Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

Associations between Human Papillomavirus Status, Weight Change, and Survival of Oropharyngeal Cancer Patients.

This study examined associations between HPV status and weight change in oropharyngeal cancer (OPC). OPC patients receiving concurrent chemoradiotherapy in Toronto, Canada were included. Relationships were assessed between HPV status and weight loss grade (WLG, combining weight loss and current body mass index); weight change during treatment; and HPV status and WLG/weight change on overall (OS) and cancer-specific (CSS) survival. Of 717 patients, WLG pre-radiation was less severe among HPV-positive compared to HPV-negative, though weight loss during treatment was greater. The adjusted odds ratio for greater WLG among HPV-positive versus HPV-negative was 0.47 (95%CI 0.28-0.78). Grade-4 WLG (worst category) experienced poorer OS and CSS (OS adjusted hazard ratio (aHR) 4.08; 95%CI 1.48-11.2, compared to Grade-0); and was non-significant for HPV-negative (aHR 2.34; 95%CI 0.69-7.95). Relationships between weight change before/during treatment and survival had similar direction between HPV-positive and HPV-negative, but of greater magnitude in HPV-positive patients.

Differential prognostic significance of sarcopenia in metastatic esophageal squamous and adenocarcinoma.

BACKGROUND: Sarcopenia indicates poor prognosis in various malignancies. We evaluated the association of sarcopenia with overall (OS) and progression-free survival (PFS) in metastatic esophageal cancer (MEC) patients, a population often presenting with poor nutritional status. METHODS: In newly diagnosed MEC patients managed at the Princess Margaret (PM) Cancer Centre (diagnosed 2006-2015), total muscle area, visceral adiposity (VA), and subcutaneous adiposity (SA) were quantified on abdominal computed tomography at L3. Sarcopenia was determined using published cutoffs, based on sex and height. RESULTS: Of 202 MEC patients, most were male (166/82%), < 65 years (116/57%), and had adenocarcinoma histology (141/70%); 110/54% had recurrent MEC after initial curative-intent treatment; 92/46% presented with de novo MEC. At stage IV diagnosis, 20/10% were underweight, 97/48% were normal-weight and 84/42% were overweight/obese; 103/51% were sarcopenic. Sarcopenia was associated with worse median OS (4.6 vs. 7.9 months; log-rank p = 0.03) and 1-year survival, even after adjusting for other body composition variables (e.g., BMI, VA, and SA): adjusted-HR 1.51 [95% CI 1.1-2.2, p = 0.02]. In post hoc analysis, sarcopenia was highly prognostic in adenocarcinomas (p = 0.003), but not squamous cell carcinomas (SCC). In patients receiving palliative systemic treatment (104/51%), sarcopenia was associated with shorter PFS (p = 0.004) in adenocarcinoma patients (75/72%). CONCLUSIONS: In metastatic esophageal adenocarcinomas, sarcopenia is associated with worse PFS and OS. In metastatic esophageal SCC, there was a non-significant trend for worse PFS but no association with OS. In order to offset the poor prognosis associated with sarcopenia particularly in metastatic esophageal adenocarcinoma patients, future research should focus on possible countermeasures.

Longitudinal health utility and symptom-toxicity trajectories in patients with head and neck cancers.

BACKGROUND: This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC). METHODS: For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. RESULTS: In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories. CONCLUSIONS: Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC. LAY SUMMARY: This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.

Internet and social media use in cancer patients: association with distress and perceived benefits and limitations.

OBJECTIVE: Cancer patients may turn to social media (SM) to cope with distress. We investigated associations between distress and internet/SM use for cancer information/support. METHODS: Adult patients at a Canadian cancer centre completed a cross-sectional survey on sociodemographics, health status, use of cancer online resources and distress (EQ5D-5L). Statistical models adjusted for relevant variables. RESULTS: Of 376 participants, median age was 52 years, time since diagnosis was 1.63 years, 272 (74%) had post-secondary education and 192 (51%) were female. For cancer information/support, 276 (73%) used internet and 147 (39%) SM. Dose response relationships were observed between distress and cancer-related internet (p = 0.02), and SM use (p < 0.001). Respondents using internet/SM for cancer information/support reported greater internet confidence (internet OR = 4.0, 95% CI: 1.9-8.3; SM OR = 4.18, 95%, CI: 1.9-11.3), higher education (internet OR = 3.0, 95% CI: 1.7-5.2; SM OR = 2.21, 95% CI: 1.2-4.1) and were more likely female (internet OR = 2.6, 95% CI 1.5-4.6; SM OR = 2.1, 95% CI: 1.3-3.4). For SM for cancer information/support, more used SM > 30 min daily (OR = 3.4; 95% CI: 2.1-5.7), and were distressed (OR = 1.67, 95% CI: 1.0-2.7). SM benefits were to learn about cancer (93; 25%), distract from cancer (85; 23%) and connect with survivors (81; 22%). SM limitations were privacy (161; 43%), quality (90; 24%) and personal applicability (85; 23%). Females used SM more to connect with survivors than males (p = 0.001). CONCLUSIONS: Greater internet confidence, higher education and being female were associated with cancer-related internet/SM use. Distressed cancer patients were also more likely to turn to SM. Privacy concerns may limit SM use for coping. Future research should determine how to optimize SM in caring for and connecting with patients and reduce cancer-related distress.

Psychometric testing of the Skull Base Inventory health-related quality of life questionnaire in a multi-institutional study of patients undergoing open and endoscopic surgery.

PURPOSE: The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. METHODS: This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. RESULTS: One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. CONCLUSION: The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.

Measuring financial toxicity incurred after treatment of head and neck cancer: Development and validation of the Financial Index of Toxicity questionnaire.

BACKGROUND: The treatment of head and neck cancer (HNC) may cause significant financial toxicity to patients. Herein, the authors have presented the development and validation of the Financial Index of Toxicity (FIT) instrument. METHODS: Items were generated using literature review and were based on expert opinion. In item reduction, items with factor loadings of a magnitude <0.3 in exploratory factor analysis and inverse correlations (r < 0) in test-retest analysis were eliminated. Retained items constituted the FIT. Reliability tests included internal consistency (Cronbach α) and test-retest reliability (intraclass correlation). Validity was tested using the Spearman rho by comparing FIT scores with baseline income, posttreatment lost income, and the Financial Concerns subscale of the Social Difficulties Inventory. Responsiveness analysis compared change in income and change in FIT between 12 and 24 months. RESULTS: A total of 14 items were generated and subsequently reduced to 9 items comprising 3 domains identified on exploratory factor analysis: financial stress, financial strain, and lost productivity. The FIT was administered to 430 patients with HNC at 12 to 24 months after treatment. Internal consistency was good (α = .77). Test-retest reliability was satisfactory (intraclass correlation, 0.70). Concurrent validation demonstrated mild to strong correlations between the FIT and Social Difficulties Inventory Money Matters subscale (Spearman rho, 0.26-0.61; P < .05). FIT scores were found to be inversely correlated with baseline household income (Spearman rho, -0.34; P < .001) and positively correlated with lost income (Spearman rho, 0.24; P < .001). Change in income was negatively correlated with change in FIT over time (Spearman rho, -0.25; P = .04). CONCLUSIONS: The 9-item FIT demonstrated internal and test-retest reliability as well as concurrent and construct validity. Prospective testing in patients with HNC who were treated at other facilities is needed to further establish its responsiveness and generalizability.

Health-related social media use and preferences of adolescent and young adult cancer patients for virtual programming.

PURPOSE: Adolescents and young adults (AYA) with cancer are increasingly using the internet and social media (SM) for cancer-related information. AYA face specific challenges and thus require tailored resources that meet their needs. We describe the internet and SM preferences of AYA related to their cancer information seeking behaviors and their preferences for a future resource compared to middle-aged adults (MAA). METHODS: Cancer patients completed a cross-sectional survey related to their internet and SM usage, cancer information, and preferences for future resources. Chi-square tests were used to compare AYA and MAA. RESULTS: The mean (±SD) age in the AYA group was 30±6.1 years (n = 129); in MAA 55±6.7 years (n = 157). In general, AYA preferred internet sites over SM platforms for cancer-related information and prefer a website platform over a SM platform for a new resource. Few AYA were aware of hospital-based AYA-specific resources. MAA were less likely to use SM compared with AYA (13% vs 4%, p = 0.01); however, websites and SM platforms that were used were similar between the 2 groups. Participants endorsed having already researched certain topics - yet, these were also those desired in a new resource. Compared to MAA, AYA sought more information on diet/nutrition, physical activity, exercise/fitness, fertility, sexual health, and body image (all p values < 0.05). CONCLUSION: AYA and MAA use similar resources on the internet and SM, but AYA sought information related to specific needs. Development of future resources should focus on an internet-based platform rather than a SM platform, coupled with promoting awareness of the resource.

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

Comparison of 68Ga-DOTATATE Positron Emmited Tomography/Computed Tomography and Gadoxetic Acid-Enhanced Magnetic Resonance Imaging for the Detection of Liver Metastases from Well-Differentiated Neuroendocrine Tumors.

This study aimed to compare the detection of neuroendocrine tumor liver metastases (NLMs) in hepatobiliary-specific contrast-enhanced MRI (pMR) versus 68Ga-DOTATATE PET/CT (DT-PET). This retrospective study cohort included 30 patients with well-differentiated neuroendocrine tumors who underwent both DT-PET and pMR. Two readers independently assessed NLMs count, SUVmax on DT-PET, and signal characteristics on pMR. A consensus review by two additional readers resolved discrepancies between the modalities. Results showed concordance between DT-PET and pMR NLM count in 14/30 patients (47%). pMR identified more NLMs in 12/30 patients (40%), of which 4 patients showed multiple deposits on pMR but only 0-1 lesions on DT-PET. DT-PET detected more in 4/30 patients (13%). Overall, pMR detected more metastases than DT-PET (p = 0.01). Excluding the four outliers, there was excellent agreement between the two methods (ICC: 0.945, 95%CI: 0.930, 0.958). Notably, pMR had a higher NLM detection rate than DT-PET, with correlations found between lesion size on pMR and DT-PET detectability, as well as diffusion restriction on pMR and SUVmax on DT-PET. In conclusion, in consecutive patients with well-differentiated NETs, the detection rate of NLM is higher with pMR than with DT-PET. However, when excluding patients whose tumors do not overexpress somatostatin receptors (13% of the cohort), high concordance in the detection of NLM is observed between DT PET and pMR.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials.

The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.

Quantifying Neck Fibrosis: Establishing the Domain Structure of the Neck Fibrosis Scale.

OBJECTIVE: We recently described the development of the Neck Fibrosis Scale (NFS). In this submission, we confirm domain structure and validate a scoring system for the NFS. STUDY DESIGN: Prospective cross-sectional study. METHODS: Between January 2020 and December 2021, 127 head and neck cancer patients with varying degrees of cutaneous neck fibrosis completed the original 15 item NFS. Exploratory factor analysis was used to identify optimal groupings with similar underlying factors. The association between the domains of the NFS and various measures of neck morbidity (i.e., construct validity) were assessed using gamma regression. RESULTS: Exploratory factor analysis confirmed 13 of the 15 items from the NFS mapped onto two factors, which were labelled 'physical' and 'emotional' domains. Of the remaining two items, 'energy' did not load uniquely onto one factor and was removed. 'Neck-swelling' did not load on either factor (loadings <0.3) but was retained within the physical domain based on clinical importance. This resulted in a revised 14-item questionnaire. Internal consistency for these two domains was high (>0.8, p < 0.01). Both the physical and emotional domains of the revised NFS show strong correlation with the neck dissection impairment index and neck range of motion. The physical domain strongly correlated with neck elasticity (0.902 [95%CI 0.839-0.972], p < 0.01). Patients receiving multimodal therapy had physical domain scores that were 31.6% [95% 13.9-51.8] higher (worse) than unimodal therapy patients. CONCLUSIONS: A domain structure and scoring strategy have been developed for the NFS. Future efforts should be directed toward an evaluation of responsiveness. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2198-2202, 2023.

Dental Extractions Before Radiation Therapy and the Risk of Osteoradionecrosis in Patients With Head and Neck Cancer.

Importance: Patients with head and neck cancer undergo extraction of teeth with poor prognoses to minimize post-radiation therapy (RT) extractions, which are known to cause osteoradionecrosis (ORN). However, many patients are required to start RT before the extraction sites are completely healed. The role of pre-RT extractions in the development of ORN has been disputed in literature. Objective: To determine whether the timing of pre-RT dental extractions is associated with ORN development in patients with head and neck cancer. Design, Setting, and Participants: This retrospective cohort study was conducted at a single institution (Princess Margaret Cancer Centre, Toronto, Canada) between January 1, 2011, and January 1, 2018, and included 879 patients with head and neck cancer who underwent pre-RT dental extractions before curative RT of 45 Gy or greater. Patient demographic information and clinical characteristics (eg, primary cancer site, nodal involvement, chemotherapy, smoking status, dental pathology) were considered. Data analyses were performed from July to December 2022. Main outcomes and measures: Timing (number of days) from dental extractions to RT start date and pre-RT extractions categorized as healed, minor bone spicules (MBS), or ORN. Results: The study population consisted of 879 patients with a median (range) age of 62 (20-96) years, with 685 men (78%) and 194 women (22%). Of these, 847 (96.3%) healed from pre-RT dental extractions, 16 (1.8%) developed MBS, and 16 (1.8%) developed ORN. The median (range) time in number of days from pre-RT extraction(s) to start of RT was 9 (0-98) days in the healed cohort, 6 (3-23) days in the MBS cohort, and 6 (0-12) days in the ORN cohort. There was a large difference in the timing of pre-RT extractions between the healed and the MBS cohorts (mean 11.9 vs 7.4 days to radiation; difference 4.4; 95% CI, 1.5-7.3), and the healed and the ORN cohorts (mean 11.9 vs 7.1 days; difference 4.8 days; 95% CI, 2.6-7.1). Conclusion: The findings of this retrospective cohort study suggest that there was an important association between the timing of pre-RT dental extractions and ORN when extractions occurred within 7 days of the RT start date. Despite this, ORN after pre-RT extractions is relatively rare. These findings indicate that patients with head and neck cancer who are to undergo RT should not delay treatment for extractions when it might compromise oncologic control.

Analysis of prognostic germline polymorphisms in patients with advanced hepatocellular carcinoma.

Background: The prognosis of hepatocellular carcinoma (HCC) is influenced by both tumor and patient specific factors. Current therapies of advanced HCC target angiogenesis and immune evasion, however there are no clinically useful biomarkers to guide clinicians. Methods: Our aim in this retrospective cohort study was to validate single nucleotide polymorphisms (SNPs) prognostic of outcome in advanced HCC from the literature, and to analyze exploratory SNPs chosen from evaluation of the HCC tumor immune microenvironment. Using a database of patients with HCC treated with sorafenib, blood samples were genotyped, clinical variables were retrospectively collected, and SNPs were analyzed for association with progression-free survival (PFS) and overall survival (OS). A subsequent analysis was conducted to determine if identified SNPs were prognostic in trans arterial chemoembolization (TACE) treated patients. Results: Literature review identified 7 SNPs in vascular endothelial growth factor (VEGF), eNOS, angiopoietin 2 (ANGPT2) and vascular endothelial growth factor receptor 2 (VEGFR2), however none were externally validated in our dataset. Of the 35 exploratory immunomodulatory SNPs, the following were associated with PFS or OS: CCL2 C-C motif ligand 2 (CCL2) (rs1024611), interleukin-10 (IL-10) (rs1800896), cytotoxic T-lymphocyte antigen-4 (CTLA-4) (rs231775) and NFKB1 (rs28362491). Conclusions: SNPs identified by literature review to be prognostic in sorafenib treated patients with advanced HCC were not validated in our dataset. Our findings suggest potentially important prognostic implications of SNPs in VEGFR2, CCL2, IL-10, CTLA-4 and NFKB1 that deserve further study.

Association of Household Income at Diagnosis With Financial Toxicity, Health Utility, and Survival in Patients With Head and Neck Cancer.

Importance: While several studies have documented a link between socioeconomic status and survival in head and neck cancer, nearly all have used ecologic, community-based measures. Studies using more granular patient-level data are lacking. Objective: To determine the association of baseline annual household income with financial toxicity, health utility, and survival. Design, Setting, and Participants: This was a prospective cohort of adult patients with head and neck cancer treated at a tertiary cancer center in Toronto, Ontario, between September 17, 2015, and December 19, 2019. Data analysis was performed from April to December 2021. Exposures: Annual household income at time of diagnosis. Main Outcome and Measures: The primary outcome of interest was disease-free survival. Secondary outcomes included subjective financial toxicity, measured using the Financial Index of Toxicity (FIT) tool, and health utility, measured using the Health Utilities Index Mark 3. Cox proportional hazards models were used to estimate the association between household income and survival. Income was regressed onto log-transformed FIT scores using linear models. The association between income and health utility was explored using generalized linear models. Generalized estimating equations were used to account for patient-level clustering. Results: There were 555 patients (mean [SD] age, 62.7 [10.7] years; 109 [20%] women and 446 [80%] men) included in this cohort. Two-year disease-free survival was worse for patients in the bottom income quartile (<$30 000: 67%; 95% CI, 58%-78%) compared with the top quartile (≥$90 000: 88%; 95% CI, 83%-93%). In risk-adjusted models, patients in the bottom income quartile had inferior disease-free survival (adjusted hazard ratio, 2.13; 95% CI, 1.22-3.71) and overall survival (adjusted hazard ratio, 2.01; 95% CI, 0.94-4.29), when compared with patients in the highest quartile. The average FIT score was 22.6 in the lowest income quartile vs 11.7 in the highest quartile. In adjusted analysis, low-income patients had 12-month FIT scores that were, on average, 134% higher (worse) (95% CI, 16%-253%) than high-income patients. Similarly, health utility scores were, on average, 0.104 points lower (95% CI, 0.026-0.182) for low-income patients in adjusted analysis. Conclusions and Relevance: In this cohort study, patients with head and neck cancer with a household income less than CAD$30 000 experienced worse financial toxicity, health status, and disease-free survival. Significant disparities exist for Ontario's patients with head and neck cancer.

Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.

OBJECTIVES: This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs. MATERIALS AND METHODS: Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively. RESULTS: Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses. CONCLUSION: Serial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

Development and Standardization of a Classification System for Osteoradionecrosis: Implementation of a Risk-Based Model.

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.