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Background: Mesenchymal stromal/stem cells (MSCs) have been suggested for salivary gland (SG) restoration following radio-induced salivary gland damage. This study aimed to determine the safety and effectiveness of MSC therapy on radio-induced SG damage and hypofunction in preclinical in vivo studies. Methods: PubMed and EMBASE were systematically searched for preclinical in vivo interventional studies evaluating efficacy and safety of MSC treatment following radio-induced salivary gland damage published before 10th of January 2022. The primary endpoint was salivary flow rate (SFR) evaluated in a meta-analysis. The study protocol was published and registered on PROSPERO (www.crd.ac.uk/prospero), registration number CRD42021227336. Results: A total of 16 preclinical in vivo studies were included for qualitative analysis (858 experimental animals) and 13 in the meta-analysis (404 experimental animals). MSCs originated from bone marrow (four studies), adipose tissue (10 studies) and salivary gland tissue (two studies) and were administered intravenously (three studies), intra-glandularly (11 studies) or subcutaneously (one study). No serious adverse events were reported. The overall effect on SFR was significantly increased with a standardized mean difference (SMD) of 6.99 (95% CI: 2.55–11.42). Studies reported improvements in acinar tissue, vascular areas and paracrine factors. Conclusion: In conclusion, this systematic review and meta-analysis showed a significant effect of MSC therapy for restoring SG functioning and regenerating SG tissue following radiotherapy in preclinical in vivo studies without serious adverse events. MSC therapy holds significant therapeutic potential in the treatment of radio-induced xerostomia, but comprehensive, randomized, clinical trials in humans are required to ascertain their efficacy in a clinical setting. [ABSTRACT FROM AUTHOR]

The pediatric voice handicap index (pVHI) questionnaire was developed in 2006 to provide parental information regarding the impact of a voice disorder on their child's life. The aim of this study was to make a Danish version of the original American pVHI and to validate the Danish pVHI by evaluating its internal consistency and reliability. The original version of the pVHI was translated into Danish. Nineteen parents of dysphonic children, diagnosed in a tertiary otolaryngology hospital department, and 43 parents of children without known voice disorder (control group) completed the questionnaire. The internal consistency, content validity including comparisons of the scores in the two groups and the test-retest reliability were assessed through statistical analysis. The total pVHI scores significantly differed between the group of parents with dysphonic children and the group of parents with children without known voice disorder (p < 0.001). The internal consistency showed an excellent consistency (Chronbach's α > 0.9) of the three subdomains score and the total pVHI score. The test-re-test reliability of the total pVHI score was "strong" with a Pearson's correlation coefficient of 0.97. The Danish pVHI is a valid and reliable instrument to assess the parents' perception of the impact of a voice disorder on a child's physical, social and emotional well-being. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent malignancy worldwide. Immunotherapy with checkpoint inhibitors such as anti-CTLA-4 anti-PD-l and anti-PD-L1 has shown promising results in treating patients with recurrent/metastatic HNSCC. We aimed to systematically review the literature on immunotherapy with checkpoint inhibitors as treatment for advanced HNSCC.Methods: PubMed, EMBASE, Google Scholar, and the Cochrane Library were systematically searched with the purpose of identifying all studies addressing the effects of checkpoint inhibitors as treatment for HNSCC in human clinical trials. We assessed effects of the treatment with checkpoint inhibitors on overall survival (OS), progression-free survival (PFS), HPV-status, PD-L1-status, and adverse events.Results: We identified eight studies (n = 1431 patients) with an OS ranging from 7.5 to 14.9 months in PD-1 checkpoint inhibition. Two studies (n = 541 patients) observed a significantly (p = 0.01) and (p = 0.007) longer OS with checkpoint inhibition compared to standard-treatment, platinum-based chemotherapy (7.5 versus 5.1 months and 14.9 months versus 10.7 months). Two studies (n = 411 patients) found an increased OS associated with PD-L1-postive patients compared to PD-L1-negative patients. The eight studies have heterogenous design with only three being randomized.Conclusion: Few clinical trials have investigated the treatment with checkpoint inhibition for HNSCC. Solely, two randomized studies comprising 240 patients treated with nivolumab (anti-PD-L) and 301 patients treated with pembrolizumab (anti-PD-L) showed a significantly prolonged survival in patients with recurrent/metastatic HNSCC compared with standard-treatment. There is a further need for randomized clinical trials investigating a putative role of checkpoint inhibition in the treatment of advanced HNSCC. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is an important risk factor in a subset of head and neck squamous cell carcinomas (HNSCC), but the association with oral cavity squamous cell carcinomas (OCSCC) remains controversial. This study aimed to identify the prevalence of HPV infection in OCSCC. A systematic search on PubMed and EMBASE was performed, including articles assessing the prevalence of HPV-positive (HPV+) OCSCC published from January 2017 to December 2022. OCSCC was considered HPV+ by the detection of HPV DNA, HPV RNA, and/or p16 overexpression in the tumor mass. A meta-analysis was made determining the overall HPV+ OCSCC prevalence. We included 31 studies comprising 5007 patients from 24 countries. The study size ranged from 17 to 940 patients. The HPV+ OCSCC proportion variated widely and ranged from 0% to 37%. Tumors in the tongue were the predominant sublocation for HPV in the oral cavity. The meta-analysis revealed that the overall HPV+ OCSCC prevalence is 6% (95% CI; 3–10%), and only one study found HPV and OCSCC significantly associated. Thus, HPV may not be a necessary or a strong risk factor in OCSCC oncogenesis, and the possibility of a site misclassification of a mobile tongue with the root of the tongue cannot be excluded. [ABSTRACT FROM AUTHOR]

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in the past decades due to carcinogenic HPV infection. As this patient group suffers from considerable mortality and treatment morbidity it is important to improve prognostic strategies in OPSCC. Inflammation plays a key role in cancer and the neutrophil-to-lymphocyte ratio (NLR) in blood has been suggested as a prognostic factor for OPSCC. This study aimed to investigate the prognostic impact of NLR on overall survival (OS) and recurrence-free survival (RFS) in a retrospective cohort of 1370 patients. Included patients had pretreatment neutrophil and lymphocyte counts available, as well as a known HPV status. Patients were treated with curative intent according to Danish national guidelines. We stratified patients in groups by NLR < 2, NLR 2–4, or NLR > 4 and analyzed the influence of the NLR tertile on OS and RFS. Kaplan–Meier curves illustrated survival probability in OS and RFS in the general cohort and were stratified by HPV status. We found that an increasing NLR was associated with inferior OS (HR = 1.5 for NLR > 4) and RFS (HR = 1.6 for NLR 2–4; HR = 1.8 for NLR > 4) in multivariable analysis. The Kaplan–Meier curves displayed inferior OS and RFS with an increasing NLR for both HPV+ and HPV− patients. In conclusion, we showed that an increasing NLR is prognostic for a worse outcome of OPSCC independently of HPV status. There are possible uses of NLR in prognostication and treatment de-escalation although further studies are warranted to determine the clinical utility. [ABSTRACT FROM AUTHOR]

Second primary cancer (SPC) is the second most common cause of death among patients diagnosed with head and neck cancer. This study examined the risk of SPC following oropharyngeal squamous cell carcinoma (OPSCC) and the impact of human papillomavirus (HPV) on survival following SPC. The study was a population-based, retrospective study including all patients diagnosed with OPSCC in eastern Denmark from 2000–2020 who received curative intended treatment. The incidence rate ratio (IRR), age-adjusted incidence rates (AAIR), and hazard ratios (HR) were calculated. A total of 2584 patients with primary OPSCC were included (median follow-up time: 3.1 years), with 317 patients (12.3%) diagnosed with SPC. The risk of SPC was approximately five times the occurrence of cancer in the general population (IRR: 4.96). The median time to SPC after a primary OPSCC was 2.0 years (interquartile range (IQR) = 0.6–4.2 years). HPV-positive (HPV+) patients had a significantly longer median time to SPC, and a significant better survival compared to HPV-negative (HPV-) patients. SPC was most frequently found in lungs, head, and neck (LHN) for HPV- OPSCC patients and lungs followed by gender-specific (prostate, ovaries, or endometrium) for HPV+ OPSCC. There was a significant difference between the two groups when distributed between "within" or "outside" LHN. Patients with SPC outside LHN had a significant better overall survival. This knowledge should be considered during post-treatment surveillance and might guide targeted imaging. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis. • The study includes 7654 oropharyngeal cancer patients. • HPV impacts overall and disease-free survival, regardless of p16 status. • HPV exerts substantial influence on survival, regardless of stage. • Incorporating HPV in cancer staging, with p16, is crucial for precise prognosis.. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Salivary gland (SG) hypofunction (objectively reduced saliva flow rate) and xerostomia (subjective sensation of dry mouth) are common and burdensome side effects of radiotherapy to the head and neck region. Currently, only sparse symptomatic treatment is available to ease the discomfort of xerostomia. The objective of this study is to assess the effect of mesenchymal stem cell (MSC) therapy on SG function after radiation-induced injury. Methods: This systematic review will include animal intervention studies assessing efficacy and safety of MSCs in treating radiation-induced SG hypofunction. The primary outcome is the effect of MSC administration on salivary flow rates (SFR), by comparing treated groups to control groups when available. Secondary outcomes are morphological and immunohistochemical effects as well as safety of MSC treatment. Electronic searches in MEDLINE (PubMed) and Embase databases will be constructed and validated according to the peer review of electronic search strategies (PRESS) and assessed by two independent researchers. Data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Risk of bias will be evaluated with the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool. Discussion: Thus far, critical appraisal of MSC therapy as an effective treatment for SG hypofunction caused solely by radiation injury has not been conducted. A summary of the existing literature on preclinical studies concerning this issue can provide valuable information about effectiveness, mode of action, and safety, allowing further optimization of preclinical and clinical trials. Systematic review registration: PROSPERO CRD42021227336 [ABSTRACT FROM AUTHOR]

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). 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. 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 (0 < x ≤ 30, 30 < x ≤ 60, and > 60 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. 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. [ABSTRACT FROM AUTHOR]

Single‐cell RNA sequencing (scRNA‐seq) is a novel method enabling genetic characterization of tumor tissue at a single‐cell level. This study systematically reviewed the literature on studies using scRNA‐seq to characterize head and neck squamous cell carcinomas (HNSCCs). Seven studies were included, of which two studies performed scRNA‐seq on 20 patients in total, and five studies used scRNA‐seq data in a subsequent clinical study. The former mentioned two studies found intra‐tumoral genetic heterogeneity among malignant cells but genetic uniformity among non‐malignant cells. The five latter studies used scRNA‐seq data in various ways. Three studies identified biomarkers related to predicting whether a patient would benefit from immunotherapeutic treatment. One study characterized genes related to the perineural invasion. One study identified genes to be used in diagnostics. Further studies performing scRNA‐seq on HNSCC are required to continue the ongoing development and use of scRNA‐seq. [ABSTRACT FROM AUTHOR]

Background: In risk assessment of recurrence, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are often grouped together as differentiated thyroid cancer (DTC). However, while risk factors affecting recurrence of PTC are well established, risk factors for recurrence of FTC are not. This systematic review examines risk factors for recurrence of FTC and evaluates their significance. Methods: A systematic search on PubMed and Embase was performed in September 2020, including studies evaluating risk factors for recurrence of FTC. A quality assessment of the enrolled studies was performed. Results: Nine studies (n = 1544 patients) from eight countries were included. The average recurrence rate was 13.6%, and distant metastasis (DM) constituted 64.8% of the recurrent cases. The risk factors examined were sex, age at diagnosis, primary tumor size, degree of invasiveness, focality, positive resection margin, lymph node (LN) metastasis, and DM at diagnosis. Risk factors correlated with recurrence of FTC were age older than 45 years, primary tumor size above 40 mm, widespread invasion, multifocality, positive resection margin, LN metastasis, and DM at diagnosis. Sex was not a statistically significant risk factor. Conclusions: We identified seven risk factors associated with recurrence of FTC. Age and multifocality were found to be of greater impact regarding recurrence risk of FTC compared with PTC. Future research needs to address the impact of different risk factors for recurrence of FTC particularly including age, primary tumor size, angioinvasion, and mutational status. [ABSTRACT FROM AUTHOR]

Patients with HPV-positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are known to have a better prognosis compared to patients with HPV-negative OPSCCs. To investigate the impact of specific HPV genotypes on survival in HPV + OPSCC. A systematic search of PubMed and Embase for studies addressing the association between specific HPV genotypes and survival among patients with OPSCC was performed. Six studies (n = 1385 patients) published between 2013 and 2017 were included. Five studies (n = 1290 patients) found a better survival among HPV16 cases compared to other high-risk (HR) HPV genotypes (HPV 33, 18, 35, 31, 39, 52, 59, 45, 56, 67, 29, and 58), of which three studies (n = 933 patients) reached significant results. Two of these studies reported a five-year overall survival (OS) of 64.6% and 71.4% in HPV16 OPSCCs vs. 45.6% and 57.1% in HR non-HPV16 OPSCCs (p =.001 and p =.010, respectively), and the last study found a better OS among HPV16 cases with a hazard ratio (HR) of 0.35, 95%. CI [0.14;0.85], p =.02. Our findings indicate a favorable prognosis among patients with HPV16 OPSCC compared with HR non-HPV16 OPSCC. These results may be important when designing future trials and in the planning of follow-up regimes. [ABSTRACT FROM AUTHOR]

• Excellent survival outcomes and low rates of ultimate failure were discovered. • HPV+ /p16 + patients had significantly better outcomes than remaining patients. • The study revealed low rates of adjuvant therapy. • Outcomes between patients treated with or without adjuvant therapy were identical. • Single modality transoral robotic surgery was a successful curative therapy. The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in recent decades, driven by infection with human papillomavirus (HPV). Transoral robotic surgery (TORS) and neck dissection (ND) has been employed as an alternative to radiotherapy/chemoradiotherapy. The current literature is lacking studies providing an exhaustive overview of recurrence characteristics and long-term outcomes in TORS-treated OPSCC-patients. All patients treated for OPSCC with primary TORS + ND in Eastern Denmark between 2013 and 2020 were included in the study. The aim was to explore overall survival (OS), recurrence-free survival (RFS), recurrence patterns, and ultimate failure rate (UFR). OS and RFS were examined using the Kaplan-Meier method. Cox proportional regression analyses were employed to examine effect of different variables on risk of death and recurrence. The study included 153 patients of which 88.9 % (n = 136) were treated with TORS alone while 11.1 % (n = 17) received adjuvant therapy. The 1-, 3-, and 5-year OS were 97.4 %, 94.1 %, and 87.6 % while 1-, 3-, and 5-year RFS were 96.6 %, 87.8 %, and 84.9 %. The UFR was 6.5 % in the cohort. Patients with HPV+/p16 + OPSCC had a significantly better 5-year OS of 92.3 % than patients with discordant or double-negative HPV/p16 status (OS = 73.3 %). No differences in outcomes between patients treated with or without adjuvant therapy were found in regression analysis. Excellent survival and disease control was obtained with TORS + ND in this cohort, despite lesser application of adjuvant therapy than other TORS-centers, implying that TORS without adjuvant therapy can be successfully applied in treatment of early-stage OPSCC. [ABSTRACT FROM AUTHOR]

Uncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas. OPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015–2020, (n = 2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1–2N0M0) and high-risk patients (UICC8 III-IV). There were significantly more HPV-positive (88.2 % vs. 63.1 %), males (89.4 % vs. 74.1 %), never-smokers (52.1 % vs. 23.7 %), lower UICC8-stage (I/II: 79.3 % vs. 68 %), and fewer patients treated with radiotherapy (RT) alone (14.8 % vs. 30.3 %) in the UTMDACC cohort. No difference in the adjusted OS was observed (hazard ratio [HR] 1.21, p = 0.23), but a significantly increased RFI HR was observed for the Copenhagen cohort (HR: 1.74, p = 0.003). Subgroup analyses of low- and high-risk patients revealed significant clinical and treatment differences. No difference in prognosis was observed for low-risk patients, but the prognosis for high-risk patients in the Copenhagen cohort was worse (OS HR 2.20, p = 0.004, RFI HR 2.80, p = 0.002). We identified significant differences in clinical characteristics, treatment modalities, and prognosis between a Northern European and Northern American OPSCC population. These differences are important to consider when comparing outcomes and for patient stratification in clinical trials, as reproducibility might be challenging. • Significant clinical and treatment differences in two high HPV prevalence cohorts. • The Copenhagen cohort included more smokers, HPV-negative and higher stage. • The overall survival for patients with HPV-positive OPSCC was equally good. • The prognosis was equally good at both centers for low-risk T1T2N0M0 patients. • The UTMDACC Stage III-IV patients had a significantly better prognosis. [ABSTRACT FROM AUTHOR]

Background: Osteoradionecrosis (ORN) of the mandible is a severe complication of radiotherapy for head and neck cancer and is arduously difficult to manage. Current treatment options carry risks with some patients remaining incurable. Mesenchymal stromal/stem cell (MSC) therapy has shown promising results supporting osteogenesis and regeneration of radiotherapy-damaged tissues. The aim of this study was to systematically review the literature on the safety and efficacy of MSCs in treating ORN. Methods: A systematic search was performed on MEDLINE, Embase, Cochranes Library online databases, and clinicaltrials.gov to identify preclinical and clinical studies examining the effect of MSCs on osseous healing of ORN. The preclinical studies were assessed according to the SYRCLEs guidelines and risk of bias tool. Results: Six studies (n = 142) from 5 countries were eligible for analysis. Of these four were preclinical studies and two clinical case studies. Preclinical studies found MSC treatment to be safe, demonstrating bone restorative effects and improved soft tissue regeneration. In the clinical cases, healing of bone and soft tissue was reported with no serious adverse events. Conclusion: The evidence from the included studies suggests that MSCs may have beneficial regenerative effects on the healing of ORN. None of the studies reported adverse events with the use of MSCs. More carefully controlled studies with well-identified cells are however needed to demonstrate the efficacy of MSCs in a clinical setting. Graphical abstract [ABSTRACT FROM AUTHOR]

• This study examined survival stratified by subsite in oral squamous cell carcinoma. • Differences in survival outcomes between subsites were apparent. • Adjusting for covariables, primarily the risk of local recurrence varied by subsite. • The study found no difference in risk of overall death between subsites. • Covariables are a likely a cause for discrepancies in outcome between subsites. Oral squamous cell carcinoma (OSCC) is responsible for high morbidity and mortality worldwide. Although the oral cavity encompasses different anatomical subsites, it is unclear whether subsite localization of carcinoma influences outcome. This retrospective cohort study examined overall survival (OS), recurrence-free survival (RFS) and local recurrence-free survival (L-RFS) at different subsites by Kaplan-Meier survival curves. Cox proportional hazards regression analysis was performed to investigate the impact of subsite on overall death, locoregional recurrence, and local recurrence. The cohort included 1702 patients treated with curative intent for OSCC according to standardized national guidelines. The 5-year OS was superior in oral tongue to retromolar trigone as well as in both oral tongue and floor-of-mouth (FOM) compared to tumors involving multiple locations. The 3-year RFS in oral tongue and FOM was superior to tumors involving multiple locations, and in FOM compared to retromolar trigone. The 3-year L-RFS in oral tongue and FOM was higher than gingiva, retromolar trigone and tumors involving multiple locations. Adjusting for relevant covariables using oral tongue as reference, tumors involving multiple locations was the only category presenting higher risk for locoregional recurrence, while risk of local recurrence was higher in gingiva, retromolar trigone, hard palate and to tumors involving multiple locations. The study found no difference in risk of death between subsites. The study found differences in survival outcomes between subsites. After adjusting for covariables, subsite mainly had significant impact on local recurrence, with no distinct pattern of influence on overall death or locoregional recurrence. [ABSTRACT FROM AUTHOR]

Objectives: Nasopharyngeal malignancies are reported having decreasing incidence and reduced mortality. This study provides a nationwide update of the incidence and survival in Denmark.Materials and Methods: The Danish Cancer Registry (DCR) and Central Population Register (CPR) were used to identify all patients registered with nasopharyngeal malignancies between 1980 and 2014 in Denmark. We evaluated the age-adjusted incidence rate (AAIR), average annual percent change (AAPC) and relative survival (RS) and also constructed age-population-cohort (APC) models.Results: 911 patients were identified with a male:female ratio of 2.2:1, a median age of 57.7 years (range 2.8-98.3 years) and an overall median follow-up time of 2.7 years (range 0-37 years). The AAIR was 0.39 cases per 100 000 in 1980 and 0.28 cases per 100 000 in 2014 with an AAPC of -3.2 (95% CI: -7.5; 1.2, p = 0.1). The overall 1-year and 5-year RS rates were 76.3% and 42.1%, respectively. We found a significant age effect in the APC model for the incidence of nasopharyngeal malignancies, but no significant cohort or period effects.Conclusion: The incidence of nasopharyngeal carcinomas has slightly decreased over the last four decades, however insignificantly. Meanwhile, the relative survival has increased significantly in Denmark since 1980. The cause of improved relative survival might be attributed to altered treatment practices. [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus infection and p16-overexpression is a principal cause and favorable prognostic factor for oropharyngeal squamous cell carcinomas but the value as prognostic marker in oral cavity squamous cell carcinomas (OSCC) is undetermined.Materials and Methods: All patients diagnosed with OSCC in Eastern Denmark in the period 2008-2014 were enrolled. Survival estimates were evaluated as overall survival (OS) and progression free survival (PFS) by Kaplan-Meier survival curves and multivariate Cox-regression analyses.Results: We included 575 patients from which 13% (n = 69) had p16-positive tumors. The 5-year OS were 55% and 62% for the p16-negative and p16-positive patients, respectively, and the 5-year PFS were 48% and 50%. In a multivariate survival analysis, p16-positivity showed no significant influence on OS (HR: 1.06 [0.67-1.70], p = 0.79) and PFS (HR: 1.11 [0.76-1.63], p = 0.58).Conclusion: In this population-based cohort of non-selected OSCC patients, we found no difference in survival outcomes when stratified on p16-overexpression status. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the genomic changes that occur in the development from dysplasia, cancer and to regional metastases in patients with oral cavity squamous cell carcinoma (OSCC)., Material and Methods: We included OSCC patients with lymph node metastases at diagnosis, treated with primary surgery at Rigshospitalet, University of Copenhagen in the period 2007-2014. The resected tumor specimens were evaluated by a pathologist, who marked areas of morphologically normal tissue and dysplasia surrounding the cancer, two areas from the cancer tissue, and one area within the lymph node metastases. From these areas a punch biopsy was taken, and DNA from each sample was extracted and sequenced using Illumina's TSO500 HT cancer panel., Results: From 51 OSCC patients, 255 samples were included, comprising a wide variety of genomic alterations. Substantial intratumor heterogeneity was found. The most commonly mutated gene was TP53 , mutated in 65% of all samples. Only two patients had no TP53 mutation in any samples. We found that morphologically normal appearing mucosa as well as surrounding dysplasia also contained malignant mutations, supporting the theory of field cancerization. There was a significant lower average tumor mutational burden (TMB) in the lymph node metastases compared to the primary tumors, supporting the theory of clonal selection., Conclusion: Substantial inter- and intratumor genomic heterogeneity was found. Mutation of TP53 was the most common and was present in all but two patients. Our data strongly supports the theory of clonal selection and the theory of field cancerization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jensen, Sjöstedt, Carmona, Ahlborn, Vieira, Nielsen, Kiss, Grønhøj and von Buchwald.)

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., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Adipose-derived mesenchymal stem/stromal cells (ASCs) are proposed as a new xerostomia treatment. The study evaluated the long-term safety and effectiveness of allogeneic ASCs in radiation-induced xerostomia among patients with previous oropharyngeal cancer., Methods: This study constitutes 3-year follow-up on the original 10 patients who received allogeneic ASCs injections to the submandibular and parotid glands as part of the MESRIX-II trial. The MESRIX-II trial included the preliminary 4-month follow-up. The primary endpoint was long-term safety. Secondary endpoints were effectiveness evaluated by changes in salivary flow rate and patient-reported outcomes (PROs). Immune response was evaluated by assessing the development of donor-specific antibodies (DSA)., Findings: All 10 MESRIX-II patients completed the long-term follow-up (ie, no missing data). During the long-term follow-up, 2 patients encountered a significant adverse event, which was determined to be unrelated to the treatment. No DSAs were detectable at 3 years. The stimulated salivary flow rate increased significantly from an average of 0.66 mL/minute at baseline to 0.86 mL/minute at follow-up, corresponding to an increase of 0.20 [95% CI 0.08 to 0.30] mL/minute, or approximately 30%. Among the PROs, sticky saliva symptoms were reduced, with a -20.0 [95% CI -37.3 to -2.7] units., Interpretation: In conclusion, this study is the first to present long-term follow-up outcomes of allogeneic ASC treatment as a therapeutic option for radiation-induced xerostomia. The study found that ASC treatment appears safe, and there were no indications of adverse immune responses at the 3-year follow-up. Further studies are warranted to evaluate the findings in larger settings., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: No effective treatment exists for radiation-induced xerostomia. The objective of this study was to compare the effect of adipose-derived mesenchymal stem/stromal cell (ASC) injection, relative to placebo, on salivary gland function in patients with radiation-induced xerostomia., Patient and Methods: In this single-centre, double-blind, placebo-controlled trial, patients with hyposalivation were randomised to receive ultrasound-guided injections of allogeneic ASCs or placebo into the submandibular glands. Patients were followed for 4 months. We evaluated unstimulated whole salivary flow rate (UWS), stimulated salivary flow rate, and patient-reported outcomes. Adverse events were recorded and immune response determined in blood samples., Results: We enrolled 120 patients. ASC treatment resulted in a statistically significant UWS increase of 0.04 [95% confidence interval (CI), 0.02-0.06] mL/min (38%) compared with pretreatment baseline whereas placebo treatment did not cause a significant increase [0.01 (95% CI, -0.01 to 0.04) mL/min (21%)]. Both the ASC and placebo treatment yielded notable symptom reductions, with dry mouth decreasing by 13.6 and 7.7 units, sticky saliva decreased by 14.8 and 9.3 units, swallowing difficulties decreased by 7.9 and 8.0 units, and the summary score of the Xerostomia Questionnaire decreased 5.9 and 5.1 units for the ASC and placebo arms, respectively. We found no statistically significant group difference between the ASC and placebo arms for any of the outcomes., Conclusions: We could not confirm superiority of the ASC relative to placebo. ASC therapy significantly improved UWS in previous patients with head and neck cancer, whereas placebo resulted in an insignificant increase., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To evaluate the accuracy of cell-free human papillomavirus-DNA (cfHPV-DNA) measurements in liquid biopsies in predicting disease in patients with HPV-positive/p16-positive (HPV+/p16+) oropharyngeal squamous cell carcinoma (OPSCC)., Experimental Design: This was a prospective cohort study. Plasma samples were collected before treatment, serially after curative intended therapy at follow-up visits 2 weeks, and 6, 9, 12, 18, 24, and 30 months after treatment. A droplet digital PCR assay comprising eight HPV genotypes was used. HPV genotypes found in plasma and tumor tissue were compared. We correlated biopsy- or imaging-verified tumor progression to cfHPV-DNA in follow-up samples., Results: We enrolled 72 patients with HPV+/p16+ OPSCC. Baseline sensitivity for cfHPV-DNA detection was 97.2% (95% confidence interval, 90.3%-99.6%). CfHPV-DNA copy number/milliliter plasma correlated with tumor stage. We found a 100% concordance between HPV genotype in tumor tissue and plasma. Fifty-four patients were followed with serial blood samples for a median of 19.7 months (interquartile range, 13.5-25.5 months). Forty-one patients had undetectable plasma cfHPV-DNA in all follow-up samples, and none developed recurrences. Thirteen patients were classified as cfHPV-DNA-positive in a follow-up plasma sample. Of these, five patients developed a recurrence, and three had residual cancer. It was possible to detect cfHPV-DNA in plasma 97 to 166 days prior to the proven recurrence., Conclusions: To our knowledge, to date, our study, comprising the largest study of patients with HPV+/p16+ OPSCC, using an ultrasensitive multiplex HPV gene panel, revealed a high sensitivity of cfHPV-DNA detection in the liquid biopsies. We recommend serial plasma HPV samples for clinical monitoring of patients with HPV+/p16+ OPSCC., (©2023 American Association for Cancer Research.)

Objectives: To investigate thresholds for lymph node yield (LNY), lymph node density (LND), and pN in patients with oral squamous cell carcinoma in relation to previous findings in the literature., Study Design: Retrospective register-based study., Setting: Copenhagen Oral Cavity Squamous Cell Carcinoma database., Methods: Appropriate thresholds for LNY, LND, and pN were determined by areas under the curve and subsequently subjected to multivariate analysis. Five-year overall survival and 3-year recurrence-free survival were determined by Kaplan-Meier survival curves., Results: In total, 413 patients diagnosed with oral squamous cell carcinoma were included. In the pN0 cohort, no superior/prognostic LNY cutoff values were detected. In the pN+ cohort, areas under the curve determined thresholds of LNY, LND, and pN to be 21 nodes, 5%, and 3 metastases, respectively. The 5-year overall survival was 52% for patients with LNY ≥21 vs 38% for patients with LNY <21 (hazard ratio [HR], 1.49; 95% CI, 1.05-2.11; P < .05), 60% for patients with LND ≤5% vs 38% for patients with LND >6% (HR, 1.63; 95% CI, 1.03-2.57; P < .05), and 43% for patients with pN <3 vs 26% for patients with pN ≥3 (HR, 1.40; 95% CI, 1.04-2.15; P < .05)., Conclusions: Increased nodal yield, decreased LND, and decreasing number of pN were associated with significantly improved survival outcomes. LNY might serve as a prognosticator of survival as well as a surgical quality indicator. LND may have implications as a tool in cancer staging and treatment planning., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Second primary cancer (SPC) is the second most common cause of death among patients diagnosed with head and neck cancer. This study examined the risk of SPC following oropharyngeal squamous cell carcinoma (OPSCC) and the impact of human papillomavirus (HPV) on survival following SPC. The study was a population-based, retrospective study including all patients diagnosed with OPSCC in eastern Denmark from 2000-2020 who received curative intended treatment. The incidence rate ratio (IRR), age-adjusted incidence rates (AAIR), and hazard ratios (HR) were calculated. A total of 2584 patients with primary OPSCC were included (median follow-up time: 3.1 years), with 317 patients (12.3%) diagnosed with SPC. The risk of SPC was approximately five times the occurrence of cancer in the general population (IRR: 4.96). The median time to SPC after a primary OPSCC was 2.0 years (interquartile range (IQR) = 0.6-4.2 years). HPV-positive (HPV+) patients had a significantly longer median time to SPC, and a significant better survival compared to HPV-negative (HPV-) patients. SPC was most frequently found in lungs, head, and neck (LHN) for HPV- OPSCC patients and lungs followed by gender-specific (prostate, ovaries, or endometrium) for HPV+ OPSCC. There was a significant difference between the two groups when distributed between "within" or "outside" LHN. Patients with SPC outside LHN had a significant better overall survival. This knowledge should be considered during post-treatment surveillance and might guide targeted imaging.

Background: Hyposalivation and xerostomia (dry mouth), are the leading site-effects to treatment of head and neck cancer. Currently, there are no effective therapies to alleviate radiation-induced hyposalivation. Adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) have shown potential for restoring salivary gland function. However, the mode of action is unknown. The purpose of the present study was therefore to characterize the effect of AT-MSC therapy on the salivary proteome in previously irradiated head and neck cancer patients., Methods: Whole saliva was collected from patients with radiation-induced salivary gland hypofunction (n = 8) at baseline, and 120 days after AT-MSC treatment, and from healthy controls (n = 10). The salivary proteome was characterized with mass spectrometry based proteomics, and data was compared within the AT-MSC group (baseline versus day 120) and between AT-MSC group and healthy controls. Significance levels between groups were determined by using double-sided t-test, and visualized by means of principal component analysis, volcano plots and cluster analysis., Results: Here we show that 140 human proteins are significantly differentially expressed in saliva from patients with radiation-induced hypofunction versus healthy controls. AT-MSC treatment induce a significant impact on the salivary proteome, as 99 proteins are differentially expressed at baseline vs. 120 days after treatment. However, AT-MSC treatment does not restore healthy conditions, as 212 proteins are significantly differentially expressed in saliva 120 days after AT-MSCs treatment, as compared to healthy controls., Conclusion: The results indicate an increase in proteins related to tissue regeneration in AT-MSCs treated patients. Our study demonstrates the impact of AT-MSCs on the salivary proteome, thereby providing insight into the potential mode of action of this novel treatment approach., (© 2022. The Author(s).)

Purpose: Mesenchymal stem/stromal cell therapy may reduce radiation-induced xerostomia. We investigated the long-term safety of autologous adipose tissue-derived mesenchymal stem/stromal cell (ASC) injections into the submandibular glands., Experimental Design: An investigator-initiated, randomized, single-center, placebo-controlled trial. Previous patients with oropharyngeal squamous cell carcinoma with radiation-induced xerostomia were randomly (1:1) allocated to receive a 2.8 million ASCs/cm3 injection or placebo in both submandibular glands and followed for a minimum of 2 years. The primary endpoint was number of serious adverse events (SAE). Secondary endpoints included whole saliva flow rates and xerostomia-related symptoms. Data analysis was based on the intention-to-treat population using repeated measures mixed-effects linear models., Results: Thirty-three patients were randomized; 30 patients were treated (ASC group, n = 15; placebo group, n = 15). Long-term safety data were collected from all 30 patients. During follow-up, 6 of 15 (40%) of the ASC-treated patients versus 5 of 15 (33%) of the placebo patients experienced an SAE; no SAEs appeared to be treatment related. Unstimulated whole saliva flow rate increased to 0.20 and 0.16 mL/minute in the ASC and placebo group, respectively, yielding a 0.05 mL/minute (95% confidence interval: 0.00-0.10; P = 0.051) difference between groups. Patient-reported xerostomia symptoms diminished according to a decreased xerostomia questionnaire summary score of 35.0 and 45.1, respectively [-10.1 (-18.1 to -2.2); P = 0.013]. Three of the visual analog scale xerostomia measures indicated clinical benefit following use of ASC., Conclusions: Our data show that ASC therapy is safe with a clinically relevant effect on xerostomia-related symptoms. Confirmation in larger randomized controlled trials is warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

No effective therapy exists for the most common long-term side effect of radiation therapy for head and neck cancer (HNC)-xerostomia. The objective was to evaluate safety and provide proof of concept for efficacy of allogeneic adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) injected into the major salivary glands of irradiated patients. This open-label, first-in-human, phase 1b, and single-center trial was conducted with repeated measurements days 0, 1, 5, and 30 and 4 months. Eligible patients with objective and subjective signs of radiation-induced salivary gland damage after treatment of oropharyngeal squamous cell carcinoma stages I-II (UICC 8) were enrolled. Twenty-five million cryopreserved AT-MSCs were injected into each submandibular and 50 million AT-MSCs into each parotid gland. Data were collected on adverse events, unstimulated and stimulated whole saliva (UWS and SWS) flow rates and saliva composition, patient-reported outcomes (EORTC QLQ-H&N35 and Xerostomia Questionnaire [XQ]), blood samples and salivary gland scintigraphy. Data were analyzed using repeated measures linear mixed models. Ten patients (7 men, 3 women, 59.5 years [range: 45-70]) were treated in 4 glands. No treatment-related serious adverse events occurred. During 4 months, UWS flow rate increased from 0.13 mL/minute at baseline to 0.18 mL/minute with a change of 0.06 (P = .0009) mL/minute. SWS flow rate increased from 0.66 mL/minute at baseline to 0.75 mL/minute with a change of 0.09 (P = .017) mL/minute. XQ summary score decreased by 22.6 units (P = .0004), EORTC QLQ-H&N35 dry mouth domains decreased by 26.7 (P = .0013), sticky saliva 23.3 (P = .0015), and swallowing 10.0 (P = .0016). Our trial suggests treatment of the major salivary glands with allogenic AT-MSCs is safe, warranting confirmation in larger trials., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Evidence suggests that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have antineoplastic properties of potential importance for survival of head and neck cancer., Methods: We conducted a nationwide cohort study including all individuals with primary head and neck squamous cell carcinoma in Denmark during 2000-2016 at age 30-84 years, with no history of cancer (except non-melanoma skin cancer), and alive at 1 year after diagnosis. Nationwide registries provided information on drug use, causes of death and potential confounders, and additional clinical information was obtained for a subpopulation. We conducted Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between post-diagnosis non-aspirin NSAID use (defined as ≥1 filled prescription within first year after diagnosis) and cancer-specific mortality., Results: Among 10,770 head and neck cancer 1-year survivors, the HR for cancer-specific mortality with non-aspirin NSAID use was 1.68 at 1 year after diagnosis, but declined and stabilized around 1.15 (95% CI 1.02-1.29) at 2 years after diagnosis. Among 2-year survivors, the HRs for cancer-specific mortality with non-aspirin NSAID use remained slightly increased in analyses stratified by age, sex, stage, and pre-diagnosis non-aspirin NSAID use. Similar results were seen in the subpopulation (n = 1029) with additional clinical information, and among 5-year survivors with additional non-aspirin NSAID exposure assessment., Conclusion: In this nationwide cohort of patients with head and neck cancer, use of non-aspirin NSAIDs was associated with a slightly increased mortality risk, warranting further evaluation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Xerostomia and salivary gland hypofunction impact oral health and quality of life and are mainly caused by the intake of medications, chronic disorders like Sjögren's syndrome, and head and neck radiation. Other aetiologies may be local diseases of the salivary glands including infections, cancer, or obstructive diseases of the salivary ducts. Management strategies are primarily alleviating symptoms. Current investigations show promising results in stem cell treatment. In this review, we want to provide comprehension of the aetiologies, evaluation, and management of xerostomia and hyposalivation.

Introduction: It has been proposed that ankyloglossia and lingual frenotomy have increased. The aim of this study was to analyse the trends of ankyloglossia and lingual frenotomy among children treated in hospitals in Denmark in the 1996-2015 period., Methods: We included children aged 0-17 years registered with the diagnosis ankyloglossia (DQ381) or the procedure frenotomy (KEJC20) using nationwide hospital-based data from the Danish National Patient Registry in 1996-2015. The incidence during the study period and the average annual percentage change (AAPC) and age-specific incidences were calculated., Results: A total of 1,608 children were diagnosed with ankyloglossia (67% boys). The overall incidence of ankyloglossia increased from 3.2 per 100,000 in 1996 to 13.6 per 100,000 in 2015, corresponding to an AAPC of 7.1%. The age-specific incidence revealed a more than ten times higher incidence of ankyloglossia among patients less than one year old compared with those aged one year or above. In all, 3,625 frenotomy procedures were carried out (66% boys). The frequency of frenotomy increased from 5.1 per 100,000 in 1996 to 38.5 per 100,000 in 2015, corresponding to an AAPC of 11.1%. The age-specific incidence of frenotomy showed a more than thirty times higher frequency among children less than one year of age., Conclusions: Ankyloglossia and frenotomy increased significantly during the period 1996-2015 among children in Denmark according to nationwide hospital data. Rates of both ankyloglossia and frenotomy were highest in children less than one year of age and among boys., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Aim: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas., Materials and Methods: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk., Results: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%)., Conclusion: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Recurrent respiratory papillomatosis (RRP) is a condition with benign tumours in the respiratory tract. RRP ensues in both children and adults. The disease is induced by low-risk human papillomavirus (HPV) types HPV-6 and HPV-11. RRP have a recurrent nature with symptoms ranging from hoarseness, dyspnoea, and dysphagia to life-threatening airway obstructions. Currently, no medical curative treatment of RRP is available, however, the literature indicates, that the HPV-vaccines could protect against RRP by preventing genital warts.

Objectives: Comorbid conditions impact outcome for patients treated for oropharyngeal squamous cell carcinoma (OPSCC) and serve as competing risk factors for death. The purpose of this study was to examine differences in comorbidities in patients with OPSCC and known HPV-DNA., Material and Methods: We included patients diagnosed with OPSCC in Eastern Denmark in 2000-2014. Patients were linked to the Danish National Patient Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at time of diagnosis and following cancer treatment. Patients were age-and sex-matched in a 1:10 ratio with a reference group and stratified according to HPV-status., Results: In total 1,499 patients (55.0% HPV+) and 14,990 controls were included. Significantly more HPV+ patients had no comorbidities compared to HPV- patients at time of diagnosis (RR: 1.5 (1.3;1.6), n = HPV+: 522, HPV-: 302) and following treatment (RR 1.5 (1.4;1.6), n = HPV+: 342, HPV-: 142). Most prevalent comorbidity was malignancy not including OPSCCs. HPV+ patients had an increased risk of having AIDS before their OPSCC diagnosis compared to the reference population (OR: 4.8 (1.8;12.9)). HPV- patients had increased risk of multiple comorbidities including cerebrovascular disease (OR: 1.9 (1.4;2.5)), peripheral vascular disease (OR: 1.7 (1.9;3.7)), dementia (OR: 2.9 (1.4;5.8)), ulcer disease (OR: 2.6 (1.9;3.5)), liver disease, mild (OR: 9.5 (7.0;13.0)) and severe (OR: 13.9 (5.8;22.8))., Conclusion: This study showed that HPV- patients had more comorbidities than HPV+ patients at the diagnosis time and following treatment. Irrespective of HPV-status, OPSCC patients had a significant increased risk of (secondary) malignancy compared to the reference population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The aim was to establish a large comprehensive database of patients with oral cavity squamous cell carcinoma (OSCC) to enable surveillance and research of the disease., Methods: All patients diagnosed and/or treated for OSCC at Rigshospitalet, University of Copenhagen, Denmark in the period 2000-2014 were included. Rigshospitalet is a tertiary treatment center and covers the Eastern Denmark region, comprising nearly half of the approximately 5.8 million inhabitants of Denmark. Data on numerous variables regarding general information of the patients at diagnosis, their primary cancer, recurrence, treatment, prior cancers, and secondary cancers were collected from the Danish Pathology Register and by evaluation of medical charts., Results: One thousand three hundred and ninety-nine OSCC patients were included in the database (62% males). The median age at diagnosis was 63 years (range: 23-99 years). The most common anatomical location was the floor of mouth (38%). Among patients with known stage, 70.0% were diagnosed in T-stage 1 or 2 and 64.9% were diagnosed in N-stage 0. Most patients were treated with primary surgery (81.7% among patients with known treatment), of these 44% received adjuvant radiotherapy after surgery. The overall age-standardized incidence of OSCC per 100,000 increased from 2.15 in 2000 to 3.04 in 2014, with a significant annual percent change of 3.2%., Conclusion: We have established a consecutive, population-based database of 1,399 OSCC patients. This creates a basis for multiple studies that will elaborate our understanding of OSCC, and hopefully improve diagnosis, treatment, and rehabilitation of OSCC patients., Competing Interests: Professor Lena Specht reports non-financial support from Merck Serono (participation in international scientific conferences), personal fees from MSD and Kyowa Kirin, personal fees and non-financial support from Takeda, and grants from Varian, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Schmidt Jensen et al.)

This is a review discussing evaluation and management of paediatric nasal fractures, which have been reported as one of the three most common facial bone fractures. Nasal fractures in children are usually treated with closed reduction after 3-5 days, while other injuries like septal haematoma must be treated at the initial presentation. It is important to pay careful attention to the nasal anatomy during the surgical management of paediatric nasal injuries, as disturbing the nasal growth zones can have an impact on future nasal development.

Distant progression (DP) in oropharyngeal squamous cell carcinoma (OPSCC) has significant impact on morbidity and mortality. This study systematically reviewed the literature on studies reporting location and timing of DP after human papillomavirus (HPV)+ or HPV- OPSCCs. PubMed, EMBASE, and the Cochrane Library were systematically searched for studies reporting DP in patients treated with curative intend for an OPSCC. Outcome was site of and time to DP stratified on HPV-status. Seven studies (n = 1564; 77% HPV+) were included in which 313 patients (20%) developed a DP (70% HPV+). The most common site of DP was the lungs (n = 232) regardless of HPV-status. Patients with HPV+ tumors were more prone to dissemination involving multiple sites (risk ratio = 16.49). There was no difference in time to DP when stratified on HPV-status (P = .10). The pattern of but not time to DP was significantly different in patients with OPSCC when stratified on HPV-status., (© 2018 Wiley Periodicals, Inc.)

Background: Thyroid cancer incidence has been reported to be increasing since the 1970 s. The aim of this study was to investigate the change in incidence and survival from 1980 to 2014 in Denmark., Methods: We identified patients registered with thyroid cancer in the period 1980-2014. We evaluated the age-adjusted incidence rate (AAIR) and the average annual percentage change (AAPC), constructed age-period-cohort models (APCs), and evaluated relative survival (RS)., Results: We included 5139 patients. The AAIR was 1.6 cases per 100,000 in 1980 and 4.5 cases in 2014 with an AAPC of 3.4%. The AAIR for papillary carcinomas (n = 2864) quintupled in the study period, and accounts for most of the observed increase in incidence with an AAPC of 4.9%. Follicular carcinomas (n = 920) nearly tripled in AAIR and had the second greatest increase in AAPC. Papillary carcinomas had the best prognosis with 1-year and 5-year RSs of 95% and 91%, followed by the follicular carcinomas with 1-year and 5-year RSs of 90% and 80%, respectively. Anaplastic carcinomas (n = 320) had the worst prognosis with 1-year and 5-year RSs of 18% and 12%. We found a significant age effect in the APC model for the incidence of thyroid cancer but no significant cohort or period effects., Conclusion: The incidence of thyroid cancer is rising. This is primarily attributable to an increase in papillary carcinomas. The relative survival has improved significantly in Denmark since 1980. The cause of the increasing incidence remains to be established, but enhanced diagnostic scrutiny and increased iodine intake may be influential., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: The incidence of human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Currently, data is sparse on the pattern and timing of recurrence. This long-term study concerning both HPV- and p16-status aimed to report predictive factors, pattern, timing of loco-regional recurrence (LRR) and distant recurrence (DR), and survival following recurrence in patients diagnosed with OPSCC., Material and Methods: We included patients diagnosed with OPSCC from 2000 to 2014 in Eastern Denmark, who were treated with curative intent. Tumors were defined as HPV-positive when they were both HPV-DNA and p16-positive. Time-to-failure and -death were estimated by the Kaplan-Meier method. Cox proportional hazards models were used to evaluate predictors of failure., Results: The cohort consisted of 1244 consecutive patients with OPSCC of which 288 patients (23%) experienced recurrence. Of these patients, the majority (n = 197/1244; 16%) experienced LRR and the remaining (n = 91/1244; 7%) DR. Significantly more HPV-negative patients experienced recurrence (n = 170/486; 35%) compared to HPV-positive patient (n = 112/726; 15%). DR occurred for both groups predominantly to the lung (n = 63/91; 69.2%) followed by the liver and bone. Factors influencing risk of LRR included gender, T-classification, and HPV-status. The same variables influenced risk of DR in addition to the UICC-8 classification, N-classification, pack years of smoking, and performance status. HPV-status was the strongest risk factor for LRR and DR., Conclusion: LRR and DR occur significantly less often in HPV-positive patients compared with HPV-negative patients. HPV-status is an independent and strong predictor of recurrence. DR most commonly occurs to the lungs, irrespective of HPV-status., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Salivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) therapy for radiation-induced xerostomia., Patient and Methods: This randomized, placebo-controlled phase 1/2 trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration., Results: No adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; P = .048) and four months (50%; P = .003), but not in the placebo-arm (P = .6 and P = .8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, P = .035) and difficulties in eating solid foods (-2%, P = .008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (P = .04 and P = .02, respectively). MRIs showed no significant differences between groups in gland size or intensity (P < .05)., Conclusions: ASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs., Methods: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined., Results: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively., Conclusions: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

Background: The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries., Methods: Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance., Results: In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration., Conclusions: Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .

Background: Information on the incidence, indications and morbidity of pediatric tracheotomy from a nationwide setting is sparse., Methods: From the nationwide Danish National Patient Registry, we identified all cases: 0-15-year-old children registered with a first-time tracheotomy from 1979 to 2014. We extracted the date of surgery, admission, discharge, age, gender, hospital, department, hospitalization length, hospital contacts, and diagnosis-code related to the surgery. We estimated age-adjusted incidence rates (AAIR) and annual (APC) and average annual percentage change (AAPC) of tracheotomy incidence., Results: A total of 510 children (328 boys, 63%) underwent tracheotomy. The median age at surgery was 8 years. The AAIR was 1.4/100,000 person-years (range 1.0-1.8) from 1980 to 2014. During 1979-2014, the AAPC decreased - 0.9% (95% confidential interval - 2.4; 0.8, p < 0.3). From 1979 to 2003 the APC decreased - 4.1% (95% CI - 5.4; - 2.8, p < 0.001) and from 2003 to 2014 the APC increased 6.6% (95% CI 2.0; 11.5, p < 0.001). Infants had the highest incidence (4.0/100,000 years) compared with the 12-15-year-olds (AAIR: 0.4/100,000 years). From 1979 to 2014 the most common indication for tracheotomy among children aged 0-2 years was congenital malformations (n = 48, 30%) and among children aged 3-11 and 12-15 years the most common indication was trauma (respectively n = 67, 36% and n = 85, 52%). During 2006-2014 the most common indications for all ages was neurological impairment (n = 25, 21%) and neoplasms (n = 20, 17%)., Conclusions: Pediatric tracheotomy was a rare surgical procedure with decreasing incidence rates from 1980-89 to 1990-99 and increasing incidence rates from 2000-2009 to 2010-2014. Indications and postoperative morbidity have changed adjunct to the treatment of chronic disorders.

Introduction: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, but data on the incidence of synchronous, bilateral tonsillar squamous cell carcinomas (BiTSCCs) is sparse. In this study, we report the incidence and tumour characteristics of BiTSCCs in a population-based, consecutive cohort of OPSCCs., Methods: We identified all patients diagnosed with tonsillar squamous cell carcinoma (TSCC) in eastern Denmark during a 15-year period to detect the incidence of synchronous BiTSCCs. The tumours were assessed for p16 Ink4a expression, the presence of HPV DNA and HPV genotypes. Furthermore, we systematically reviewed the literature examining BiTSCCs., Results: Of the total of 1119 TSCCs diagnosed in eastern Denmark from 2000 to 2014, we identified 12 BiTSCCs, nine of which initially presented as a cancer of unknown primary (CUP) in the neck. Nine cases were bilaterally HPV16 positive (HPV16+), while two cases were HPV16+ in one tonsil and respectively, HPV33 and HPV35 positive in the contralateral tonsil. One case was bilaterally HPV-negative. We also identified an increase in the incidence of BiTSCCs after 2012 when histological examination of the entire tonsil tissue became routine, suggesting that BiTSCCs might be underdiagnosed. In the literature, we identified 15 studies from six countries, encompassing 25 cases in total., Conclusions: BiTSCCs were primarily HPV16+ and were most often diagnosed as part of the diagnostic work-up for CUP. We found an incidence of 9% BiTSCCs in patients with TSCC after 2012 and we therefore recommend focusing on putative BiTSCC with total embedding and histological examination of tonsils harvested by bilateral tonsillectomies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is rapidly increasing in incidence and has a favourable prognosis compared with HPV-negative disease. Current combined therapies include significant risks of morbidity for the growing group of survivors. This systematic review and meta-analysis investigates how treatment affects quality of life (QoL) in survivors of oropharyngeal cancer. PubMed, EMBASE and the Cochrane Library were systematically searched for all studies reporting patient-assessed QoL at least 1 year after treatment for OPC. In a meta-analysis, weighted average QoL scores from the four most commonly utilised QoL instruments were compared with baseline and reference group scores using the concept of minimal clinically important difference. The meta-analysis included data from 1366 patients from 25 studies and 12 countries. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) was answered by 704 patients, 644 patients answered the EORTC QLQ Head and Neck-35 (H&N-35), 474 patients answered the University of Washington Quality of Life Questionnaire, and 381 patients answered the M. D. Anderson Dysphagia Inventory. Moderate to large clinically important deteriorations in QoL were found in the domains dry mouth and sticky saliva for the EORTC QLQ-H&N35, saliva, chewing, swallowing, speech, taste, appearance and shoulder for the University of Washington Quality of Life Questionnaire, and the global, physical and emotional subscales for the M. D. Anderson Dysphagia Inventory. In conclusion, survivors of OPC face clinically important deteriorations in QoL that most markedly centre on xerostomia, dysphagia and chewing. These ailments indicate a potential for improvement in patient management., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer is rising in the Western world, but little is known about transmission of the infection and the premalignant phase of the disease. In this article there is an overview of current knowledge with focus on transmission of HPV and risk factors which may lead to persistent infection and eventually cancer. Furthermore, there is a discussion about issues concerning the ability to measure and detect infection and the premalignant stadium in the oropharyngeal tissue.