Little is known about the infiltrative pattern of innate immune cells in primary melanoma compared with their paired metastases and in BRAF V600E -mutated tumors. Therefore, our aim was to characterize the inflammatory microenvironment in primary ulcerated and nonulcerated melanomas and paired metastases, to investigate the relation between inflammation and BRAF V600E mutation in primary melanoma and paired metastases, and to evaluate the effect of the analyzed biomarkers on melanoma-specific survival. A total of 385 primary tumors and 96 paired metastases were stained with immunohistochemistry for BRAF V600E , CD163+ macrophages, CD123+ plasmacytoid dendritic cells, CD66b+ neutrophils, and E-cadherin and estimated using objective computer-assisted image analysis. BRAF V600E was semiquantitatively scored as either present or absent. In metastases of nonulcerated melanomas, we observed higher neutrophil ( P =0.02) and macrophage ( P =0.01) numbers. In the metastases of ulcerated melanomas, we found a higher number of macrophages ( P <0.0001). Increase in the neutrophil numbers in the metastases was associated with poor patient survival after first relapse (hazard ratio=1.19, 95% confidence interval: 1.03–1.38, P =0.02). BRAF V600E -positive primary tumors ( P =0.02) and metastases ( P =0.01) exhibited increased plasmacytoid dendritic cell numbers compared with BRAF V600E -negative tumors. Lastly, primary melanomas in men had higher neutrophil numbers than women ( P ≤0.0001), and men had worse melanoma-specific survival (hazard ratio=1.52, 95% confidence interval: 1.04–2.21, P =0.03). Our data show that melanoma metastases are densely infiltrated with neutrophils, which affects survival. Our results also highlight the importance of recognizing the presence of inflammatory cells in the metastases as a prognostic marker, and that they may potentially be used to improve the precision of immunotherapy and BRAF V600E targeted therapy.
Introduction Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16 INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16 INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16 INK4a as a predictor for CIN2 regression is lacking. Methods and analysis We will conduct a historical cohort study including 500 women aged 23–40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000–2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16 INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome. Ethics and dissemination The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings. Trial registration number NCT05049252 .
Keratitis-ichthyosis-deafness syndrome is a rare genodermatosis, which has recently been connected with mutations in the connexin-26 gene, GJB2.We present a 15-year-old boy with erythroderma, hyperkeratotic plaques and deafness.Sequencing analysis showed a heterozygous missense mutation D50N (148GwA) in GJB2.The boy has not yet manifested characteristic eye lesions but his case shows that tardy development of eye signs should not preclude a clinical diagnosis of keratitis-ichthyosis-deafness syndrome.Besides the typical clinical features, the patient's height was above the 98th percentile and he displayed a delayed bone age in his hands.Additionally, he suffered from migrainoid headaches and the results of a magnetic resonance scan of the cerebrum showed he had a large cisterna magna which probably occurred independently from the syndrome.This patient is the first Danish patient in whom the keratitis-ichthyosis-deafness syndrome has been verified by mutation analysis.
Abstract Chronic alcohol abuse ( CAA ) has deleterious effects on skeletal health. This study examined the impact of CAA on bone with regard to bone density, structure, and strength. Bone specimens from 42 individuals with CAA and 42 individuals without alcohol abuse were obtained at autopsy. Dual‐energy X‐ray absorptiometry ( DEXA ), compression testing, ashing, and bone histomorphometry were performed. Individuals with CAA had significantly lower bone mineral density ( BMD ) in the femoral neck and significantly lower bone volume demonstrated by thinner trabeculae, decreased extent of osteoid surfaces, and lower mean wall thickness of trabecular osteons compared to individuals without alcohol abuse. No significant difference was found for bone strength and structure. Conclusion: CAA leads to low bone mass due to a decrease in bone formation but with no destruction of bone architecture nor a decrease in bone strength. It is questionable whether this per se increases fracture risk.
Abstract Galectin‐1 (Gal‐1) has been associated with adverse prognosis in several cancers including lymphoma entities with CD30 expression. However, Gal‐1 expression has not been systematically assessed in peripheral T‐cell lymphomas (PTCL). Specimens from 169 nodal PTCL were assessed for intratumoural Gal‐1 expression by immunohistochemistry. Overall survival (OS) in groups exhibiting high and low Gal‐1 expression was compared in the cohort and in a subset analysis of CD30‐positive PTCL only. Gal‐1 expression was also correlated with biomarkers of the tumour microenvironment. No significant difference in OS based on Gal‐1 expression was observed in the entire PTCL cohort. However, in the CD30‐positive cohort, patients with high Gal‐1 levels had significantly poorer outcome (5 years OS 10%, 95% confidence interval CI, 1‐36) than their low Gal‐1 counterparts (5 years OS 48%, 95% CI, 30‐64, P = .021). In univariate analyses age 60 or younger, non‐elevated lactate dehydrogenase (LDH), and performance score less than 2 correlated with superior survival but high Gal‐1 expression significantly predicted adverse outcome at both univariate (HR 2.5, 95% CI, 1.1‐5.7, P = .026) and multivariate levels (HR 3.2, 95% CI, 1.2‐8.5, P = .017). Tumours with high Gal‐1 had few cytotoxic T cells in the tumour microenvironment. High intratumoural Gal‐1 expression before therapeutic intervention correlates with adverse outcome in nodal CD30 + , ALK − PTCL patients.
