of Patient Injury Compensation 2001-14 following nerve blockade. / Klager etter nerveblokade til Norsk pasientskadeerstatning 2001 ­ 14.

BACKGROUND: There has been a steady increase in cases reported to the Norwegian System of Patient Injury Compensation (NPE). We wished to look into what might characterise those cases of central and peripheral nerve blockade for anaesthesia that led to compensation claims. MATERIAL AND METHOD: Cases with codes for central and peripheral blockade within the field of anaesthesiology were retrieved from the NPE database for the period 2001 ­ 14. The cases were evaluated on the basis of variables including sex, age, type of anaesthesia, diagnosis, type of injury, site of injury, damages received, and written descriptions of treatment and injury. The expert reports were anonymised and reviewed in detail. RESULTS: A total of 339 patient compensation claims relating to nerve blockade were identified, of which 149 concerned spinal anaesthesia, 142 epidural anaesthesia, 21 combined spinal and epidural anaesthesia and 27 peripheral nerve blockade. The group consisted of 236 women and 103 men, and the average age was 46 years. The 339 cases comprised 0.8 % of all cases reported to the NPE in this period. A total of 107 claims resulted in compensation. Eighty-two million Norwegian kroner were paid out in total. INTERPRETATION: Peripheral and central nerve blockade accounts for only a small proportion of cases handled by the NPE. Only one in three applicants had their claim upheld, but when claims were upheld, the injuries were often severe and led to substantial pay-outs.