Editorial: Angiogenesis and Angiogenesis Inhibitors in Oral Cancer

Non peer reviewe

Erfaringer med økonomiske støtteordninger for tannbehandling hos personer som er behandlet for hode-halskreft

Source at https://www.tannlegetidende.no/i/2021/11/m-255.Medlemmer i Munn- og halskreftforeningen mottok et spørreskjema for å kartlegge erfaringer med økonomiske refusjonsordninger for tannbehandling og kostnader til tannbehandling hos personer som er behandlet for hode-halskreft i Norge. I tillegg kartla vi utviklingen i Folketrygdens honorartakster for tannbehandling i perioden 2015-2020, og sammenlignet honorartakstene for 2021 med takstene for voksenbehandling i Den offentlige tannhelsetjenesten i Troms og Finnmark. Av de 216 som besvarte spørreskjemaet rapporterte halvparten kostnader til tannbehandling etter kreftdiagnose, og en fjerdedel hadde hatt utlegg på 10 000 kroner eller mer. De med moderat og dårlig tannhelse rapporterte betydelig høyere kostnader enn de med god tannhelse. Andelen som oppga at de hadde fått god hjelp av tannlege til å få den økonomiske støtten de hadde krav på var høyest blant dem med store utgifter. Funnene indikerer at honorartakstene til Folketrygden ikke gjenspeiler prisene for tannbehandling av voksne i Norge. Mens konsumprisindeksen økte med 14 % mellom januar 2015 og desember 2020, økte Folketrygdens honorartakster for tannbehandling i gjennomsnitt med 5-6 %, og takstene for 2021 lå gjennomsnittlig nesten 40 % under takstene for voksenbehandling i Den offentlige tannhelsetjenesten i Troms og Finnmark. Tross rettigheter gjennom folketrygdloven kan derfor hode-halskreftpasienter oppleve økonomiske barrierer for å motta nødvendig tannhelsehjelp

Presence of tumour high-endothelial venules is an independent positive prognostic factor and stratifies patients with advanced-stage oral squamous cell carcinoma

Accepted manuscript version. The final publication is available at Springer via http://dx.doi.org/10.1007/s13277-015-4036-4Background: Staging of oral squamous cell carcinoma is based on the TNM system, which has been deemed insufficient for prognostic purposes. Hence, better prognostic tools are needed to reflect the biological diversity of these cancers. Previously, high numbers of specialized blood vessels called high-endothelial venules have been reported to be associated with prolonged survival in patients with breast cancer. In this study, we analysed the prognostic value and morphological characteristics of tumour-associated high-endothelial venules in oral cancer. Methods: The presence of tumour-associated high-endothelial venules was evaluated by immunohistochemistry in 75 patients with oral squamous cell carcinoma and analysed with correlation to clinicopathological parameters, patients’ survival, and vessel morphology. Ten of the samples were analysed at multiple levels to evaluate intratumoural heterogeneity. Results: The presence of tumour-associated high-endothelial venules was found to be associated with lower disease-specific death in multivariate regression analyses (P=0.002). High-endothelial venules were present in all (n=53) T1-T2 tumours, but only in two-thirds (n=14) of the T3-T4 tumours. The morphology of high-endothelial venules was heterogeneous and correlated with lymphocyte density. High-endothelial venules were found to be distributed homogeneously within the tumours. Conclusion: We found the presence of tumour-associated high-endothelial venules to be an easy-to-use, robust, and independent positive prognostic factor for patients with oral cancer. Absence of these vessels in advancedstage tumours might identify patients with more aggressive disease. Evaluating the presence of tumour-associated high-endothelial venules might help to tailor the treatment of oral cancer patients to their individual need

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

Periodontitis is associated with decreased experimental pressure pain tolerance: The Tromsø Study 2015–2016

Aim - To assess the relationship between periodontitis and experimental pain tolerance. Materials and Methods - Participants from the population-based seventh survey of the Tromsø Study with data on periodontitis were included (n = 3666, 40–84 years old, 51.6% women). Pain tolerance was assessed through (i) pressure pain tolerance (PPT) test with a computerized cuff pressure algometry on the leg, and (ii) cold-pressor tolerance (CPT) test where one hand was placed in circulating 3°C water. Cox proportional hazard regression was used to assess the association between periodontitis and pain tolerance adjusted for age, sex, education, smoking and obesity. Results - In the fully adjusted model using the 2012 Centers for Disease Control/American Academy of Periodntology case definitions for surveillance of periodontitis, moderate (hazard ratio [HR] = 1.09; 95% confidence interval [CI]: 1.01, 1.18) and severe (HR = 1.25, 95% CI: 1.11, 1.42) periodontitis were associated with decreased PPT. Using the 2018 classification of periodontitis, having Stage II/III/IV periodontitis was significantly associated with decreased PPT (HR = 1.09; 95% CI: 1.01, 1.18) compared with having no or stage I periodontitis. There were no significant associations between periodontitis and CPT in fully adjusted models. Conclusions - Moderate and severe periodontitis was associated with experimental PPT

Intracellular MMP-2 Activity in Skeletal Muscle is Associated with Type II Fibers

Matrix metalloproteinase 2 (MMP-2) is a proteolytic enzyme implicated in motility, differentiation, and regeneration of skeletal muscle fibers through processing of extracellular substrates. Although MMP-2 has been found to be localized intracellularly in cardiomyocytes where the enzyme is thought to contribute to post-ischemic loss of contractility, little is known about intracellular MMP-2 activity in skeletal muscle fibers. In the present study we demonstrate intracellular MMP-2 in normal skeletal muscle by immunohistochemical staining. Immunogold electron microscopic analyses indicated that the enzyme was concentrated in Z-lines of the sarcomers, in the nuclear membrane, and in mitochondria. By use of in situ zymography, we found that gelatinolytic activity in muscle fibers was co-localized with immunofluorecent staining for MMP-2. Staining for MMP-9, the other member of the gelatinase group of the MMPs, was negative. The broad-spectrum metalloprotease inhibitor EDTA and the selective gelatinase inhibitor CTT2, but not the cysteine inhibitor E64, strongly reduced the gelatinolytic activity. The intracellular gelatinolytic activity was much more prominent in fast twitch type II fibers than in slow twitch type I fibers, and there was a decrease in intracellular gelatinolytic activity and MMP-2 expression in muscles from mice exposed to high intensity interval training. Together our results indicate that MMP-2 is part of the intracellular proteolytic network in normal skeletal muscle, especially in fast twitch type II fibers. Further, the results suggest that intracellular MMP-2 in skeletal muscle fibers is active during normal homeostasis, and affected by the level of physical activity

Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carsinoma

Oral squamous cell carcinomas (OSCC) are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules (HEV), whereas expression of programmed-death ligand 1 (PD-L1) can impair T cell function. Thus, we hypothesize that these factors are important in shaping the immune response in OSCC. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 OSCC patients. We used immunohistochemistry to determine the distribution of immune cell subsets, HEV and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, HEV, PD-L1 and the clinicopathological parameters including patient survival. The presence of HEV correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors’ T-stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive HEV-status, and low T- and N-stages predicted longer patient survival. However, only the presence of HEV and a low T-stage were independent positive prognosticators. This indicates that HEV are important mediators and a convenient marker of an antitumor immune response in OSCC. Our findings support HEV as a potential immunomodulatory target in OSCC. PD-L1 staining in tumor cells correlated with lower T-stage, increased infiltration of CD4+ cells and higher expression of several inflammation-related cytokines. Thus, OSCC tumors rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy

Proteases in Plasma and Kidney of db/db Mice as Markers of Diabetes-Induced Nephropathy

Db/db mice are overweight, dyslipidemic and develop diabetic complications, relevant for similar complications in human type 2 diabetes. We have used db/db and db/+ control mice to investigate alterations in proteinase expression and activity in circulation and kidneys by SDS-PAGE zymography, electron microscopy, immunohistochemistry, Western blotting, and in situ zymography. Plasma from db/db mice contained larger amounts of serine proteinases compared to db/+ mice. Kidneys from the db/db mice had a significantly larger glomerular surface area and somewhat thicker glomerular basement membranes compared to the db/+ mice. Furthermore, kidney extracts from db/+ mice contained metalloproteinases with Mr of approximately 92000, compatible with MMP-9, not observed in db/db mice. These results indicate that higher levels of serine proteinases in plasma may serve as potential markers for kidney changes in db/db mice, whereas a decrease in MMP-9 in the kidney may be related to the glomerular changes

Tumour Cells Express Functional Lymphatic Endothelium-Specific Hyaluronan Receptor In Vitro and In Vivo: Lymphatic Mimicry Promotes Oral Oncogenesis?

Lymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC—lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin+/LYVE-1+, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.Peer reviewe