Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration.Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed.Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006).Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background p16(INK4a) (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74middot7%) of 7654 patients were male and 1940 (25middot3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10middot9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0middot744, p=0middot0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29middot7% vs 9middot0%, p<0middot0001). 5-year overall survival was 81middot1% (95% CI 79middot5-82middot7) for p16+/HPV+, 40middot4% (38middot6-42middot4) for p16-/HPV-, 53middot2% (46middot6-60middot8) for p16-/HPV+, and 54middot7% (49middot2-60middot9) for p16+/HPV-. 5-year disease-free survival was 84middot3% (95% CI 82middot9-85middot7) for p16+/HPV+, 60middot8% (58middot8-62middot9) for p16-/HPV-; 71middot1% (64middot7-78middot2) for p16-/HPV+, and 67middot9% (62middot5-73middot7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd

Analysis of Faults in Software Systems Using Tsallis Distribution: A Unified Approach

The identification of the appropriate distribution of faults is important for ensuring the reliability of a software system and its maintenance. It has been observed that different distributions explain faults in different types of software. Faults in large and complex software systems are best represented by Pareto distribution, whereas Weibull distribution fits enterprise software well. An analysis of faults in open-source software endorses generalized Pareto distribution. This paper presents a model, called the Tsallis distribution, derived using the maximum-entropy principle, which explains faults in many diverse software systems. The effectiveness of Tsallis distribution is ascertained by carrying out experiments on many real data sets from enterprise and open-source software systems. It is found that Tsallis distribution describes software faults better and more precisely than Weibull and generalized Pareto distributions, in both cases. The applications of the Tsallis distribution in (i) software fault-prediction using the Bayesian inference method, and (ii) the Goal and Okumoto software-reliability model, are discussed

Green techniques for reduction of α, β-unsaturated carbonyl compounds

ABSTRACT The present work describes the asymmetric reduction of α-bromo cinnamaldehyde and benzylidene acetone catalyzed by baker&apos;s yeast in free as well as immobilized form. Electrochemical Reduction of the above compounds was also employed in the present work using Stainless Steel (SS-316) under galvanostatic conditions at pH = 9.0. Prior to electrochemical reduction cyclic voltammograms of α-bromo cinnamaldehyde and benzylidene acetone were recorded at different pH (5.0, 7.0, &amp; 9.0) to establish the optimum conditions of the reduction. In both of the above reduction methods applied, selective reduction of C=O moiety was observed. Optically active products, were obtained in good yields (75-90 %) with high enantiomeric excess (ee &gt; 81 %) were then isolated, purified and characterized by combined application of chromatographic and spectroscopic techniques

HPV-induced tumors in the ENT region-The next challenge: are gynecologists also required?

A variety of human papillomavirus (HPV) types are responsible for the emergence of benign and malignant ear, nose and throat (ENT) tumors, which are sometimes associated with severe courses. In head and neck oncology, the current focus is on the oropharyngeal carcinoma, due to the recognition of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity and due to the continually increasing incidence. Due to the consistent promotion of the vaccination program, particularly also for boys, the incidence of all benign and the majority of malignant ENT tumors could be greatly reduced in the future. In particular, the sharply increasing incidence curve of HPV-associated OPSCC could be markedly flattened