Adrian Mendez

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The genomic and evolutionary landscapes of anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs wit... more Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas and multi-region whole-genome sequencing. Anaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Specific cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. We unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas, and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

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A Sinonasal NUT Midline Carcinoma in an 84-year-old Man Undergoing Radiation and Proton Therapy

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

eBioMedicine

Surgical margins of the oral cavity: is 5 mm really necessary?

Journal of Otolaryngology - Head & Neck Surgery

Background Squamous cell carcinoma is the most common malignancy of the oral cavity. Primary trea... more Background Squamous cell carcinoma is the most common malignancy of the oral cavity. Primary treatment involves surgical resection of the tumour with a surrounding margin. Historically, the most commonly accepted margin clearance is 5 mm. This distance is controversial, with recent publications suggesting closer margins do not impact local recurrence and survival. The objective of this study is to determine the closest surgical margin that does not impact local recurrence and overall survival. Methods A retrospective review of the London Health Sciences Centre Head and Neck Multidisciplinary Clinic between 2010 and 2018 was performed. Demographic data, subsite, tumour staging, treatment modality, margins, and survival outcomes were analyzed. The primary endpoint was local recurrence free survival. Secondary endpoints included recurrence-free survival and overall survival. Descriptive statistics, as well as univariable and multivariable Cox proportional hazards regression modelling w...

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Demographic and pathologic factor regression to a growth rate model of p16 ‐negative oral cavity squamous cell carcinoma

Laryngoscope Investigative Otolaryngology

Objectives: The current study aims to quantify the growth rate of p16-negative oral cavity squamo... more Objectives: The current study aims to quantify the growth rate of p16-negative oral cavity squamous cell carcinoma, characterize causative relationships between demographic risk factors and tumor growth, and examine pathologic findings associated with the tumor growth rate at a tertiary care institution. It is hypothesized that causative relationships will be drawn between the individual sociodemographic and pathologic factors and oral cavity p16-negative squamous cell carcinoma growth rate. Methods: Prospectively recruited participants, receiving surgical intervention only, were followed from initial staging CT scan to surgical resection. Interval growth was calculated in cm 3 /week. Demographic information including age, sex, smoking history, alcohol consumption history, previous all-type malignancy, previous chemotherapy treatment, previous head or neck radiation exposure, and time interval elapsed between diagnosis and surgery was collected from each participant, and regression analysis was applied to determine causality. Results: Summary statistics revealed a mean growth rate for the study sample of 1.385cm 3 /week. Statistically significant regression correlations were detected between tumor growth and alcohol consumption, origination at the retromolar trigone, and clinical nodal stage. Conclusions: Through a small prospective cohort sample, the current study suggests clinical associations between alcohol consumption, origination at the retromolar trigone, and clinical nodal stage with rate of tumor growth. Future work will validate these relationships in a larger patient cohort, and against stronger modeling techniques.

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Risk Factors for Poor Survival Outcomes in Parotid Metastatic Cutaneous Squamous Cell Carcinoma

The Laryngoscope

Tumor molecular differences associated with outcome disparities of Black patients with head and neck cancer

Head & Neck

Numerous studies of head and neck squamous cell carcinoma (HNSCC) have demonstrated disparate out... more

Introduction and expression of PIK3CAE545K in a papillary thyroid cancer BRAFV600E cell line leads to a dedifferentiated aggressive phenotype

Journal of Otolaryngology - Head & Neck Surgery, 2022

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, wh... more Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of...

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A Clinically Translatable Immune-based Classification of HPV-associated Head and Neck Cancer with Implications for Biomarker-Driven Treatment Deintensification and Immunotherapy

PurposeHuman papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is th... more PurposeHuman papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the fastest rising cancer in North America. There is significant interest in treatment de-escalation for these patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to predict the survival of patients with newly diagnosed HPV+ HNSCC.MethodsWe created a prognostic score (UWO3) that was successfully validated in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Transcriptomic data from two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes.ResultsA three-gene immune score classified patients into three immune ...

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Transoral robotic surgery for the identification of unknown primary head and neck squamous cell carcinomas: Its effect on the wait and the weight

Head & Neck, 2022

Neck carcinoma of unknown primary (CUP) is a frequent scenario. Transoral robotic mucosectomies (... more

The Impact of Surgical Resectability on Outcomes for Patients Undergoing Primary Radiation Treatment for Human Papillomavirus-Related Oropharyngeal Cancer

International Journal of Radiation Oncology*Biology*Physics, 2022

INTRODUCTION Primary radiotherapy ± chemotherapy (RT/CRT) is the most common treatment for oropha... more INTRODUCTION Primary radiotherapy ± chemotherapy (RT/CRT) is the most common treatment for oropharyngeal squamous cell carcinomas (OPSCC), but there has been an increase in transoral surgery (TOS) for T1-2 tumors. Since only a subset of T1-2 tumors are TOS-favorable, non-randomized comparisons between RT/CRT and TOS could be confounded by indication. We aimed to compare outcomes of potential TOS-candidates vs. non-TOS candidates, among patients who underwent RT/CRT for early T-stage OPSCC. METHODS For patients treated with RT/CRT for early-stage human papilloma virus (HPV) positive OPSCC between 2014 and 2018, pretreatment imaging was reviewed by three head-and-neck surgeons, blinded to outcomes, to assess primary-site appropriateness for TOS, and extracapsular extension (ECE) was scored by a head-and-neck neuroradiologist. We compared outcomes based on surgical favorability pertaining to: 1) the primary site tumor alone, and 2) the primary site and an absence of ECE. Kaplan-Meier estimates for overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared using the log-rank test, with Cox regression used for multivariable modelling. RESULTS One hundred and forty-three patients were evaluated, of which 121 were male (84.6%), the median age was 59.4 years, and all of them were p16 positive (100%). The primary site was TOS-favorable in 115/143 (80.4%). Patients with TOS-favorable primary site experienced superior 5-year OS (89.8% vs. 71.2% p=0.017), DSS (90.4% vs. 63.4% p=0.022), and RFS (83% vs. 49.4% p=0.04) compared with TOS-unfavorable patients. Similarly, patients with a TOS-favorable primary site and no ECE on imaging 101/143 (70.6%), had improved OS, DSS, and RFS (p<0.05) compared with TOS-unfavorable patients. CONCLUSION In this first study to assess surgical favorability as a prognostic factor among patients with T1/2 p16+ OPSCC, patients with TOS-favorable early-stage OPSCC have better outcomes than TOS-unfavorable patients. This provides valuable prognostic information for patients, and also suggests the risk of confounding by indication in non-randomized comparisons of treatment modalities.

Additional file 2 of Modern treatment outcomes for early T-stage oropharyngeal cancer treated with intensity-modulated radiation therapy at a tertiary care institution

Additional file 2. Univariable and multivariable analysis of disease-free survival in all patient... more Additional file 2. Univariable and multivariable analysis of disease-free survival in all patients with early stage disease seen in the London Health Sciences Centre from 2014 to 2018 by clinical characteristics. Samples missing clinical information were excluded (32 patients were excluded, 166 remaining samples in the analysis). Backwards step-wise method was utilized to arrive at the final multivariate model that was based on patient age, sex, and alcohol abuse. P-values

Additional file 3 of Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial

Additional file 3. Study information and consent form.

Additional file 2 of Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial

Additional file 2. Follow-up evaluation schedule.

Additional file 4 of Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial

Additional file 4. WHO trial registration data set.

Additional file 1 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Additional file 1. Treatment Planning Guidelines.

Additional file 2 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Additional file 2. Surgical Credentialling Form.

Additional file 5 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Additional file 5. Study Information and Informed Consent Form.

Additional file 4 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Additional file 4. Lab Guidelines.

Additional file 6 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Additional file 6. World Health Organization Trial Registration Dataset.

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