Impact of human papillomavirus on the tumor microenvironment in oropharyngeal squamous cell carcinoma.

Increasing evidence has elucidated the clinicopathological significance of tumor microenvironment (TME) cells. However, TME differences associated with human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) have not been well characterized. In our study, we comprehensively determined the TME infiltration patterns in 315 OPSCC patients, and systematically correlated the TME phenotypes with genomic characteristics and clinical features of OPSCCs. In this way, we observed the enrichment of high endothelial cells and adaptive immune cells in HPV-positive (HPV+) OPSCCs, in contrast to the enrichment of fibroblasts and capillary endothelial cells in HPV- negative (HPV-) OPSCCs. By focusing on immune checkpoint genes, we constructed a coexpression network using genes that were differentially expressed between HPV+ and HPV- OPSCCs. Functional analysis of the network indicated that HPV+ OPSCCs had elevated immune activities by promoting adaptive immune response and suppressing activities related to extracellular matrix organization. Subsequently, clinical analysis showed that identified TME-relevant genes were closely associated with the prognosis and therapy response in OPSCC. Importantly, results from the TME analysis were further validated using an independent OPSCC cohort.

Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. METHODS: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR , is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. RESULTS: MuNI was statistically significantly different between Black (mean, 3.88e-4; median, 3.67e-04) and White patients (mean, 3.36e-04; median, 2.99e-04), with p = .0078. Using TTR , MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21-2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18-2.51). Population-specific cutoff, TW , yielded improved HR of 1.77 (p = .003; 95% CI, 1.21-2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2-1.80). CONCLUSIONS: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.

Reduced Wide Local Excision Margins are Associated with Increased Risk of Relapse and Death from Merkel Cell Carcinoma.

INTRODUCTION: Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established. METHODS: WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS). RESULTS: Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). At 3 years, the DSS was 57.7%, 82.6%, and 100% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). Multivariable Cox analysis demonstrated that every 1-cm increase in WLE margins was associated with improved RRFS [hazard ratio (HR) = 0.28, 95% confidence interval (CI): 0.11-0.75], DRFS (HR 0.30, CI 0.08-0.99), DFS (HR 0.42, CI 0.21-0.86), and DSS (HR 0.16, CI 0.04-0.61). WLE and pathologic margin size were moderately-to-strongly correlated (r = 0.66). Close or positive pathologic margins (< 3 mm) were associated with reduced DRFS (HR 6.83, CI 1.80-25.9), DFS (HR 2.98, CI 1.31-6.75), and DSS (HR 3.52, CI 1.14-10.9). CONCLUSION: Reduced WLE and pathologic margins were associated with higher risk of relapse and death from MCC. Larger WLE margins are important in populations with lower rates of adjuvant radiation.

Management of primary skin cancer during a pandemic: Multidisciplinary recommendations.

During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making regarding the pros and cons of early versus delayed interventions for localized skin cancer. Patients at highest risk of COVID-19 complications are older; are immunosuppressed; and have diabetes, cancer, or cardiopulmonary disease, with multiple comorbidities associated with worse outcomes. Physicians must weigh the patient's risk of COVID-19 complications in the event of exposure against the risk of worse oncologic outcomes from delaying cancer therapy. Herein, the authors have summarized current data regarding the risk of COVID-19 complications and mortality based on age and comorbidities and have reviewed the literature assessing how treatment delays affect oncologic outcomes. They also have provided multidisciplinary recommendations regarding the timing of local therapy for early-stage skin cancers during this pandemic with input from experts at 11 different institutions. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, but a short delay can be considered for patients with favorable T1 disease who are at higher risk of COVID-19 complications. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For patients with cutaneous squamous cell carcinoma, those with Brigham and Women's Hospital T1 to T2a disease can have their treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1-month to 2-month delay is unlikely to worsen disease-specific mortality. For patients with squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless the individual is highly symptomatic.

Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials.

BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. CONCLUSIONS: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.

Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil.

BACKGROUND: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.

Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234).

BACKGROUND: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival. METHODS: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group. RESULTS: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status. CONCLUSIONS: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464-71. © 2016 American Cancer Society.

Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

A comparative study based on image quality and clinical task performance for CT reconstruction algorithms in radiotherapy.

CT image reconstruction is typically evaluated based on the ability to reduce the radiation dose to as-low-as-reasonably-achievable (ALARA) while maintaining acceptable image quality. However, the determination of common image quality metrics, such as noise, contrast, and contrast-to-noise ratio, is often insufficient for describing clinical radiotherapy task performance. In this study we designed and implemented a new comparative analysis method associating image quality, radiation dose, and patient size with radiotherapy task performance, with the purpose of guiding the clinical radiotherapy usage of CT reconstruction algorithms. The iDose4 iterative reconstruction algorithm was selected as the target for comparison, wherein filtered back-projection (FBP) reconstruction was regarded as the baseline. Both phantom and patient images were analyzed. A layer-adjustable anthropomorphic pelvis phantom capable of mimicking 38-58 cm lateral diameter-sized patients was imaged and reconstructed by the FBP and iDose4 algorithms with varying noise-reduction-levels, respectively. The resulting image sets were quantitatively assessed by two image quality indices, noise and contrast-to-noise ratio, and two clinical task-based indices, target CT Hounsfield number (for electron density determination) and structure contouring accuracy (for dose-volume calculations). Additionally, CT images of 34 patients reconstructed with iDose4 with six noise reduction levels were qualitatively evaluated by two radiation oncologists using a five-point scoring mechanism. For the phantom experiments, iDose4 achieved noise reduction up to 66.1% and CNR improvement up to 53.2%, compared to FBP without considering the changes of spatial resolution among images and the clinical acceptance of reconstructed images. Such improvements consistently appeared across different iDose4 noise reduction levels, exhibiting limited interlevel noise (< 5 HU) and target CT number variations (< 1 HU). The radiation dose required to achieve similar contouring accuracy decreased when using iDose4 in place of FBP, up to 32%. Contouring accuracy improvement for iDose4 images, when compared to FBP, was greater in larger patients than smaller-sized patients. Overall, the iDose4 algorithm provided superior radiation dose control while maintaining or improving task performance, when compared to FBP. The reader study on image quality improvement of patient cases shows that physicians preferred iDose4-reconstructed images on all cases compared to those from FBP algorithm with overall quality score: 1.21 vs. 3.15, p = 0.0022. However, qualitative evaluation strongly indicated that the radiation oncologists chose iDose4 noise reduction levels of 3-4 with additional consideration of task performance, instead of image quality metrics alone. Although higher iDose4 noise reduction levels improved the CNR through the further reduction of noise, there was pixelization of anatomical/tumor structures. Very-low-dose scans yielded severe photon starvation artifacts, which decreased target visualization on both FBP and iDose4 reconstructions, especially for the 58 cm phantom size. The iDose4 algorithm with a moderate noise reduction level is hence suggested for CT simulation and treatment planning. Quantitative task-based image quality metrics should be further investigated to accommodate additional clinical applications.

Eliminating radiotherapy to the contralateral retropharyngeal and high level II lymph nodes in head and neck squamous cell carcinoma is safe and improves quality of life.

BACKGROUND: Radiation treatment volumes in head and neck squamous cell carcinoma (HNSCC) are controversial. The authors report the outcomes, patterns of failure, and quality of life (QOL) of patients who received treatment for HNSCC using intensity-modulated radiation therapy (IMRT) that eliminated the treatment of contralateral retropharyngeal lymph nodes (RPLNs) in the clinically uninvolved neck. METHODS: A prospective institutional database was used to identify patients who had primary oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and unknown primary HNSCC for which they received IMRT. There were 3 temporal groups (generations 1-3). Generation 1 received comprehensive neck IMRT with parotid sparing, generation 2 eliminated the contralateral high level II (HLII) lymph nodes, and generation 3 further eliminated the contralateral RPLNs in the clinically uninvolved neck. Patterns of failure and survival analyses were completed, and QOL data measured using the MD Anderson Dysphagia Inventory were compared in a subset of patients from generations 1 and 3. RESULTS: In total, 748 patients were identified. Of the 488 patients who received treatment in generation 2 or 3, 406 had a clinically uninvolved contralateral neck. There were no failures in the spared RPLNs (95% confidence interval, 0%-1.3%) or in the high contralateral neck (95% confidence interval, 0%-0.7%). QOL data were compared between 44 patients in generation 1 and 51 patients in generation 3. QOL improved both globally and in all domains assessed for generation 3, in which reduced radiotherapy volumes were used (P < .007). CONCLUSIONS: For patients with locally advanced HNSCC, eliminating coverage to the contralateral HLII lymph nodes and contralateral RPLNs in the clinically uninvolved side of the neck is associated with minimal risk of failure in these regions and significantly improved patient-reported QOL.

Merkel cell carcinoma, version 1.2014.

Merkel cell carcinoma is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer with the regional and distant metastatic rates of thick melanoma. The NCCN Guidelines for Merkel Cell Carcinoma provide recommendations on the diagnosis and management of this aggressive disease based on clinical evidence and expert consensus. This version includes revisions regarding the use of PET/CT imaging and the addition of a new section on the principles of pathology to provide guidance on the analysis, interpretation, and reporting of pathology results.

Dermatofibrosarcoma protuberans, version 1.2014.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor characterized by a relatively high risk of local recurrence and low risk of metastasis. The NCCN Guidelines for DFSP provide multidisciplinary recommendations on the management of patients with this rare disease. These NCCN Guidelines Insights highlight the addition of the Principles of Pathology section, which provides recommendations on the pathologic assessment of DFSP. Because DFSP can mimic other lesions, immunohistochemical studies are often required to establish diagnosis. Cytogenetic testing for the characteristic translocation t(17;22)(q22;q13) can also be valuable in the differential diagnosis of DFSP with other histologically similar tumors.

Poor Dental Health as a Risk Factor for Alveolar Ridge Malignancies.

OBJECTIVE: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites. STUDY DESIGN: Case-control and cross-sectional METHODS: A case-control study was performed using a population-based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross-sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0-6, 7-24, 25-28) as a surrogate for poor dental health, which was self-reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models. RESULTS: Near complete tooth loss (25-28 teeth) was associated with a 3.5-fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14-11.01, P = .03) in the CHANCE study. This association was confirmed in our cross-sectional analysis (WashU/Siteman study) where missing 25-28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97-11.10, P = .001). CONCLUSIONS: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies.

Trends in ototoxicity monitoring among cisplatin-treated patients with cancer.

PURPOSE: This study aims to characterize patterns in ototoxicity monitoring and identify potential barriers to audiologic follow-up. METHODS: We performed a single-institution retrospective cohort study on adult (≥ 18 years old) cancer patients treated with cisplatin from January 2014 to September 2021. Our primary outcomes were rates of baseline and post-treatment audiograms at the following time points: 3, 6, 12, and greater than 12 months. Time-to-event analyses were performed to describe additional insights to ototoxicity monitoring patterns. RESULTS: Nine hundred fifty-five patients with cancer were included for analysis. The most common primary cancer sites were head and neck (64%), followed by cervical (24%). Three hundred seventy-three patients (39%) underwent baseline audiometric assessment, 38 patients (4%) received audiologic evaluation during chemotherapy, and 346 patients (36%) obtained at least one post-treatment audiogram. Audiologic follow-up was greatest within 3 months of completing chemotherapy (26%), but this tapered dramatically to less than 10% at every other post-treatment time point. Patients with head and neck cancer achieved higher rates of audiologic follow-up at every time point than patients with non-head and neck cancer except for during treatment. CONCLUSIONS: Ototoxicity monitoring is an inconsistent practice, particularly during chemotherapy and for long-term surveillance of hearing loss. Patients with non-head and neck cancer may be at increased risk for loss of audiologic follow-up. IMPLICATIONS FOR CANCER SURVIVORS: Cisplatin ototoxicity is a common occurrence that can be effectively managed with auditory rehabilitation. Therefore, referrals to audiology and counseling on treatment-related ototoxicity are recommended throughout chemotherapy and cancer survivorship.

A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis.

Oropharyngeal squamous cell carcinoma (SCC) is strongly associated with human papillomavirus (HPV) infection, which is distinctively different from most other head and neck cancers. However, a robust quantitative reverse transcription PCR (RT-qPCR) method for comprehensive expression profiling of HPV genes in routinely fixed tissues has not been reported. To address this issue, we have established a new real-time RT-PCR method for the expression profiling of the E6 and E7 oncogenes from 13 high-risk HPV types. This method was validated in cervical cancer and by comparison with another HPV RNA detection method (in situ hybridization) in oropharyngeal tumors. In addition, the expression profiles of selected HPV-related human genes were also analyzed. HPV E6 and E7 expression profiles were then analyzed in 150 archived oropharyngeal SCC samples and compared with other variables and with patient outcomes. Our study showed that RT-qPCR and RNA in situ hybridization were 100% concordant in determining HPV status. HPV transcriptional activity was found in most oropharyngeal SCC (81.3%), a prevalence that is higher than in previous studies. Besides HPV16, three other HPV types were also detected, including 33, 35 and 18. Furthermore, HPV and p16 had essentially identical expression signatures, and both HPV and p16 were prognostic biomarkers for the prediction of disease outcome. Thus, p16 mRNA or protein expression signature is a sensitive and specific surrogate marker for HPV transcriptional activity (all genotypes combined).

A microRNA expression signature for the prognosis of oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (SCC) rates have been increasing significantly in recent years, despite a decreasing incidence of head and neck cancer in general. Oropharyngeal SCC has many characteristics that are distinct from other head and neck cancers, and thus it is important to focus specifically on cancers arising in this region, with the goal of improving patient outcomes. One important goal is to identify those patients who are likely to fail standard therapy and who could potentially benefit from alternative or targeted treatments. METHODS: In the current study, the prognostic value of microRNAs (miRNAs) was evaluated in patients with oropharyngeal SCC. miRNAs are small, noncoding RNAs that are master regulators of many important biological processes. In total, 150 oropharyngeal tumors were analyzed using the recently developed quantitative polymerase chain reaction-based method for miRNA expression profiling. In addition, the expression of miRNAs was also compared with human papillomavirus (HPV) transcriptional activities. RESULTS: The current study identified 6 miRNAs that were found to be significantly associated with cancer survival. A combined expression signature of these miRNAs was prognostic of oropharyngeal SCC, independent of common clinical features or HPV status. CONCLUSIONS: This new miRNA signature was experimentally validated in an independent oropharyngeal SCC cohort. Furthermore, 5 HPV-related miRNAs were identified, which may help to characterize HPV-induced cancers including both oropharyngeal and cervical SCC.

Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx.

Although a strong etiologic relationship between human papillomavirus (HPV) and a majority of oropharyngeal squamous cell carcinomas has been established, the role of HPV in non-oropharyngeal head and neck carcinomas is much less clear. Here, we investigated the prevalence and clinicopathologic significance of HPV and its reported biomarkers, CDKN2A(p16) and CDKN1A(p21), in laryngeal squamous cell carcinomas in patients treated either with primary surgery and postoperative radiation or with definitive radiation-based therapy. Nearly all of 76 tumors were keratinizing and none displayed the nonkeratinizing morphology that is typically associated with HPV infection in the oropharynx. However, CDKN2A(p16) immunohistochemistry was positive in 21 cases (28%) and CDKN1A(p21) in 34 (45%). CDKN2A(p16) and CDKN1A(p21) status strongly correlated with each other (P=0.0038). Yet, only four cases were HPV positive by DNA in situ hybridization or by reverse transcriptase PCR E6/E7 mRNA (all four were CDKN2A(p16) and CDKN1A(p21) positive). Unexpectedly, 9 additional tumors out of 20 CDKN2A(p16) positive cases harbored high-risk HPV DNA by PCR. For further investigation of this unexpected result, in situ hybridization for E6/E7 mRNA was performed on these nine cases and all were negative, confirming the absence of transcriptionally active virus. Patients with CDKN1A(p21)-positive tumors did have better overall survival (69% at 3 years) than those with CDKN1A(p21)-negative tumors (51% at 3 years) (P=0.045). There was also a strong trend towards better overall survival in the CDKN2A(p16)-positive group (P=0.058). Thus, it appears that the role of HPV is more complex in the larynx than in the oropharynx, and that CDKN2A(p16) and CDKN1A(p21) expression may not reflect HPV-driven tumors in most cases. Because of this, CDKN2A(p16) should not be used as a definitive surrogate marker of HPV-driven tumors in the larynx.

No survival benefit in never-smoker never-drinker patients with oral cavity cancer.

BACKGROUND: Although strongly associated with tobacco and alcohol use, many oral cavity squamous cell carcinoma (OCSCC) cases occur in patients without exposure to either, known as "never-smoker, never-drinkers" (NSND). We aimed to compare clinical outcomes between NSND and tobacco/alcohol-exposed populations and to define demographic characteristics of NSND. METHODS: We performed a retrospective, single-institution cohort study of 672 OCSCC patients. Cox models were used to estimate differences in overall survival (OS) and recurrence-free survival (RFS) between NSND and tobacco/alcohol-exposed patients while adjusting for confounders. RESULTS: NSND represented 25.6% of our cohort and were older, more female, and more economically advantaged. Among NSND, oral tongue tumors dominated in younger patients, while alveolar ridge tumors dominated in elderly patients. Multivariate survival analysis revealed no differences in OS or RFS between NSND and tobacco/alcohol-exposed patients. CONCLUSION: When adjusted for independent biologic features, clinical outcomes in OCSCC are similar between NSND and tobacco/alcohol-exposed patients.

Risk Factors for Functional Outcomes in Advanced Laryngeal Squamous Cell Carcinoma.

OBJECTIVE: Chemoradiation for patients with laryngeal squamous cell carcinoma (SCC) may achieve organ preservation, but appropriate patient selection remains unknown. This study investigates pre-treatment risk factors associated with functional and survival outcomes after radiation-based therapy in patients with advanced laryngeal SCC. METHODS: A retrospective cohort study was performed on 75 adult patients with stage III or IV laryngeal SCC receiving definitive radiation-based therapy from 1997 to 2016 at a tertiary care center. Tracheostomy and gastrostomy dependence were the primary functional outcomes. Multivariable logistic regressions were performed to evaluate relationships between pre-treatment factors and tracheostomy and gastrostomy dependence. Time-to-event analyses were performed to determine risk factors associated with overall survival. RESULTS: Among 75 patients included in the analysis, 30 (40%) patients were tracheostomy dependent and 31 (41%) were gastrostomy tube dependent. The median length of follow-up was 31 months (range = 1 to 142 months). Pre-treatment tracheostomy was a significant predictor of post-treatment tracheostomy (aOR = 13.9, 95% CI = 3.35 to 57.5) and moderate-severe comorbidity was a significant predictor of post-treatment gastrostomy dependence (aOR = 2.96, 95% CI = 1.04 to 8.43). The five-year overall survival was 51% (95% CI = 38 to 64%). Pre-treatment gastrostomy tube dependence was associated with an increased risk of death (aHR = 2.45, 95% CI = 1.09 to 5.53). CONCLUSIONS: Baseline laryngeal functional status and overall health in advanced laryngeal SCC are associated with poor functional outcomes after radiation-based therapy, highlighting the importance of patient selection when deciding between surgical and non-surgical treatment plans. Laryngoscope, 133:594-600, 2023.

Hearing Outcomes in a Deintensification Trial of Adjuvant Therapy for HPV-Related Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To explore whether deintensification of adjuvant therapy reduces ototoxicity among patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective cohort study. SETTING: Single academic center. METHODS: The ototoxicity rate among adult patients with HPV-related OPSCC enrolled in the Minimalist Trial (MINT), a prospective phase 2 trial of surgery followed by risk-adjusted deintensified adjuvant therapy (42 Gy radiation given alone or with a single 100 mg/m2 dose of cisplatin), was compared to that among a historical cohort treated with standard adjuvant therapy (60-66 Gy radiation with up to three 100 mg/m2 doses of cisplatin). Ototoxicity was defined as Common Terminology Criteria for Adverse Events v5.0 ≥ Grade 2. Mixed model analysis was performed to investigate the association between deintensified adjuvant therapy and treatment-related hearing loss. RESULTS: A total of 29 patients (58 ears) were analyzed in the MINT cohort, and 27 patients (54 ears) in the historical cohort. The ototoxicity rate was 5% (n = 3/58 ears) in the MINT cohort and 46% (n = 25/54 ears) in the historical cohort (difference, 41%; 95% confidence interval [CI] = 27%-56%). Patients in the MINT cohort demonstrated a 95% decrease in risk of ototoxicity compared to those in the historical cohort (adjusted odds ratio: 0.05, 95% CI = 0.01-0.31). Differences in estimated marginal mean threshold shifts were statistically and clinically significant at frequencies ≥ 3 kHz. CONCLUSION: The deintensified adjuvant therapy given in MINT led to less ototoxicity than standard adjuvant therapy among patients with HPV-related OPSCC.