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Supplementary Figure from Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma

Supplementary Data from Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma

Purpose:Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation.Experimental Design:We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I–IVA human papillomavirus–negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls.Results:CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated (r > 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples.Conclusions:Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

List of shRNAs on the custom reductase library.

Supplementary Figure Legends from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Evaluation of SN30000-induced bystander cell killing in a co-culture system (S1); SN30000 clonogenic survival curves for HT-29, PANC-1 cells and HKO1 (S2); Plating efficiency in HT-29, PANC-1 and HKO2 reductase screens (S3); Density distributions and correlations of reductase screen sequencing data (S4); Log2 enrichment factors of shRNAs significantly selected in the reductase screens (S5); Depletion of POR protein by shRNAs in PANC-1 and HT-29 cells (S6); Replicate SN30000 clonogenic survival assays performed in stably transduced HT-29 and PANC-1 cells (S7); Measurement of plating efficiency in HKO1 and HKO2 whole-genome screens (S8); Coincidence of shRNAs significantly selected (Z > 1.96) in HT-29 and PANC-1 reductase screens and the HKO1 genome-wide screen (S9); Validation of POR shRNAs and clonogenic survival following SN30000 treatment of POR-knockout HCT116 cells (S10); Spatial distribution of POR and CA-IX expression in tongue SCC (S11); Quantitation of POR and CA-IX expression in HNSCC (S12); POR IHC staining in isogenic xenografts used for method development (S13); POR mRNA expression and sequence variation in the TCGA HNSCC dataset (S14).

IMPORTANCE: Patient-derived xenografts (PDXs) offer the opportunity to identify patients with oral cavity squamous cell carcinoma (OSCC) who are at risk for recurrence and optimize clinical decision-making. OBJECTIVE: To develop and validate a prediction score for locoregional failure (LRF) and distant metastases (DM) in OSCC that incorporates PDX engraftment in addition to known clinicopathological risk factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, PDX models were generated from patients with OSCC treated with curative intent at Princess Margaret Cancer Centre (Toronto, Canada) between 2006 and 2018. The cohort included 288 patients (aged ≥18 years) with a new diagnosis of nonmetastatic (M0) OSCC whose tumor samples were available for engraftment under the skin of xenograft mice. Patients were scored as a nonengrafter if PDX formation did not occur within 6 months. Data analysis was performed between August 2006 and May 2018. INTERVENTIONS: All patients received up-front curative-intent surgery followed by either observation or postoperative radiation with or without concurrent chemotherapy based on institutional guidelines. MAIN OUTCOMES AND MEASURES: Main outcomes were LRF, DM, and overall survival (OS). Multivariable analysis (MVA) was used to identify predictors of LRF and DM. Factors retained in the final MVA were used to construct a prediction score and classify patients into risk groups. RESULTS: Overall, 288 patients (mean [SD] age at diagnosis, 63.3 [12.3] years; 112 [39%] women and 176 [61%] men) with OSCC were analyzed. The MVA identified pT3-4, pathologic extranodal extension, and engraftment as predictors of LRF and DM. Patients whose tumors engrafted (n = 198) were more likely to develop LRF (hazard ratio [HR], 1.98; 95% CI, 1.24-3.18) and DM (HR, 2.64; 95% CI, 1.21-5.75) compared with nonengrafters. A prediction score based on the aforementioned variables identified patients at high risk and low risk for LRF (43.5% vs 26.5%), DM (38.2% vs 8.4%), and inferior OS (34% vs 66%) at 5 years. Additionally, rapid engraftment was shown to be similarly prognostic, with rapid engrafters demonstrating higher rates of relapse and poor OS. CONCLUSIONS: In this cohort study, a prediction score using OSCC PDX engraftment, in conjunction with pT3-4 and pathologic extranodal extension, was associated with improved prognostic utility of existing clinical models and predicted patients at risk for LRF, DM, and poor survival.

Purpose Patients undergoing head and neck surgery are often elderly and frail with significant comorbidities. Discussion and documentation of what patients would desire for end‐of‐life care and decision‐making is, therefore, essential for delivering patient‐centered care. Materials and Methods This was a retrospective, cross‐sectional study of patients undergoing surgery for head and neck cancer at two large, academic, tertiary care centers in Canada. Advance care planning was defined as any documentation of advance directives, resuscitation orders, or end‐of‐life care preferences. Results Among 301 patients, advance care planning was documented for 31 (10.3%). Patients with locally advanced disease (T3+) were twice as likely to have advance care planning documentation compared to those with early disease (RR 1.97, 95%CI [0.98, 3.97]). Conclusions In this multi‐institutional cross‐sectional study of two large academic centers, we have demonstrated that advance care planning and documentation is overall poor in patients undergoing surgery for oral cancer. These findings may have health policy implications, as advance care planning is associated with increased patient and provider satisfaction and improved alignment of patient goals and care delivered. Future work will investigate barriers and facilitators to advance care‐planning documentation in this setting.

Highlights • Definitive RT/CRT for OSCC achieved acceptable rate of locoregional control. • Definitive RT is a reasonable alternative treatment strategy if surgery is not possible. • cN2-3 is associated with poor distant control, DFS, and OS., Purpose To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT). Methods All OSCC patients treated radically with IMRT (without primary surgery) between 2005–2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed. Results Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p

The study objective was to measure the prevalence and predictors of cognitive impairment (CI) and delirium. Adults undergoing major head and neck cancer surgery completed the Clock Draw Test to screen for CI, defined as a score of 0 or 1. Postoperative delirium was recorded. Predictors of delirium and length of stay were assessed by univariate logistic regression and the latter with multivariate linear regression. Overall 274 patients were included, of which 47% had a Clock Draw Test score of 0 or 1. Post-operative delirium occurred in 17 (6%). CI was a predictor of postoperative delirium (odds ratio, 3.9; 95% CI, 1.2-12; P = .02). Postoperative delirium was a predictor of increased length of stay (adjusted odds ratio, 1.30; 95% CI, 1.07-1.57; P = .0073) on multivariate regression while baseline Clock Draw Test result was not a predictor on univariate regression (P = .98). Screening for CI can help predict delirium and facilitate targeted interventions in the postoperative period.

Background Being able to predict negative postoperative outcomes is important for helping select patients for treatment as well for informed decision‐making by patients. Frailty measures are often time and resource intensive to use as screening measures, whereas the Braden scale, a commonly used measure to assess patients at risk of developing pressure ulcers after surgery, may be a potential tool to predict postoperative complication rates and longer length of stay (LOS) in patients undergoing major head and neck cancer surgery. Methods A retrospective analysis of Braden scale scores was performed on a prospectively collected cohort of patients undergoing major head and neck surgery recruited between December 2011 and April 2014. The association of Braden scale score with the primary outcomes of complications and LOS was analyzed using logistic regression and linear regression models on univariate analysis (UVA), respectively. Multivariate analysis (MVA) was performed based on a backward stepwise selection algorithm. Results There were 232 patients with a mean (SD) Braden scale score of 14.9 (2.8) with a range from 9 to 23. The Braden scale (β = −.07 per point; 95% CI −0.09, −0.04, P, Being able to predict negative postoperative outcomes is important for helping select patients for treatment as well for informed decision‐making by patients. The Braden Scale, a commonly used measure to assess patients at risk of developing pressure ulcers after surgery, may be a potential tool to predict postoperative complication rates and longer length of stay in patients undergoing major head and neck cancer surgery. In the sample population the Braden scale did not demonstrate an ability to predict negative outcomes in head and neck surgery patients

Background: Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly being considered. There is limited understanding of why individuals with low-risk PTC may choose AS over traditional surgical management. Methods: We present a mixed-methods analysis of a prospective observational real-life decision-making study regarding the choice of thyroidectomy or AS for management of localized, low-risk PTCs

The most common pattern of failure in major salivary gland carcinoma (SGC) is development of distant metastases (DMs). The objective of this study was to develop and validate a prediction score for DM in SGC.Patients with SGC treated curatively at four tertiary cancer centers were divided into discovery (n = 619) and validation cohorts (n = 416). Multivariable analysis using competing risk regression was used to identify predictors of DM in the discovery cohort and create a prediction score of DM; the optimal score cut-off was determined using a minimal P value approach. The prediction score was subsequently evaluated in the validation cohort. The cumulative incidence and Kaplan-Meier methods were used to analyze DM and overall survival (OS), respectively.In the discovery cohort, DM predictors (risk coefficient) were: positive margin (0.6), pT3-4 (0.7), pN+ (0.7), lymphovascular invasion (0.8), and high-risk histology (1.2). High DM-risk SGC was defined by sum of coefficients greater than two. In the discovery cohort, the 5-year incidence of DM for high- versus low-risk SGC was 50% versus 8% (P0.01); this was similar in the validation cohort (44% versus 4%; P0.01). In the pooled cohorts, this model performed similarly in predicting distant-only failure (40% versus 6%, P0.01) and late (2 years post surgery) DM (22% versus 4%; P0.01). Patients with high-risk SGC had an increased incidence of DM in the subgroup receiving postoperative radiation therapy (46% versus 8%; P0.01). The 5-year OS for high- versus low-risk SGC was 48% versus 92% (P0.01).This validated prediction-score model may be used to identify SGC patients at increased risk for DM and select those who may benefit from prospective evaluation of treatment intensification and/or surveillance strategies.

BackgroundSitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.MethodsPatients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib–nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.ResultsTen patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib–nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.ConclusionsThe SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib–nivolumab and revealed patients with distinct tumor biology behavior.Trial registration numberNCT03575598.

BACKGROUND Out-of-pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment-related challenges, but to date OOPC have been understudied in this population. AIMS This study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario. METHODS HNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post-surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression. RESULTS A total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0-14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid-treatment time-point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p

The objective of this study was to evaluate the construct validity of 2 health utility instruments-the EuroQoL-5 Dimension (EQ-5D) and the Health Utilities Index-Mark 3 (HUI-3)-and to compare them with disease-specific measures in patients with head and neck cancer.Prospective cross-sectional analysis.Princess Margaret Cancer Centre.Patients were administered the EQ-5D, HUI-3, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its head and neck cancer module (EORTC QLQ-HN35), and the University of Washington Quality of Life Questionnaire (UWQoL). Several a priori expected relations were examined. The correlative and discriminative properties of the various instruments were examined.A total of 209 patients completed the 4 questionnaires. A significant ceiling effect was observed among EQ-5D responses (23% reported a maximum score of 1). The EQ-5D (rho = 0.79) and HUI-3 (rho = 0.60) had a strong correlation with the social-emotional domain of the UWQoL. The EQ-5D had a moderate correlation with the physical domain of the UWQoL (rho = 0.42), whereas the HUI-3 had a weak correlation (rho = 0.29). The EQ-5D and HUI-3 were able to distinguish among levels of health severity measured on the EORTC QLQ-C30 though not the QLQ-HN35. Comparatively, the UWQoL was able to distinguish levels of disease severity on the EORTC QLQ-C30 and QLQ-HN35.The results of this study demonstrate that disease-specific domains from head and neck quality-of-life instruments are not strongly correlated with the EQ-5D and HUI-3. Consideration should be put toward development of a disease-specific preference-based measure for health economic evaluation.4.

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 has upended surgical practice. In an effort to preserve resources, mitigate risk, and maintain health system capacity, nonurgent surgeries have been deferred in many jurisdictions, with urgent procedures facing increasing wait times and unpredictability given potential future surges. Shared decision making, a process that integrates patient values and preferences with the scientific expertise of clinicians, may be of particular benefit during these unprecedented times. Aligning patient choices with their values, reducing unnecessary health care use, and promoting consistency between providers are now more critical than ever before. We review important aspects of shared decision making and provide guidance for its perioperative application during the coronavirus disease 2019 pandemic.

Highlights • Tissue segmentation can be achieved using a spatially registered cytokeratin mask. • Automated and manual cell counts and stain intensities were highly correlated. • Smokers had significantly stronger PD-L1 stain intensity and higher numbers TILs. • After radiotherapy, greater CD8+ TILs was associated with inferior survival., Oral tongue squamous cell carcinoma (OTSCC) displays variable levels of immune cells within the tumor microenvironment. The quantity and localization of tumor infiltrating lymphocytes (TILs), specific functional TIL subsets (e.g., CD8+), and biomarker-expressing cells (e.g., PD-L1+) may have prognostic and predictive value. The purpose of this study was to evaluate the robustness and utility of computer-assisted image analysis tools to quantify and localize immunohistochemistry-based biomarkers within the tumor microenvironment on a tissue microarray (TMA). We stained a 91-patient OTSCC TMA with antibodies targeting CD3, CD4, CD8, FOXP3, IDO, and PD-L1. Cell populations were segmented into epithelial (tumor) or stromal compartments according to a mask derived from a pan-cytokeratin stain. Definiens Tissue Studio was used to enumerate marker-positive cells or to quantify the staining intensity. Automated methods were validated against manual tissue segmentation, cell count, and stain intensity quantification. Univariate associations of cell count and stain intensity with smoking status, stage, overall survival (OS), and disease-free survival (DFS) were determined. Our results revealed that the accuracy of automated tissue segmentation was dependent on the distance of the tissue section from the cytokeratin mask and the proportion of the tissue containing tumor vs. stroma. Automated and manual cell counts and stain intensities were highly correlated (Pearson coefficient range: 0.46–0.90; p

Objective A number of in vitro and clinical studies have suggested potential antineoplastic effects of metformin. The impact of this medication on outcomes in head and neck cancer is less clear. Our aim was to determine the effect of metformin on outcomes within our large cohort of head and neck cancer patients with Type II Diabetes (T2DM). Study design Retrospective cohort study. Setting Tertiary Cancer Centre. Subjects and methods A retrospective review of individuals with head and neck squamous carcinoma (HNSCC) and T2DM between January 2005 and December 2011 at Princess Margaret Cancer Centre was conducted. Medication history was obtained from surveys at initial presentation and electronic medical record review. Using Cox regression analyses, the association between metformin use and local, regional and distant failures was explored. Subgroup analyses were conducted for oral cavity, oropharynx and larynx. Results A total of 329 HNSCC patients with T2DM were identified, including 195 metformin users and 134 non-metformin users. Patients were well-matched in terms of clinical, pathologic, and treatment factors. No difference in local, regional, or distant failure was observed between diabetic metformin users and diabetic non-metformin users for the entire cohort or within subgroup analysis for subsite. No difference between the two groups was observed for overall survival, recurrence-free survival, and disease-specific survival at 5 years. Conclusion No association between metformin use and oncologic outcomes were observed in this large cohort of HNSCC patients. Multicenter, prospective studies may be needed to verify previous studies identifying a potential anti-neoplastic effect of this medication.

The prevalence of human papillomavirus (HPV) in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN), and prognosis by HPV status of SCCUPHN patients has been difficult to estimate because of the rarity of this subtype. In MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, EMBASE, Cochrane library and Web of Science searches, observational studies and clinical trials that reported survival rates of patients with SCCUPHN by HPV status were identified. Meta-analysis estimated the prevalence and prognosis (overall survival, OS; progression-free survival, PFS) of SCCUPHN by HPV status, and compared them to studies of oropharyngeal squamous cell carcinoma (OPSCC) from the same institutions and across continents. In 17 SCCUPHN studies (n = 1,149) and 17 institution-matched OPSCC studies (n = 6,522), the pooled HPV prevalence of SCCUPHN was 49%, which was only 10% (95%CI: 1-19%) lower than OPSCC prevalence in the underlying population. Estimated 5-year OS for HPV-negative SCCUPHN was 44% (95%CI: 36-51%) vs. HPV-positive SCCUPHN of 91% (95%CI: 86-96%); hazard ratio (HR) for OS was 3.25 (95%CI: 2.45-4.31) and PFS was 4.49 (95%CI: 2.88-7.02). HRs by HPV status for OPSCC were similar to that in SCCUPHN. While North American SCCUPHNs had higher HPV prevalence than European SCCUPHNs (OR = 2.68 (95%CI: 1.3-5.6)), HR of OS for HPV-negative vs. HPV-positive patients were similar in both continents (HRs of 3.78-4.09). Prevalence of HPV among SCCUPHN patients were lower than in OPSCC. The survival benefit conferred by being HPV-positive was similar in SCCUPHN as in OPSCCs, independent of continent.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).

Abstract Active surveillance (AS) in the management of small, low risk papillary thyroid cancer (PTC) as an alternative option to thyroidectomy, is an area of active research. A national Canadian study is proposed to evaluate the long-term outcomes of patients with small, low risk PTC who choose AS or surgery. This letter describes the proceedings of a national investigator meeting to plan the study. Graphical abstract

Made available in DSpace on 2020-12-12T01:55:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-01 Canada Foundation for Innovation Ontario Institute for Cancer Research Canada Research Chairs Prognostic biomarkers for recurrence of Oral Squamous Cell Carcinoma (OSCC) are urgently needed. We aimed to independently validate a 4-gene expression signature (MMP1, COL4A1, P4HA2, THBS2) predictive of OSCC recurrence risk. Gene expression was measured using Nanostring nCounter® in 245 histologically normal surgical resection margins from 62 patients. Association between risk scores for individual patients and recurrence was assessed by Kaplan-Meier analysis. Signature performance was quantified by concordance index (CI), hazard ratio (HR) and the area under receiver operating characteristics (AUC). Risk scores for recurrence were significantly higher than recurrence-free patients (p = 9.58e-7, Welch’s t-test). A solid performance of the 4-gene signature was determined: CI = 0.64, HR = 3.38 (p = 1.4E-4; log-rank test), AUC = 0.71. We showed that three margins per patient are sufficient to preserve predictive performance (CI = 0.65; HR = 2.92; p = 2.94e-3; AUC = 0.71). Association between the predicted risk scores and recurrence was assessed and showed HR = 2.44 (p = 9.6E-3; log-rank test, N = 62). Signature performance analysis was repeated using an optimized threshold (70th percentile of risks), resulting in HR = 3.38 (p = 1.4E-4; log-rank test, N = 62). The 4-gene signature was validated as predictive of recurrence risk in an independent cohort of patients with resected OSCC and histologically negative margins, and is potentially applicable for clinical decision making on adjuvant treatment and disease monitoring. São Paulo State University UNESP Faculty of Medicine Department of Surgery and Orthopedics Krembil Research Institute University Health Network Department of Clinical Pathology Sunnybrook Health Sciences Centre Princess Margaret Cancer Centre University Health Network Brazilian Institute for Cancer Control Department of Pathology Toronto General Hospital University Health Network Departments of Medical Biophysics University of Toronto Department of Computer Science University of Toronto Institute of Neuroimmunology Slovak Academy of Sciences Clinical Laboratory Genetics Genome Diagnostics University Health Network Department of Laboratory Medicine and Pathobiology The University of Toronto São Paulo State University UNESP Faculty of Medicine Department of Surgery and Orthopedics

IntroductionAdvanced oral cancer and its ensuing treatment engenders significant morbidity and mortality. Patients are often elderly with significant comorbidities. Toxicities associated with surgical resection can be devastating and they are often highlighted by patients as impactful. Given the potential for suboptimal oncological and functional outcomes in this vulnerable patient population, promotion and performance of shared decision making (SDM) is crucial.Decision aids (DAs) are useful instruments for facilitating the SDM process by presenting patients with up-to-date evidence regarding risks, benefits and the possible postoperative course. Importantly, DAs also help elicit and clarify patient values and preferences. The use of DAs in cancer treatment has been shown to reduce decisional conflict and increase SDM. No DAs for oral cavity cancer have yet been developed.This study endeavours to answer the question: Is there a patient or surgeon driven need for development and implementation of a DA for adult patients considering major surgery for oral cancer?Methods and analysisThis study is the first step in a multiphase investigation of SDM during major head and neck surgery. It is a multi-institutional convergent parallel mixed-methods needs assessment study. Patients and surgeon dyads will be recruited to complete questionnaires related to their perception of the SDM process (nine-item Shared Decision-Making Questionnaire, SDM-Q-9 and SDM-Q-Doc) and to take part in semistructured interviews. Patients will also complete questionnaires examining decisional self-efficacy (Ottawa Decision Self-Efficacy Scale) and decisional conflict (Decisional Conflict Scale). Questionnaires will be completed at time of recruitment and will be used to assess the current level of SDM, self-efficacy and conflict in this setting. Thematic analysis will be used to analyse transcripts of interviews. Quantitative and qualitative components of the study will be integrated through triangulation, with matrix developed to promote visualisation of the data.Ethics and DisseminationThis study has been approved by the research ethics boards of the Nova Scotia Health Authority (Halifax, Nova Scotia) and the University Health Network (Toronto, Ontario). Dissemination to clinicians will be through traditional approaches and creation of a head and neck cancer SDM website. Dissemination to patients will include a section within the website, patient advocacy groups and postings within clinical environments.

Objective The aim of this study is to determine if Hyams grade may help predict which patients with esthesioneuroblastoma (ENB) tumors are likely to develop regional recurrences, and to determine the impact of tumor extent on regional failure in ENB patients without evidence of nodal disease at presentation. Design The study was designed as a retrospective review for ENB patients. Settings The study was prepared at tertiary care academic center for ENB patients. Participants Patients with ENB were included in the study. Main Outcome Measures Oncologic outcomes (5-year regional and locoregional control (LRC) and overall survival) in patients with Hyams low grade versus high grade. Oncologic outcomes based on radiographic disease extent. Results A total of 43 patients were included. Total 25 patients (58%) had Hyams low-grade tumor, and 18 (42%) had high-grade tumor. Of the 34 patients without regional disease at presentation, 8 (24%) were treated with elective nodal radiation. There were no statistically significant differences in 5-year regional control in the Hyams low-grade versus high-grade groups (78 vs. 89%; p = 0.4). The 5-year LRC rates in patients with low grade versus high grade were 73 versus 89% (p = 0.6). The 5-year overall survival rates in patients with low-grade versus high-grade tumors were 86 versus 63% (p = 0.1). Radiographic extension of disease into the olfactory groove, olfactory nerve, dura, and periorbita were statistically associated with decreased 5-year overall survival (5-year OS 49 vs. 91% [p = 0.04], 49 vs. 91% [p = 0.04], 44 vs. 92% [p = 0.02], and 44 vs. 80% [p = 0.04], respectively). Conclusion ENBs are associated with a risk of regional failure. The current analysis suggests that Hyams low-grade and high-grade malignancies have comparable rates of early and delayed regional recurrences, although small sample size may limit our conclusions.

Background In the wake of the coronavirus disease 2019 (COVID‐19) pandemic, access to surgical care for patients with head and neck cancer (HNC) is limited and unpredictable. Determining which patients should be prioritized is inherently subjective and difficult to assess. The authors have proposed an algorithm to fairly and consistently triage patients and mitigate the risk of adverse outcomes. Methods Two separate expert panels, a consensus panel (11 participants) and a validation panel (15 participants), were constructed among international HNC surgeons. Using a modified Delphi process and RAND Corporation/University of California at Los Angeles methodology with 4 consensus rounds and 2 meetings, groupings of high‐priority, intermediate‐priority, and low‐priority indications for surgery were established and subdivided. A point‐based scoring algorithm was developed, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN‐HN). Agreement was measured during consensus and for algorithm scoring using the Krippendorff alpha. Rankings from the algorithm were compared with expert rankings of 12 case vignettes using the Spearman rank correlation coefficient. Results A total of 62 indications for surgical priority were rated. Weights for each indication ranged from −4 to +4 (scale range; −17 to 20). The response rate for the validation exercise was 100%. The SPARTAN‐HN demonstrated excellent agreement and correlation with expert rankings (Krippendorff alpha, .91 [95% CI, 0.88‐0.93]; and rho, 0.81 [95% CI, 0.45‐0.95]). Conclusions The SPARTAN‐HN surgical prioritization algorithm consistently stratifies patients requiring HNC surgical care in the COVID‐19 era. Formal evaluation and implementation are required. Lay Summary Many countries have enacted strict rules regarding the use of hospital resources during the coronavirus disease 2019 (COVID‐19) pandemic. Facing delays in surgery, patients may experience worse functional outcomes, stage migration, and eventual inoperability.Treatment prioritization tools have shown benefit in helping to triage patients equitably with minimal provider cognitive burden.The current study sought to develop what to the authors' knowledge is the first cancer–specific surgical prioritization tool for use in the COVID‐19 era, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN‐HN). This algorithm consistently stratifies patients requiring head and neck cancer surgery in the COVID‐19 era and provides evidence for the initial uptake of the SPARTAN‐HN., To the authors' knowledge, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN‐HN) is the first cancer surgery–specific prioritization tool for use during the coronavirus disease 2019 (COVID‐19) pandemic. The SPARTAN‐HN algorithm is reliable and valid for the stratification of patients with head and neck cancer who require urgent cancer care in resource‐restricted practice environments.

Importance Active surveillance is sometimes considered as a disease management option for individuals with small, low-risk papillary thyroid carcinoma. Objective To assess whether patient age is associated with progression of low-risk papillary thyroid carcinoma (tumor growth or incident metastatic disease) in adults under active surveillance. Evidence Review Eight electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Emcare, PsycINFO, Web of Science, and ClincalTrials.gov) were searched from inception to March 2019, supplemented with a hand search. Two investigators independently screened citations, reviewed full-text articles, and abstracted data. Additional data were sought from authors. Random-effects meta-analyses were performed using incidence data (statistically adjusted for confounders and crude rates). Findings A total of 1658 unique citations were screened, and 62 full-text articles were reviewed, including 5 studies. Three studies included exclusively microcarcinomas and 2 included tumors up to 2 cm in maximal diameter. The mean age of participants was 51.0 to 55.2 years in 4 studies reporting this value. The mean or median follow-up was 5 years or more in 3 studies and approximately 2 years in 2 studies. The pooled risk ratio for tumor growth of 3 mm or more in maximal diameter in individuals aged 40 to 50 years or older compared with younger individuals was 0.51 when adjusted for confounders (95% CI, 0.29-0.89; 1619 patients, 2 studies), and the unadjusted risk ratio of this outcome for individuals 40 years or older was 0.55 (95% CI, 0.36-0.82; 2097 patients, 4 studies). In adults aged 40 to 45 years or older, the unadjusted risk ratio for any tumor volume increase compared with younger individuals was 0.65 (95% CI, 0.51-0.83; 1232 patients, 4 studies). The pooled risk ratio for incident nodal metastases in individuals 40 years or older was 0.22 (95% CI, 0.10-0.47; 1806 patients, 3 studies); however, in a secondary analysis, the risk difference was not significantly different. There was no statistically significant heterogeneity in any of the meta-analyses. There were no thyroid cancer–related deaths nor incident distant metastases. Conclusions and Relevance This study suggests that older age may be associated with a reduced risk of primary papillary thyroid carcinoma tumor growth under active surveillance. Incident metastatic disease is uncommon during active surveillance.

HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles. We were able to determine the specificity, on average, of 12.2% of the TILs recognizing a mean of 3.1 shared antigen-derived epitopes across HLA-A, B, and C. Furthermore, we isolated a number of cognate T cell receptor genes with tumor reactivity. Our novel strategy allows for a more complete examination of the immune response and development of novel cancer immunotherapy not limited by HLA allele prevalence or tumor mutation burden., eLife digest The immune system is the body’s way of defending itself, offering protection against diseases such as cancer. But to remove the cancer cells, the immune system must be able to identify them as different from the rest of the body. All cells break down proteins into shorter fragments, known as peptides, that are displayed on the cell surface by a protein called human leukocyte antigen, HLA for short. Cancer cells display distinctive peptides on their surface as they generate different proteins to those of healthy cells. Immune cells called T cells use these abnormal peptides to identify the cancer so that it can be destroyed. Sometimes T cells can lack the right equipment to detect abnormal peptides, allowing cancer cells to hide from the immune system. However, T cells can be trained through a treatment called immunotherapy, which provides T cells with new tools so that they can spot the peptides displayed by HLA on the previously ‘hidden’ cancer cells. There are many different forms of HLA, each of which can display different peptides. Current research in immunotherapy commonly targets only a subset of HLA forms, and not all cancer patients have these types. This means that immunotherapy research is only likely to be of most benefit to a limited number of patients. Immunotherapy could be made effective for more people if new cancer peptides that are displayed by the other ‘under-represented’ forms of HLA were identified. Murata, Nakatsugawa et al. have now used T cells that were taken from tumors in eight patients with melanoma, which is a type of skin cancer. A library of fluorescent HLA-peptides was generated – using a new, simplified methodology – with 25 forms of HLA that displayed over 800 peptides. T cells were then mixed with the library to identify which HLA-peptides they can target. As a result, Murata, Nakatsugawa et al. found the cancer targets of around 12% of the tumor-infiltrating T cells tested, including those from under-represented forms of HLA. Consequently, these findings could be used to develop new immunotherapies that can treat more patients.

PurposeThis study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking.MethodsA case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed.ResultsMost individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13-1.28) and HNC (1.12, 95%CI = 1.04-1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65-5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67-1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures.ConclusionNicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures.