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This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals between 2017 and 2022 were reviewed. Twenty-four patients had TERT promoter mutations based on molecular profile testing. Clinicodemographic data, mutational profiles, and histopathological features were assessed. Descriptive analysis, Fisher’s exact test, and binary logistic regression were performed. Seven patients had single-gene TERT promoter mutations, and 17 had concurrent mutations, including BRAF V600E, HRAS, NRAS, PIK3CA, and EIF1AX. The overall prevalence of malignancy was 95.8%, of which 78.3% were aggressive thyroid cancers. There was a statistically significant association between concurrent mutations and disease aggressiveness. The odds of having aggressive disease were 10 times higher in patients with a TERT promoter mutation and a concurrent molecular alteration than in those with a TERT promoter mutation alone. This is an important finding for thyroid specialists to consider when counseling patients concerning risk stratification and management options.

Background While some studies suggest that the BRAF V600E mutation correlates with a high-risk phenotype in papillary thyroid microcarcinoma (PTMC), more evidence is necessary before this mutation can be used to help guide decision making in the management of small thyroid nodules. This study investigated whether BRAF V600E mutation is associated with aggressive features in PTMC (≤ 1 cm) and small PTC (1–1.5 cm). Methods Retrospective chart review was performed on 121 patient cases. Patients who underwent thyroid surgery for PTMC (≤ 1 cm) or small PTC (1–1.5 cm) were included if molecular testing was done for BRAF V600E mutation. Two study groups were created based on tumour size: PTMC (n = 55) and small PTC (n = 66). The groups were analysed for the presence of a BRAF V600E mutation and aggressive features, including macroscopic extrathyroidal extension (ETE), lymph node metastasis (LNM), and high-risk histological features (tall cell, columnar cell, hobnail, solid/trabecular, and diffuse sclerosing). The Fischer exact test was used to calculate statistical significance. Results BRAF V600E mutations were detected in 43.6% of PTMC and 42.4% of small PTC. Of the mutated PTMC nodules, 54.1% demonstrated aggressive characteristics as compared to 19.4% of the non-mutated PTMCs (p = 0.010). Of the mutated small PTC tumours, 82.1% had aggressive features. In contrast, 28.9% of the non-mutated small PTCs showed aggressive features (p Conclusions Our findings demonstrate an association between a BRAF V600E mutation and aggressive features in PTMC (≤ 1 cm) and small PTC (1–1.5 cm). Therefore, determining the molecular status of these thyroid nodules for the presence of BRAF V600E can help guide patient management. Graphical Abstract

Objective: Major postoperative adverse events (MPAEs) following head and neck surgery are not infrequent and lead to significant morbidity. The objective of this study was to ascertain which factors are most predictive of MPAEs in patients undergoing head and neck surgery. Methods: A cohort study was carried out based on data from patients registered in the National Surgical Quality Improvement Program (NSQIP) from 2006 to 2018. All patients undergoing non-ambulatory head and neck surgery based on Current Procedural Terminology codes were included. Perioperative factors were evaluated to predict MPAEs within 30-days of surgery. Age was classified as both a continuous and categorical variable. Retained factors were classified by attributable fraction and C-statistic. Multivariate regression and supervised machine learning models were used to quantify the contribution of age as a predictor of MPAEs. Results: A total of 43 701 operations were analyzed with 5106 (11.7%) MPAEs. The results of supervised machine learning indicated that prolonged surgeries, anemia, free tissue transfer, weight loss, wound classification, hypoalbuminemia, wound infection, tracheotomy (concurrent with index head and neck surgery), American Society of Anesthesia (ASA) class, and sex as most predictive of MPAEs. On multivariate regression, ASA class (21.3%), hypertension on medication (15.8%), prolonged operative time (15.3%), sex (13.1%), preoperative anemia (12.8%), and free tissue transfer (9%) had the largest attributable fractions associated with MPAEs. Age was independently associated with MPAEs with an attributable fraction ranging from 0.6% to 4.3% with poor predictive ability (C-statistic 0.60). Conclusion: Surgical, comorbid, and frailty-related factors were most predictive of short-term MPAEs following head and neck surgery. Age alone contributed a small attributable fraction and poor prediction of MPAEs. Level of evidence: 3

Background The American Thyroid Association supports same-day thyroid surgery (SDT) in select patients. In practice, it is common for thyroid surgeons to monitor patients overnight for postoperative complications such as cervical hematoma, recurrent laryngeal nerve injury (RLN) and symptomatic hypocalcemia. We sought to determine the safety profile and predictive factors of adverse postoperative outcomes for SDT based on the experience of three large institutions. Methods A retrospective cohort study was conducted for all thyroidectomies performed at three McGill University tertiary and quaternary care centers in Montreal, Canada between January 1st, 2016 and November 13th, 2020. Patient characteristics were associated with outcomes by bivariate and multivariate analyses. Results A total of 2297 records were surveyed and 1983 patients (1513 females, 470 males) met the inclusion criteria. Amongst them, 603 (30.4%) patients were discharged the same day. The overall postoperative complication rate amongst SDT was 3.6% compared with 10.7% for inpatients (p p = 0.061). RLN injury occurred in 7 SDT (1.2%), compared with 35 (2.5%) inpatients (p = 0.050). Symptomatic hypocalcemia occurred in 3 SDT (0.5%) compared with 73 (5.3%) inpatients (p p p p = 0.041) and reoperation (p = 0.037) rates compared with the inpatient group. Conclusion This study demonstrates that SDT are safe in a select group of patients under the care of experienced thyroid surgeons at high volume thyroid surgery centers. SDT can also lead to significant cost savings in a publicly funded health care system. Further exploration is needed to clarify patient profiles most amenable to SDT and inform clinical decision-making.

The rise in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has prompted a quest for further understanding of the role of high-risk HPV in tumor initiation and progression. Patients with HPV-positive OPSCC (HPV+ OPSCC) have better prognoses than their HPV-negative counterparts; however, current therapeutic strategies for HPV+ OPSCC are overly aggressive and leave patients with life-long sequalae and poor quality of life. This highlights a need for customized treatment. Several clinical trials of treatment de-intensification to reduce acute and late toxicity without compromising efficacy have been conducted. This article reviews the differences and similarities in the pathogenesis and progression of HPV-related OPSCC compared to cervical cancer, with emphasis on the role of prophylactic and therapeutic vaccines as a potential de-intensification treatment strategy. Overall, the future development of novel and effective therapeutic agents for HPV-associated head and neck tumors promises to meet the challenges posed by this growing epidemic.

This study aimed at identifying supportive care needs of patients with head and neck cancer (HNC-P) immediately post-treatment, finding early predictors of unmet needs, and contrasting how immediate post-treatment needs differed from needs in longer-term survivorship. Prospective longitudinal study of 223 consecutive adults (313 approached; 72% participation) newly diagnosed with a first occurrence of primary HNC. Patients completed the Supportive Care Needs Survey–Short Form (SCNS), the Structured Clinical Interview for DSM-IV, and other outcomes. Medical chart reviews were conducted. A total of 68% of patients (n = 145/223) completed the SCNS. The multiple linear regression indicated that when controlled for medical variables, patients presented higher levels of unmet needs when they presented with higher level of anxiety upon HNC diagnosis (p = 0.03), higher neuroticism (p = 0.03), and more stressful life events in the year pre-diagnosis (p = 0.01). Patients immediately post-treatment had a wider variety of unmet needs compared with those in extended survivorship, with psychological unmet needs most prevalent at both time points. Immediately post-treatment, patients needed more support regarding pain (p = 0.04) and worries about treatment results (p = 0.05), whereas patients in longer-term survivorship needed more support regarding anxiety (p = 0.02), changes in sexual relationships (p = 0.04), and fear of death and dying (p = 0.001). This study identifies areas needing further development to improve quality of care for HNC-P in the immediate post-treatment period, as well as early determinants of unmet needs. HNC clinics may want to routinely screen for anxiety, neuroticism, and burden from other life events, to pro-actively address needs upon treatment completion and alleviate disease burden.

To examine various factors associated with an increased risk of reoperation for persistent or recurrent malignant thyroid cancers.Retrospective cohort study.Tertiary academic hospital centers.Patients undergoing surgery for thyroid cancer at 2 tertiary academic institutions from 2006 to 2020 were included. Those who underwent a reoperative procedure were compared with patients only requiring 1 procedure. The Pearson chi-square and independentThis study included 2266 patients with surgically managed thyroid malignancy, of which 54 (2.4%) necessitated reoperations. Those requiring a second surgical procedure were more likely to be male (40.7% vs 20.9%,This study identified patient- and cancer-related characteristics associated with an increased risk of requiring reoperation for thyroid malignancies.

While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs.

ImportanceThe association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors.ObjectiveTo evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study.Design, Setting, and ParticipantsThis multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria.ExposuresTumor volume as measured on diagnostic imaging by expert neuroradiologists.Main Outcomes and MeasuresPrimary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study.ResultsThe mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76).Conclusions and RelevanceIncreasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Infection with HPV virus and exposure to extrinsic carcinogens are the main causative factors for oropharyngeal squamous cell carcinoma (OPSCC). While HPV-related OPSCC typically shows a better prognosis and may be a candidate for de-intensification therapy, there is a subset of HPV-related cancers that show aggressive phenotype with frequent metastatic spread. The identification and refinement of molecular markers can better serve for prediction of prognosis and thus improve treatment decisions and outcome. We conducted a systematic review according to the PRISMA guidelines of all relevant studies addressing novel biomarkers in publications prior to July 2021. We identified studies that evaluated the association between molecular markers and prognosis in HPV-positive OPSCC. Full-text publications were entirely reviewed, classified, and selected if a clear predictive/prognostic value was seen in patients with HPV-positive OPSCC. Furthermore, a functional analysis of the target genes was conducted to understand biological processes and molecular pathways impacting on HPV-positive OPSCC outcomes. The systematic review yielded a total of 14 studies that matched the inclusion and exclusion criteria. Differential expression was identified for 31 different biomarkers. The first common pattern identified was the association of HPV-related circulating antibodies to activated immune function. Second, gene-gene interaction analysis further identified interacting gene networks tightly implicated in hypoxia tumor metabolism including the Warburg effect. Survival in HPV-positive OPSCC can be predicted by distinct selective biomarkers mainly indicative of immune host response and oxidative metabolism. Among these markers, some were identified to be unsuitable for HPV-positive de-escalation trials aimed at improving patients' quality of life.

Background An international group of experts recommended reclassifying non-invasive follicular variant of papillary thyroid cancers (FVPTC) as ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP) in April 2016. The purpose of this study was to establish preoperative clinical, laboratory, ultrasonographic, and cytological variables, which can differentiate NIFTP from FVPTC. Methods We conducted a retrospective chart review of consecutive patients from a single institution evaluated between January 2012 and December 2017. 203 adult patients underwent lobectomy or total thyroidectomy for a FVPTC during that period. Each patient’s medical chart was reviewed and information on pre-operative variables was recorded. An expert pathologist reviewed all surgical specimens and reclassified a subset of FVPTC as NIFTP according to the specific criteria. Results Overall, 44 patients were included in the NIFTP group and 159 in the non-NIFTP group. Mean age was 50.1 years in the NIFTP group and 50.7 in the non-NIFTP group. Most patients were female (86.4% (38/44) in the NIFTP group vs 79.8% (127/159) in the non-NIFTP group). More patients underwent lobectomy in the NIFTP group (50% (22/44) vs 16.4% (26/159) in the non-NIFTP group, p = p = 0.0177). Preoperative thyroglobulin levels were lower in NIFTP patients (Median 25.55 mcg/L +/− 67.8 vs 76.06 mcg/L +/− 119.8 in Non-NIFTP, p = 0.0104). NIFTP nodules were smaller (Mean size 22.97 mm +/− 12.3 vs 25.88 mm +/− 11.2 for non-NIFTP, p = 0.0448) and more often solid than non-NIFTP (93.2% (41/44) vs 74.8% (119/159) for non-NIFTP, p = 0.0067). 2017 ACR TIRADS nodule category of 1–4 on ultrasound had a negative predictive value and a sensitivity of 100% for NIFTP. ROC Curve Analysis demonstrated that a preoperative thyroglobulin level of 31.3 mcg/L had a sensitivity of 75% and a specificity of 62.5% to differentiate NIFTP from non-NIFTP cancers. Conclusion Lower preoperative thyroglobulin levels, smaller nodule size, solid texture and 2017 ACR TIRADS Category of 1–4 are more strongly associated with NIFTP than FVPTC and can favour less invasive surgical options such as lobectomy.

Summary Background Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment. Methods The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0–2, and with T1–T2, N0–2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1–2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting. Findings 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20–33) for the radiotherapy group and 29 months (23–43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS. Interpretation Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options. Funding Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.

BACKGROUND We ascertain the association of postoperative infection on survival in patients with locoregionally advanced oral cavity squamous cell carcinoma (OCSCC). METHODS A retrospective study of patients with stage III/IVA OCSCC undergoing curative-intent surgery was performed. Postoperative infection was considered within 30 days after surgery. Kaplan-Meier survival curves were used to compare overall survival (OS) in patients with postoperative infection. Cox regression and propensity-score matching were used to adjust for confounders. RESULTS Fifty-four of 114 patients had a postoperative infection. The 5-year OS in patients with a postoperative infection (24.1%) was lower than those without (65.2%; P

OBJECTIVES The aim of this study was to ascertain the relationship between Bethesda category and molecular mutation of thyroid nodules in patients undergoing thyroidectomy. DESIGN A retrospective cohort of patients who underwent thyroidectomy following needle biopsy and molecular profile testing was performed. SETTING Two tertiary care academic hospitals. PARTICIPANTS Consecutive patients with a dominant thyroid nodule who underwent both USFNA and molecular profile testing followed by thyroidectomy were included in the study. MAIN OUTCOME AND MEASURES The main outcome was postoperative diagnosis of thyroid cancer and aggressivity of disease based on histopathological variants, nodal metastasis or extra-thyroidal extension. Associations between Bethesda category, molecular mutation and postoperative pathology was assessed using descriptive analysis and chi-square testing. RESULTS Four hundred fifty-one patients were included. 95.9% (93/97) of patients with a BRAFV600E mutation had a Bethesda category V or VI (p

Objective This study aimed to: 1) determine the contribution of pre-cancer psychosocial vulnerability as an independent predictor of Anxiety Disorder (AD) onset immediately post-treatment in patients diagnosed with a first occurrence of head and neck cancer, controlling for sociodemographics and medical variables; and 2) estimate prevalence of AD and identify trajectories from the moment of diagnosis to the immediate post-treatment (i.e., over a period of three months) in this population. Methods 224 consecutive patients (participation rate = 72%) newly diagnosed with a primary HNC were assessed with a structured clinical interview for a mental disorder, validated psychometric measures, and medical chart reviews. Results Twenty-five percent of patients presented a lifetime AD, 19.4% within 2 weeks of HNC diagnosis, and 16.6% immediately post-treatment; representing 26.7% of patients with AD at any timepoint from the moment of diagnosis to immediately post-treatment. Patients were more likely to present an AD immediately post-treatment when they: were diagnosed with advanced-stage cancer (O.R.=3.40, , p=0.006), presented a upon cancer diagnosis AD (O.R.=2.45, p=0.008) and/or experienced childhood abuse (O.R.=1.96, p=0.03). Conclusions Several AD trajectories may arise when patients are diagnosed with primary HNC. Health professionals should address AD and screen for risk factors (i.e., advanced stage cancer, AD upon cancer diagnosis, history of childhood abuse) as early as possible to assure optimal mental health care in this vulnerable population. This article is protected by copyright. All rights reserved.

Objective: Examine the association of Graves’ disease with the development of postoperative neck hematoma. Design: A cohort of patients participating in the Thyroid Procedure-Targeted Database of the National Surgical Quality Improvement Program from January 1, 2016 to December 31, 2018. Setting: A North American surgical cohort study. Methods: 17 906 patients who underwent thyroidectomy were included. Propensity score matching was performed to adjust for differences in baseline covariates. Multivariate logistic regression was used to ascertain the association between thyroidectomy for Graves’ disease and risk of postoperative adverse events within 30 days of surgery. The primary outcome was postoperative hematoma. Secondary outcomes were postoperative hypocalcemia and recurrent laryngeal nerve injury. Results: One-to-three propensity score matching yielded 1207 patients with mean age (SD) of 42.6 (14.9) years and 1017 (84.3%) female in the group with Graves’ disease and 3621 patients with mean age (SD) of 46.7 (15.0%) years and 2998 (82.8%) female in the group with indications other than Graves’ disease for thyroidectomy. The cumulative 30-day incidence of postoperative hematoma was 3.1% (38/1207) in the Graves’ disease group and 1.9% (70/3621) in other patients. The matched cohort showed that Graves’ disease was associated with higher odds of postoperative hematoma (OR 1.65, 95% CI 1.10-2.46) and hypocalcemia (OR 2.04, 95% CI 1.66-2.50) compared with other indications for thyroid surgery. There was no difference in recurrent laryngeal nerve injury among the 2 groups. Conclusions: Patients with Graves’ disease undergoing thyroidectomy are more likely to suffer from postoperative hematoma and hypocalcemia compared to patients undergoing surgery for other indications.

Purpose/Objective(s) Widespread oral human papillomavirus (HPV) infections have led to a rapid increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC). HPV-related OPSCCs have a better prognosis than conventional alcohol- and smoking-related OPSCCs, suggesting a role for treatment de-escalation. The goal of this phase II randomized trial was to assess survival, oncologic, and toxicity outcomes with two de-escalation approaches: primary reduced-dose radiotherapy (RT) vs. primary transoral surgery plus neck dissection (TOS + ND) with reduced-dose adjuvant therapy. Materials/Methods Weenrolled patients with T1-T2N0-2 (AJCC 8th edition) p16-positive OPSCC. After stratifying by smoking status, we randomized patients (1:1) to either the primary RT arm, which consisted of 60 Gy of RT and concurrent weekly cisplatin chemotherapy in node-positive patients vs. the TOS + ND arm, consisting of surgery and neck dissection, with adjuvant reduced-dose RT depending on pathologic findings. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), quality of life (QOL, using the MDADI and other metrics), and toxicity. The trial was closed to accrual in November 2020 due to excessive toxicity in the TOS + ND arm, consisting of two treatment-related deaths from known complications of TOS (one bleed and one cervical osteomyelitis following post-operative RT). After closure to accrual, all previously enrolled patients remained on follow-up. All analyses were pre-specified and intention-to-treat, unless otherwise specified. Due to these unexpected toxicity findings, the trial is being reported while survival outcomes remain immature, and therefore p-values are not reported for OS and PFS comparisons. Results BetweenFebruary 2018 and November 2020, 61 patients were randomized (n=30 in the RT arm and n=31 in the TOS + ND arm). Median age was 61.9 years, most patients (51%) were never-smokers, and the large majority of patients (n=51; 86%) were male. The arms were well-balanced. Median follow-up was 17 months (IQR: 15-20 months). Two-year estimates of OS were 100% in the RT arm (95% confidence interval [CI]: 100%-100%) and 89.1% (95% CI: 69.6%-96.4%) in the TOS + ND arm. Two-year PFS estimates were 100% in the RT arm (95% CI: 100%-100%) and 83.5% (95% CI: 60.8%-93.7%) in the TOS + ND arm. Grade 2-5 toxicities occurred in 67% of patients in the RT arm and 71% in the TOS + ND arm, with significantly more anorexia and dysgeusia in the RT arm. Mean (±SD) MDADI total scores at 1-year were similar between arms (85.7 ± 15.6 and 84.7 ± 14.5, respectively). One patient in each arm required a percutaneous feeding tube, and none required feeding tubes at 1-year. Conclusion The primary RT approach achieved excellent oncologic outcomes in treatment de-escalation, with a moderate toxicity profile, and should be tested in phase III trials. The primary TOS approach was associated with an upfront risk of treatment-related mortality and suboptimal PFS. (NCT03210103)

Simple Summary There is clinical evidence that ulcerated and inflammatory cell-infiltrated oral cancer is frequently associated with early metastases. Our results from genomic screening in patients with metastatic oral cancer identified specific changes in genes that regulate macrophage chemotaxis and drive tumor progression. This opens up potential therapeutic opportunities toward personalized medicine tailored to manage patients with advanced disease. Abstract Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of TWIST1, a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (CSF1), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, p = 0.0035 and p = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that TWIST1 gene overexpression induces the activation of CSF1 while TWIST1 gene silencing down-regulates CSF1 preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing TWIST1. In summary, this study provides insight into the cooperation between TWIST1 transcription factor and CSF1 to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.

In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression. Here, we conducted a systematic review in order to assess whether DNA hypermethylated genes are predictive of high risk of developing HNC and/or impact on survival and outcomes in non-HPV/non-tobacco/non-alcohol associated HNC. We identified 85 studies covering 32,187 subjects where the relationship between DNA methylation, risk factors and survival outcomes were addressed. Changes in DNA hypermethylation were identified for 120 genes. Interactome analysis revealed enrichment in complex regulatory pathways that coordinate cell cycle progression (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 and RASSF1). However, not all these genes showed significant statistical association with alcohol consumption, tobacco and/or HPV infection in the multivariate analysis. Genes with the most robust HNC risk association included TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARβ. From these candidates, we further validated CD44 at translational level in an independent cohort of 100 patients with tongue cancer followed-up beyond 10 years. CD44 expression was associated with high-risk of tumor recurrence and metastasis (P = 0.01) in HPV-cases. In summary, genes regulated by methylation play a modulatory function in HNC susceptibility and it represent a critical therapeutic target to manage patients with advanced disease.

Background: Although the current gold standard for diagnosing thyroid nodule malignancy is ultrasound-guided fine-needle aspiration (FNA) cytology, about 20–25% of cytological evaluations are consi...

Background Molecular testing has been used for cytologically indeterminate thyroid nodules (Bethesda III and IV), where the risk of malignancy is 10–40%. However, to date, the role of molecular testing in cytologically suspicious or positive for malignancy (Bethesda V and VI) thyroid nodules has been controversial. The aim of this study was to determine whether patients who had molecular testing in Bethesda V and VI thyroid nodules had the optimal extent of surgery performed more often than patients who did not have molecular testing performed. Methods A retrospective chart review of 122 cases was performed: 101 patients from the McGill University teaching hospitals and 21 patients from the Hillel Yaffe Medical center, Technion University. Patients included in the study were those with Bethesda V or VI thyroid nodules who underwent molecular testing (ThyGenext® or ThyroseqV3®) (McGill n = 72, Hillel Yaffe n = 14). Patients with Bethesda V or VI thyroid nodules who did not undergo molecular testing were used as controls (McGill n = 29, Hillel Yaffe n = 7). Each case was reviewed in order to determine whether the patient had optimal surgery. This was defined as total thyroidectomy in the presence of either a positive lymph node, extrathyroidal extension, or an aggressive pathological variant of papillary thyroid carcinoma (tall cell, hobnail, columnar cell, diffuse sclerosing, and solid/trabecular) documented on the final pathology report. In all other cases, a lobectomy/hemi/subtotal thyroidectomy was considered as optimal surgery. Chi-squared testing was performed to compare groups. Results When molecular testing was done, 91.86% (79/86) of surgeries in the molecular testing group were optimal, compared to 61.11% (22/36) in the control group. At McGill University teaching hospitals and at Hillel Yaffe, 91.67% (66/72) and 92.86% (13/14) of surgeries in the intervention group were considered as optimal, respectively. This compares to 58.62% (17/29) at McGill and 71.43% (5/7) at Hillel Yaffe when molecular testing was not performed (p = .001, p = .186). Conclusions In this study, molecular testing in Bethesda V and VI thyroid tumors significantly improved the likelihood of optimal surgery. Therefore, molecular testing may have an important role in optimizing surgical procedures performed in the setting of Bethesda V and VI thyroid nodules. Prospective studies with larger sample sizes are required to further investigate this finding. Graphical abstract

Objective The aim of this study was to develop and validate a patient-reported outcome measure to evaluate body image concerns in head and neck cancer (HNC) patients. Methods Items were created using a combination of deductive (eg, US Food and Drug Administration Qualification of Clinical Outcome Assessments, literature review) and inductive approaches (eg, subject matter experts, HNC patients). Items were translated for use in both Canadian English and Canadian French using back-translation. A two-step empirical validation process using the Classical Test Theory (CTT) and Rasch Measurement Theory (RMT) was conducted with 224 and 258 HNC patients, respectively, having undergone disfiguring surgery within the past 3 years. Results Analyses suggest two subscales for MBIS-HNC: social discomfort (10 items) and negative self-image (11 items). The McGill Body Image Concerns Scale-Head and Neck Cancer (MBIS-HNC) is reliable with high internal consistency (0.98), high test-retest reliability over a two-week period (ICC = 0.88), moderate to high convergent validity (range r = 0.43-0.81), and divergent validity (range r = 0.12-0.15). RMT was used in addition to CTT. Disordered thresholds led to the modification of the number of response options, and items were deleted based on differential item functioning and high local dependency. Unidimensionality of both subscales and supporting a total score was confirmed. The measure was however characterized by the presence of an important floor effect, confirmed with poor targeting as demonstrated by the person-item threshold distribution. Conclusion Evidence gathered from our theory-driven validation study using CTT and RMT provides practitioners and researchers with a useful and easy to use self-report measure.

Objective The primary purpose of this study was to identify predictors of Major Depressive Disorder in head and neck cancer (HNC) patients in the immediate post-treatment period (ie, at 3 months post-diagnosis), with a focus on previously unexamined historical and contextual factors. Methods Prospective longitudinal study of 223 consecutive adults (72% participation) newly diagnosed with a first occurrence of primary HNC, including validated psychometric measures, Structured Clinical Interviews for DSM Disorders, and medical chart reviews. Results The 3-month period prevalence of Major Depressive Disorder was 20.4%; with point prevalences of 6.8% upon HNC diagnosis, 14.2% at 3 months, and 22.6% lifetime. Patients most susceptible to developing Major Depressive Disorder in the immediate post-treatment period: were diagnosed with advanced-stage cancer rather than early-stage cancer (O.R. = 4.94, P = 0.04), received surgery only (O.R. = 8.73, P = 0.04), presented a lifetime history of Anxiety Disorder on SCID-I (O.R. = 6.62; P = 0.01), and indicated higher pre-treatment levels of anxiety on the HADS (O.R. = 0.45, P = 0.05). Conclusions Our results outline the predominant role of anxiety upon diagnosis as a precursor to post-treatment Major Depressive Disorder, suggesting the need for identification and prophylactic treatment of anxiety upon diagnosis in head and neck cancer patients. Further investigation into pathways by which pre-treatment anxiety predisposes to post-treatment Major Depressive Disorder in this population is warranted.

Objective Additive manufacturing offers a tailored approach to tissue engineering by providing anatomically precise scaffolds onto which stem cells and growth factors can be supplied. Polyetherketoneketone (PEKK), an ideal candidate biomaterial, is limited by a poor implant–bone interface but can be functionalized with adipose-derived stem cells (ADSC) to promote integration. This in vivo study examined the interaction of a three-dimensional printed PEKK/ADSC implant within the critical-sized mandibular defect in a rabbit model. Study Design/Methods Trapezoidal porous scaffolds with dimensions of 1.5 × 1.0 × 0.5 cm were printed using selective laser sintering. ADSCs were seeded on the scaffolds that were then implanted in marginal defects created in New Zealand rabbits. Rabbits were euthanized at 10- and 20-week intervals. Microcomputed tomography was used to characterize bone ingrowth and was correlated with histological analysis. Stress testing was performed on the scaffolds before and after implantation. Results All scaffolds were well integrated into adjacent bone. Bone-to-tissue volume increased from 30.34% ( ± 12.46) to 61.27% ( ± 8.24), and trabecular thickness increased from 0.178 mm ( ± 0.069) to 0.331 mm ( ± 0.0306) in the 10- and 20-week groups, respectively, compared to no bone regrowth on the control side (P

// Joshua Lubov 1 , Mariana Maschietto 2 , Iman Ibrahim 1 , Alex Mlynarek 1 , Michael Hier 1 , Luiz Paulo Kowalski 3 , Moulay A. Alaoui-Jamali 1 and Sabrina Daniela da Silva 1 1 Department of Otolaryngology Head and Neck Surgery, Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine and Oncology, McGill University, Montreal, QC, Canada 2 Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas, SP, Brazil 3 Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center, Sao Paulo, SP, Brazil Correspondence to: Sabrina Daniela da Silva, email: sabrinadaniela@hotmail.com Keywords: miRNAs, prognosis, head and neck cancer, therapeutics Received: February 09, 2017 Accepted: June 05, 2017 Published: July 13, 2017 ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, incurring significant high mortality and morbidity. This review explored the risk stratification of miRNAs, and investigated the impact of miRNA networking in HNSCC prognostication. We performed a meta-analysis and a systematic literature search on online databases for papers published prior to December 1, 2016. The list of miRNAs was uploaded to MetacoreTM to construct a protein-protein interaction network, which was used to identify targets of the miRNAs and potential drugs. In addition, a representative network was further validated by immunohistochemistry in a cohort of 100 patients. We found 116 studies that included 8,194 subjects, in which the relationship between miRNA expression and prognosis of HNSCC were analyzed. Significant elevated expressions of 27 miRNAs and decreased expression of 26 miRNAs were associated with poor outcome. After excluding the studies causing heterogeneity, a fixed model was applied, which showed a statistically significant association between increased expression of miR-21 and poor survival (Pooled HR = 1.81,95% CI = 0.66–2.95, P < 0.005). We identified four networks affected by the miRNAs expression and enriched in genes related to metabolic processes and regulation of cell mitogenesis in response to extracellular stimuli. One network point out to 16 miRNAs directly or indirectly involved in the regulation of androgen-receptor (AR). Evaluation of AR protein expression in our cohort revealed that patients with upregulation of AR had poor survival rates (log-rank test, P < 0.005). This study showed that miRNAs have potential prognostic value to serve as screening tool for HNSCC during the follow-up. In addition, the implementation of a network-based analysis may reveal proteins with potential to be used as a biomarker.

Background The incidence of thyroid nodules is increasing among patients in North America. Few of these nodules harbour malignancy, thus further research is required to identify predictive markers of malignant thyroid disease. This study set out to understand the relationship between the levels of fT4 and fT3 and differentiated thyroid cancer. Methods A case-control study was conducted with 142 cases and 86 controls from the McGill University Teaching Hospitals. All patients underwent thyroid surgery. Cases were defined as patients with malignant nodules confirmed on final pathology and controls were defined as patients with benign nodules. The serological levels of TSH, fT4 and fT3 were measured preoperatively. Odds ratios were determined for each parameter and logistic regressions were calculated between markers and probability of malignancy. Additionally, fT4 values were divided by fT3 values (fT4/fT3 quotient) for each patient and an odds ratio was calculated. Results Amongst cases, the mean TSH was 2.25 ± 0.360U/mL, fT4 was 14.8 ± 0.689pmol/L, and fT3 was 4.65 ± 0.463pmol/L. Amongst controls, the mean TSH was 2.36 ± 1.68U/mL, fT4 was 14.3 ± 1.71pmol/L, and fT3 was 5.27 ± 0.957pmol/L. Patients in the control group were more likely to have low TSH, while patients in the case group would have high fT4 and patients in the control group were more likely to have a low fT4. The OR for patients with TSH >4.4U/mL was 2.13 (0.97, 4.65), and for patients with TSH 16pmol/L was 2.10 (1.09, 4.06), and for patients with fT4 5.5pmol/L was 0.39 (0.14, 1.28). The OR for patients with fT3 3.3 (OR =6.00 (2.94, 12.25)). Conclusion In this study, a direct relationship between high levels of fT4 and malignancy was uncovered. Furthermore, low levels of TSH and fT4 increased the likelihood that a nodule was benign. In this study a fT4/fT3 ratio >3.3 increased the risk of malignancy by 3.6 times (p-value =0.0013).

Background Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. Methods This is a multicenter phase II study randomizing one hundred and forty patients with T1–2 N0–2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50–60 Gy based on risk factors). Patients will be stratified based on smoking status ( Discussion This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. Trial Registration Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Regional metastasis is the single most important prognostic factor in oral squamous cell carcinoma (OSCC). Abnormal expression of N-myc downstream-regulated genes (NDRGs) has been identified to occur in several tumor types and to predict poor prognosis. In OSCC, the clinical significance of deregulated NDRG expression has not been fully established. In this study, NDRG1 relevance was assessed at gene and protein levels in 100 OSCC patients followed up by at least 10 years. Survival outcome was analyzed using a multivariable analysis. Tumor progression and metastasis was investigated in preclinical model using oral cancer cell lines (HSC3 and SCC25) treated with epidermal growth factor (EGF) and orthotopic mouse model of metastatic murine OSCC (AT84). We identified NDRG1 expression levels to be significantly lower in patients with metastatic tumors compared with patients with local disease only (P = 0.001). NDRG1 expression was associated with MMP-2, -9, -10 (P = 0.022, P = 0.002, P = 0.042, respectively) and BCL2 (P = 0.035). NDRG1 lower expression was able to predict recurrence and metastasis (log-rank test, P = 0.001). In multivariable analysis, the expression of NDRG1 was an independent prognostic factor (Cox regression, P = 0.013). In invasive OSCC cells, NDRG1 expression is diminished in response to EGF and this was associated with a potent induction of epithelial–mesenchymal transition phenotype. This result was further confirmed in an orthotopic OSCC mouse model. Together, this data support that NDRG1 downregulation is a potential predictor of metastasis and approaches aimed at NDRG1 signaling rescue can serve as potential therapeutic strategy to prevent oral cancer progression to metastasis.