Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Epidemiological trends and survival of oropharyngeal cancer in a high HPV-prevalent area: A Danish population-based study from 2000 to 2020.

Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16- and HPV testing covering a consecutive 21-year period. Age-adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional-hazards model were employed. Two thousand eight hundred thirty-four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV-)/p16 negative (p16-), 4% HPV+/p16-, and 4.8% HPV-/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV-/p16- OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5-year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16- OS: 50.4%; HPV-/p16+ OS: 49.4%; HPV-/p16- OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV-/p16- OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de-escalating/escalating.

Advances in testing for human papillomavirus -mediated head and neck cancer.

PURPOSE OF REVIEW: New evidence has recently emerged regarding the utility and benefits of dual p16 INKa (p16) and Human papillomavirus (HPV) status testing when determining the diagnosis and prognosis of patients with oropharyngeal cancer. RECENT FINDINGS: HPV RNA polymerase chain reaction (PCR) is the most accurate diagnostic test. The other assays (HPV DNA PCR, HPV DNA/RNA in-situ hybridization (ISH) and p16) applied to formalin fixed tumour tissue have varying but high sensitivities and specificities. Dual p16 and HPV testing identifies discordant (p16+/HPV- or p16-/HPV+) results in 9.2% of cases, who have significantly poorer prognoses than p16+/HPV+, particularly in smokers. The proportion of discordant cases varies by region, and appears to be highest in regions with lowest attributable (p16+/HPV+) fractions. Dual testing improves prognostication for oropharyngeal cancer cases by identifying discordant cases and improving the prognostic power of the Tumour Node Metastasis (TNM) classification, especially in regions with high discordant rates. SUMMARY: Dual testing is essential when considering patients for clinical trials of treatment de-escalation, and may be important when counselling patients on prognosis, especially in regions with high discordant rates and in smokers.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

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

BACKGROUND: p16INK4a (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 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) 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. FUNDING: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society.

Higher SARS-CoV-2 detection of oropharyngeal compared with nasopharyngeal or saliva specimen for molecular testing: a multicentre randomised comparative accuracy study.

BACKGROUND: Testing is critical for detecting SARS-CoV-2 infection, but the best sampling method remains unclear. OBJECTIVES: To determine whether nasopharyngeal swab (NPS), oropharyngeal swab (OPS) or saliva specimen collection has the highest detection rate for SARS-CoV-2 molecular testing. METHODS: We conducted a randomised clinical trial at two COVID-19 outpatient test centres where NPS, OPS and saliva specimens were collected by healthcare workers in different orders for reverse transcriptase PCR testing. The SARS-CoV-2 detection rate was calculated as the number positive by a specific sampling method divided by the number in which any of the three sampling methods was positive. As secondary outcomes, test-related discomfort was measured with an 11-point numeric scale and cost-effectiveness was calculated. RESULTS: Among 23 102 adults completing the trial, 381 (1.65%) were SARS-CoV-2 positive. The SARS-CoV-2 detection rate was higher for OPSs, 78.7% (95% CI 74.3 to 82.7), compared with NPSs, 72.7% (95% CI 67.9 to 77.1) (p=0.049) and compared with saliva sampling, 61.9% (95% CI 56.9 to 66.8) (p<0.001). The discomfort score was highest for NPSs, at 5.76 (SD, 2.52), followed by OPSs, at 3.16 (SD 3.16) and saliva samples, at 1.03 (SD 18.8), p<0.001 between all measurements. Saliva specimens were associated with the lowest cost, and the incremental costs per detected SARS-CoV-2 infection for NPSs and OPSs were US$3258 and US$1832, respectively. CONCLUSIONS: OPSs were associated with higher SARS-CoV-2 detection and lower test-related discomfort than NPSs for SARS-CoV-2 testing. Saliva sampling had the lowest SARS-CoV-2 detection but was the least costly strategy for mass testing. TRIAL REGISTRATION NUMBER: NCT04715607.

Clinical implication of genetic intratumor heterogeneity for targeted therapy in head and neck cancer.

BACKGROUND: Genomic profiling is increasingly used both in therapeutic decision-making and as inclusion criteria for trials testing targeted therapies. However, the mutational landscape may vary across different areas of a tumor and intratumor heterogeneity will challenge treatments or clinical decisions based on single tumor biopsies. The purpose of this study was to assess the clinical relevance of genetic intratumor heterogeneity in head and neck squamous cell carcinomas (HNSCC) using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). MATERIALS AND METHODS: This prospective study included 33 whole tumor specimens from 28 patients with primary or recurrent HNSCC referred for surgery. Three tumor blocks were selected from central, semi-peripheral, and peripheral positions, mimicking biopsies in three different locations. Genetic analysis of somatic copy number alterations (SCNAs) was performed on the three biopsies using Oncoscan, focusing on 45 preselected HNSCC genes of interest. Clinical relevance was assessed using the ESCAT score to investigate whether and how treatment decisions would change based on the three biopsies from the same tumor. RESULTS: The SCNAs identified among 45 preselected genes within the three tumor biopsies derived from the same tumor revealed distinct variations. The detected discrepancies could potentially influence treatment approaches or clinical decisions in 36% of the patients if only one tumor biopsy was used. Recurrent tumors exhibited significantly higher variation in SCNAs than primary tumors (p = .024). No significant correlation between tumor size and heterogeneity (p = .7) was observed. CONCLUSION: In 36% of patients diagnosed with HNSCC, clinically significant intratumor heterogeneity was observed which may have implications for patient management. This finding substantiates the need for future studies that specifically investigate the clinical implications associated with intratumor heterogeneity.

Diagnostic accuracy of combined optical- and radio-guided SNB for neck staging of oral squamous cell carcinoma lesions in the anterior oral cavity.

PURPOSE: The purpose was to investigate the diagnostic performance of bimodal optical and radio-guided sentinel node biopsy (SNB) for oral squamous cell carcinoma (OSCC) sub-sites in the anterior oral cavity. METHODS: Prospective study of 50 consecutive patients with cN0 OSCC scheduled for SNB was injected with the tracer complex Tc99m:ICG:Nacocoll. A near-infrared camera was applied for optical SN detection. Endpoints were modality for intraoperative SN detection and false omission rate at follow-up. RESULTS: In all patients, a SN could be detected. In 12/50 (24%) of cases, the SPECT/CT showed no focus in level 1, but intraoperatively a SN in level 1 was optically detected. In 22/50 cases (44%), an additional SN was identified only due to the optical imaging. At follow-up, the false omission rate was 0%. CONCLUSION: Optical imaging appears to be an effective tool to allow real-time SN identification comprising level 1 unaffected by possible interference of radiation site from the injection.

Effect of near infrared autofluorescence guided total thyroidectomy on postoperative hypoparathyroidism: a randomized clinical trial.

PURPOSE: The purpose of this single-blinded, 2-centre, randomized controlled trial was to test if near-infrared (NIR) autofluorescence image guidance for parathyroid gland (PG) detection during total thyroidectomy can reduce the incidence of hypoparathyroidism in both malignant and benign cases. METHOD: Patients admitted for primary or completion total thyroidectomy were randomized to either the NIR intervention group or the standard care NONIR (no near infrared) group. The primary endpoint was the rate of hypoparathyroidism at the 3-month follow-up, defined as hypocalcemia and inappropriately low parathyroid hormone levels and/or continuous treatment with active vitamin D. The secondary endpoint was the PG identification rate. RESULTS: A total of 147 patients were included of whom 73 were allocated to NIR. Primary or completion thyroidectomy was conducted in 84 and 63 cases, respectively. A total of 130 completed 3 months follow-up. Postoperative hypoparathyroidism in the NIR group at 12 h, 1 month and 3 months was, respectively, 31.8, 14.1, 6.5% compared with 35.9, 18.9, 11.8% in the NONIR group (all p > 0.46). In the NIR group, the identification rate of PGs was 69.5% (146 of 210 PGs), and 9% (19 of 210 PGs) were identified only due to additional use of NIR. For 15 out of 69 patients (21.7%) additionally PGs was found. CONCLUSION: Hypoparathyroidism was nominally less frequent in the NIR group, although not statistically significant. Further studies are needed to confirm if NIR may be a supportive PG identification tool to minimize the number of PG which would have been otherwise missed, especially during more complicated thyroid procedures. TRIAL REGISTRY: ClinicalTrials.gov: NCT04193332. Registration date: 16.08.2019.

Potential of uPAR, αvß6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry.

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0-12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvß6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6-9), 12 (12-12), and 6 (2.5-7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvß6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences.

Low-dose aspirin use and mortality risk in patients with head and neck cancer: A nationwide cohort study of 10 770 patients.

Several recent observational studies have linked low-dose aspirin use to improved survival in patients with head and neck cancer. However, studies of patterns of aspirin use and risk of cancer-specific mortality are lacking. This nationwide cohort study included all patients in the Danish Cancer Registry with a primary diagnosis of head and neck squamous cell cancer (HNSCC) during 2000 to 2016, aged 30 to 84 years, without prior cancer (except nonmelanoma skin cancer) and alive 1 year after diagnosis. Nationwide registries provided information on filled prescriptions, mortality and potential confounding factors. For a subpopulation, a clinical database provided additional information, including human papillomavirus (HPV) tumor status. We used Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between postdiagnostic low-dose aspirin use (≥1 prescription within first year after diagnosis) and risk of cancer-specific mortality. We identified 10 770 patients with HNSCC during a median follow-up of 3.9 years. Of these, 1799 (16.7%) were low-dose aspirin users. Postdiagnostic use of low-dose aspirin was associated with a HR of 0.97 (95% CI 0.82-1.15) for cancer-specific mortality. Similar neutral associations were found according to patterns of aspirin use. No apparent trends emerged according to age, sex, topography or stage. A tendency towards a decreased cancer-specific mortality risk with low-dose aspirin use was observed among HPV-positive patients; however, the statistical precision was low. In conclusion, we did not observe an association between postdiagnostic low-dose aspirin use and cancer-specific mortality in a nationwide cohort of patients with HNSCC.

Impact of specific high-risk human papillomavirus genotypes on survival in oropharyngeal cancer.

The increases observed in incidence and survival of oropharyngeal squamous cell carcinoma (OPSCC) have been attributed to human papillomavirus (HPV) infection, but the survival-impact of specific genotypes is poorly understood. We investigated the potential influence of HPV genotypes on survival in HPV-positive (HPV+) OPSCC. All patients with HPV+/p16+ OPSCC and available genotype data within the period 2011 to 2017 in Eastern Denmark were included. Descriptive statistics on clinical and tumor data, as well as overall survival (OS) and recurrence-free survival (RFS) with Cox hazard models and Kaplan-Meier plots were performed. Overall, 769 HPV+/p16+ OPSCC patients were included of which genotype HPV16 accounted for 86% (n = 662). Compared to high-risk non-HPV16 genotypes (HR non-HPV16), HPV16 patients were younger at diagnosis (median years, 60 vs 64), had a higher male to female ratio (3.7:1 vs 2.1:1), and lower performance scores of ≤1 (90%, n = 559, vs 81%, n = 74). Regarding 5-year OS and RFS, no difference was observed between HPV16 and HR non-HPV16 patients. Subgrouping the HR non-HPV16 group into HPV33 (n = 57), HPV35 (n = 26) and "other genotypes" (n = 24) a significantly worse OS in the "other genotypes" group (hazard rate: 2.33, P = .027) was shown. With similar survival results between HPV16 and non-HPV16 genotypes, genotyping in OPSCC is interesting from an epidemiological point of view as well as in vaccination programs, but not a necessary addition in prognostication of HPV+/p16+ OPSCC.

Second primary cancer following primary oral squamous cell carcinoma: a population-based, retrospective study.

BACKGROUND: Second primary cancer (SPC), defined as a metachronous solid cancer resulting from neither a recurrence of the primary cancer nor a metastasis, is a leading long-term cause of death for survivors of primary oral squamous cell carcinoma (OSCC). This study examined the risk of SPC following treatment of primary OSCC. MATERIALS AND METHODS: This semi-national, population-based, retrospective study included all patients with primary OSCC treated with curative intent in Eastern Denmark in 2000-2014. The presence of SPC was confirmed from medical records and the Danish Pathology Data Bank. The rate of SPC was compared to the occurrence of any cancer in the Eastern Danish population using data from the Danish Cancer Registry. RESULTS: A total of 936 patients with primary OSSC were enrolled. Of these, 219 patients (23%) were diagnosed with SPC during the follow-up (median 8.9 years, IQR: 5.4-12.6 years). The rate of SPC was four times higher than the occurrence of any cancer among the Eastern Danish population i.e., with a standardized incidence ratio (SIR) of 4.13 (95%CI: 3.55-4.80). SPCs were most frequently found in head and neck region (n = 97, SIR = 43.6), lower respiratory organs (n = 38, SIR = 5.6) and gastrointestinal organs (n = 33, SIR = 3.2) with increased SPC rates in all locations. Among patients who developed SPC within the study period the median time from OSCC to the first SPC was 4.4 years (IQR: 2.5-6.2). Significant associations were found between both smoking and excessive alcohol consumption after treatment of OSCC and the risk of SPC. CONCLUSIONS: A noteworthy increased rate of SPC following treatment of primary OSCC was found, especially in the head and neck region and in the lungs. Healthcare professionals should be aware of this increased risk.

The impact of tobacco smoking on survival of patients with oral squamous cell carcinoma: a population-based retrospective study.

BACKGROUND: This article aims to evaluate the impact of smoking status, accumulated tobacco exposure (ATE), and smoking cessation on overall- and disease-free survival (OS and DFS) of patients with oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Patients with primary OSCC treated with curative intent between 2000 and 2019 in Copenhagen were included (n = 1808). Kaplan-Meier curves and multivariable Cox regression analyses were performed to compare the survival of patients with different smoking history. Interactions between ATE and (A) tumor subsite and (B) excessive alcohol consumption (EAC) on the survival were evaluated using multivariable Cox regression analyses with interaction terms. RESULTS: We included 1717 patients with known smoking status (62.8% males, median age: 64 years (IQR: 57-71 years)), who had a 5-year OS of 53.7% (95%CI: 49.8%-57.9%). Based on fully adjusted multivariable Cox regression analyses, significantly elevated hazard ratios (HRs) for OS and DFS were identified for current, but not former smokers, compared to never-smokers. An approximately linear relationship between continuous ATE and survival estimates was identified. ATE analyzed as a categorical variable showed significantly elevated HRs for OS of patients with all categories (060 PYs), however only for DFS of patients with >60 PYs, compared to 0 PYs. Furthermore, an unfavorable long-term prognosis was evident after >3.5 (OS) and >2.5 (DFS) years from diagnosis for patients who continued smoking compared to patients with smoking cessation at diagnosis. The survival estimates of patients with different tumor subsite and alcohol consumption differed with increasing ATE. CONCLUSION: Tobacco smoking (assessed as smoking status and ATE) was associated with inferior survival (OS and DFS) among patients with OSCC. Unfavorable long-term prognosis was significant for patients who continued smoking compared to patients with smoking cessation at diagnosis. The impact of ATE on survival of patients with OSCC may depend on the tumor subsite and/or alcohol consumption.

Days alive and out of hospital following primary surgery for oral cavity squamous cell carcinoma.

BACKGROUND: Days Alive and Out of Hospital (DAOH) is a recently introduced, readily obtainable postoperative outcome measure method that expresses procedure and disease-associated morbidity and mortality. In this study, we evaluated DAOH with 30- and 365-days follow-up periods after primary surgery (DAOH30 and DAOH365, respectively) for patients with oral cavity squamous cell carcinoma (OSCC). The aim of this study is to identify patient-, procedure- and disease-associated risk factors for patients treated with primary surgery for primary OSCC. MATERIAL AND METHODS: This retrospective cohort study from a prospective collected database represents patients from Eastern Denmark surgically treated for primary OSCC in the period 2000-2014. DAOH30 and DAOH365 were calculated and associations with patient characteristics including comorbidity, tumor characteristics, clinical outcomes such as length of stay, readmission, and mortality were evaluated. Tests for difference and significance between groups were assessed with Mann-Whitney U test and quantile linear regression. RESULTS: We included 867 patients (63% males, median age: 63 years (IQR 56-70 years)). Median DAOH30 and DAOH365 after OSCC surgery were 25 days (IQR 21-27 days) and 356 days (IQR 336-360 days), respectively. Alcohol consumption had a significant association with a lower DAOH365, p < 0.01, but not with DAOH30. Advanced T-stage, adjuvant radiotherapy (RT) and increased Charlson Comorbidity Index (CCI) score was significantly associated with a lower DAOH30 and DAOH365. CONCLUSION: In this population-based study in OSCC patients treated with primary surgery, we found that DAOH after 30 days was 25 days (83%), while DAOH after 365 days was 356 days (98%). Advanced T-stage acts as a predictor for significant DAOH30 and DAOH365 reduction while excessive alcohol consumption predicts a significant DAOH365 reduction. Readmission within 30 days following surgery was associated with further readmission within one year.

Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers : A Randomized Controlled Trial.

BACKGROUND: Observational evidence suggests that mask wearing mitigates transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. OBJECTIVE: To assess whether recommending surgical mask use outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures. DESIGN: Randomized controlled trial (DANMASK-19 [Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection]). (ClinicalTrials.gov: NCT04337541). SETTING: Denmark, April and May 2020. PARTICIPANTS: Adults spending more than 3 hours per day outside the home without occupational mask use. INTERVENTION: Encouragement to follow social distancing measures for coronavirus disease 2019, plus either no mask recommendation or a recommendation to wear a mask when outside the home among other persons together with a supply of 50 surgical masks and instructions for proper use. MEASUREMENTS: The primary outcome was SARS-CoV-2 infection in the mask wearer at 1 month by antibody testing, polymerase chain reaction (PCR), or hospital diagnosis. The secondary outcome was PCR positivity for other respiratory viruses. RESULTS: A total of 3030 participants were randomly assigned to the recommendation to wear masks, and 2994 were assigned to control; 4862 completed the study. Infection with SARS-CoV-2 occurred in 42 participants recommended masks (1.8%) and 53 control participants (2.1%). The between-group difference was -0.3 percentage point (95% CI, -1.2 to 0.4 percentage point; P = 0.38) (odds ratio, 0.82 [CI, 0.54 to 1.23]; P = 0.33). Multiple imputation accounting for loss to follow-up yielded similar results. Although the difference observed was not statistically significant, the 95% CIs are compatible with a 46% reduction to a 23% increase in infection. LIMITATION: Inconclusive results, missing data, variable adherence, patient-reported findings on home tests, no blinding, and no assessment of whether masks could decrease disease transmission from mask wearers to others. CONCLUSION: The recommendation to wear surgical masks to supplement other public health measures did not reduce the SARS-CoV-2 infection rate among wearers by more than 50% in a community with modest infection rates, some degree of social distancing, and uncommon general mask use. The data were compatible with lesser degrees of self-protection. PRIMARY FUNDING SOURCE: The Salling Foundations.

Human papillomavirus testing in metastatic squamous cell carcinoma of the neck with unknown primary using PCR on fine-needle aspiration smears: a prospective clinical study.

PURPOSE: Squamous cell carcinoma metastasis of the head and neck with unknown primary tumor (CUP) comprises a diagnostic challenge. Human papillomavirus (HPV) testing on cytologic specimens is gaining increasing focus as this may facilitate an early diagnosis of HPV-induced oropharyngeal carcinoma. This study aimed to prospectively assess PCR-based HPV-DNA testing on FNA smears in a clinical setting. METHODS: Patients referred to a tertiary Head and Neck Cancer Center with suspected CUP were included from November 2016 to November 2018. Scraped cell material from FNA smears was analyzed for HPV-DNA with PCR using general primers (GP5 + /GP6 +) and correlated with the origin and histology of the primary tumor (oropharynx vs. outside oropharynx or benign tumor). The turn-around time reflecting the workflow for HPV-DNA testing by PCR was also calculated. RESULTS: A total of 93 patients were enrolled in the study. The sensitivity and specificity were 86.7% [95% CI 75.4-94.1%] and 92.0% [95% CI 74.0-99.0%], and the positive and negative predictive values were 96.3% [95% CI 87.3-99.0%] and 74.2% [95% CI 59.9-84.7%], respectively. The turn-around time for HPV testing was a mean four calendar days. CONCLUSION: HPV-DNA testing on FNA smears can be performed within a reasonable timeframe and can guide for the detection of an HPV-positive oropharyngeal primary tumor in the clinical setting for patients presenting with CUP of the head and neck.

FDG-PET/CT identified distant metastases and synchronous cancer in squamous cell carcinoma of the head and neck: the impact of smoking and P16-s.

PURPOSE: Whole-body FDG-PET-CT is widely used at diagnosis of squamous cell carcinoma of the head and neck (SCCHN) but may identify suspicious lesions outside the neck that require investigation. This study evaluated the impact of smoking and P16-status on the incidence of malignant disease outside the head and neck region in newly diagnosed patients with SCCHN. METHODS: All PET-positive foci outside the head-neck area were registered in 1069 patients planned for postoperative or curative intent radiotherapy with whole-body FDG-PET/CT from 2006 to 2012. All patient files were retrospectively investigated and clinical parameters, tobacco use, HPV (P16)-status and subsequent malignant disease registered. RESULTS: Malignancy outside the neck was diagnosed in 9% of smokers, 2% of never-smokers, and 5% of patients with P16-positive oropharyngeal squamous cell carcinoma (OPSCC). Clinically suspicious PET-positive foci outside the head-neck were malignant in 55% of smokers, 34% of never-smokers, and in 38% of P16-pos OPSCC. All but two patients with cancer occurring outside the head and neck region were smokers. CONCLUSION: Malignancy outside the neck at diagnosis was more frequent in smokers compared to non-smokers or P16-pos OPSCC. A high proportion of clinically suspicious PET-positive foci were non-malignant.

Low-dose aspirin use and risk of head and neck cancer-A Danish nationwide case-control study.

Results concerning a potential preventive effect of aspirin on head and neck cancer (HNC) are conflicting. We examined the association between low-dose aspirin use and HNC risk overall and by degree of human papillomavirus association in a nested case-control study using nationwide registries. Cases (n = 12 389) were all Danish residents diagnosed with primary HNC (2000-2015). Age- and sex-matched population controls (n = 185 835) were selected by risk-set-sampling. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios and 95% confidence intervals for HNC associated with low-dose aspirin use (≥2 prescriptions). No association was observed between low-dose aspirin ever-use and overall HNC (odds ratio: 1.03, 95% confidence interval: 0.97-1.10). Estimates remained neutral according to patterns of use. Low-dose aspirin use appeared to slightly decrease HNC risk among the eldest (71-84 y), independently of human papillomavirus association, while slightly increase HNC risk among younger age groups (30-60, 61-70 y), driven by an increased risk of oral cancer. However, no consistent patterns in risk estimates were found according to duration and consistency of low-dose aspirin use in the age-stratified analyses.

Impact of human papillomavirus in sinonasal cancer-a systematic review.

BACKGROUND: Human papillomavirus (HPV) is an established prognostic marker in oropharyngeal squamous cell carcinoma. Currently, the role of HPV in sinonasal carcinoma is being explored. OBJECTIVES: This systematic review addresses the role of HPV in sinonasal cancer, establishing the occurrence of HPV-positive cancers and the influence of HPV-positivity on prognosis in sinonasal cancer as well as the utility of the putative surrogate marker of HPV (p16) in sinonasal cancer. MATERIAL AND METHODS: Studies were identified with searches of Medline via PubMed and Embase via OVID (4 May 2020). Articles on original research concerning sinonasal cancer and HPV in humans written in English were included. Case reports with less than five cases were excluded. RESULTS: Initially, 545 articles were identified; 190 duplicate articles were removed leaving 355 articles for title/abstract screening. Title/abstract screening excluded 243 articles, leaving 112 studies assessed for eligibility. After full-text screening, 57 studies were included. All articles investigated the significance of HPV in sinonasal carcinomas. HPV was reported in approximately 30% of sinonasal squamous cell carcinoma (SNSCC), where it was associated with a better prognosis. In sinonasal cancer, p16 is associated with diagnostic pitfalls and a putative utility of p16 in SNSCC has yet to be established. HPV was not frequently reported in other types of sinonasal carcinomas, besides the recently described subtype, HPV-dependent Multiphenotypic Sinonasal Carcinoma. In other types of sinonasal carcinoma, HPV is not frequently found. CONCLUSION: Approximately 30% of SNSCC are HPV-positive. HPV-positivity in SNSCC is associated with improved survival. HPV occurs only rarely in other sinonasal cancers. There is currently not sufficient evidence for p16 as a surrogate marker of HPV in SNSCC.