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.

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.

Poor oral health influences head and neck cancer patient survival: an International Head and Neck Cancer Epidemiology Consortium pooled analysis.

BACKGROUND: Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes. METHODS: Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival. RESULTS: Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (>5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival. CONCLUSIONS: Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients.

Sensitive MRD detection from lymphatic fluid after surgery in HPV-associated oropharyngeal cancer.

PURPOSE: To demonstrate lymphatic drainage fluid (lymph) has improved sensitivity in quantifying postoperative minimal residual disease (MRD) in locally advanced HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) compared to plasma, which can be leveraged for patient risk stratification. EXPERIMENTAL DESIGN: We prospectively collected lymph samples from neck drains of 106 HPV (+) OPSCC patients, along with 67 matched plasma samples, 24 hours after surgery. PCR and next-generation sequencing were used to quantify cancer-associated cell-free HPV (cf-HPV) and tumor-informed variants in lymph and plasma. Next, lymph cf-HPV and variants were compared to TMN stage, extranodal extension (ENE), and composite definitions of high-risk pathology. We then created a machine learning model, informed by lymph MRD and clinicopathological features, to compare with progression-free survival (PFS). RESULTS: Postoperative lymph was enriched with cf-HPV compared to plasma (P < 0.0001) and correlated with pN2 stage (P = 0.003), ENE (P < 0.0001), and trial-defined pathological risk criteria (mean AUC = 0.78). Additionally, the lymph mutation number and variant allele frequency (VAF) were higher in pN2 ENE (+) necks than in pN1 ENE (+) (P = 0.03, P = 0.02) or pN0-N1 ENE (-) (P = 0.04, P = 0.03, respectively). The lymph MRD-informed risk model demonstrated inferior PFS in high-risk patients (AUC = 0.96, P < 0.0001). CONCLUSIONS: Variant and cf-HPV quantification, performed in 24-hour postoperative lymph samples, reflect single- and multi-feature high-risk pathological criteria. Incorporating lymphatic MRD and clinicopathological feature analysis can stratify PFS early after surgery in patients with HPV (+) head and neck cancer.

Barriers to Human Papillomavirus Vaccination Initiation and Completion among Adults Aged 18-26 Years in a Large Healthcare System.

Human papillomavirus (HPV) is a common sexually transmitted infection, with over 40% prevalence in the US. Oropharyngeal cancers (OPCs) driven by high-risk HPV are increasing (up to 90%), with HPV vaccination being the only prevention available. The aim of this study was to investigate HPV vaccination among patients aged between 18 and 26 years old with at least one encounter at a large healthcare system and identify sociodemographic factors associated with vaccine initiation and completion. A cross-sectional retrospective study was conducted between 2018 and 2021, including 265,554 patients identified from the Clinical Data Warehouse. HPV vaccination status by age, sex, race/ethnicity, insurance type, primary care (PCP) visits in the past year, alcohol, tobacco, illicit drug use, and age at vaccination was examined. Overall, 33.6% of females and 25.4% of males have completed the HPV vaccine. Black Americans were 35% more likely to initiate the vaccine than White Americans but were less likely to complete the entire course. Overall, HPV vaccination prevalence was far below the Health People 2030 goal of 80%, especially in young males. This low rate is troubling, since many patients had a PCP visit and remained unvaccinated, which serves as a missed opportunity for vaccination.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.

Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. EXPERIMENTAL DESIGN: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. RESULTS: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. CONCLUSIONS: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.

Emerging Roles of Circulating Tumor DNA for Increased Precision and Personalization in Radiation Oncology.

Recent breakthroughs in circulating tumor DNA (ctDNA) technologies present a compelling opportunity to combine this emerging liquid biopsy approach with the field of radiogenomics, the study of how tumor genomics correlate with radiotherapy response and radiotoxicity. Canonically, ctDNA levels reflect metastatic tumor burden, although newer ultrasensitive technologies can be used after curative-intent radiotherapy of localized disease to assess ctDNA for minimal residual disease (MRD) detection or for post-treatment surveillance. Furthermore, several studies have demonstrated the potential utility of ctDNA analysis across various cancer types managed with radiotherapy or chemoradiotherapy, including sarcoma and cancers of the head and neck, lung, colon, rectum, bladder, and prostate . Additionally, because peripheral blood mononuclear cells are routinely collected alongside ctDNA to filter out mutations associated with clonal hematopoiesis, these cells are also available for single nucleotide polymorphism analysis and could potentially be used to detect patients at high risk for radiotoxicity. Lastly, future ctDNA assays will be utilized to better assess locoregional MRD in order to more precisely guide adjuvant radiotherapy after surgery in cases of localized disease, and guide ablative radiotherapy in cases of oligometastatic disease.

Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma.

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

Audiologic Follow-up in Patients With Head and Neck Cancer Treated With Cisplatin and Radiation.

OBJECTIVES: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center. METHODS: We performed a single-institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post-treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow-up after pre-treatment evaluation. RESULTS: Two hundred ninety-four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post-treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow-up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow-up (aOR = 7.18, 95% CI = 2.75-19.90; aOR = 1.96, 95% CI = 1.02-3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one. CONCLUSIONS: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow-up rates for at least one post-treatment audiogram. However, follow-up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long-term audiologic follow-up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:3161-3168, 2023.

Human Papillomavirus Vaccination Prevalence and Disproportionate Cancer Burden Among US Veterans.

This cross-sectional study examines the rate of HPV vaccination and the number eligible for this vaccination among younger veterans and civilians.

A Multi-institutional Analysis of Late Complications in Scapula, Fibula, and Osteocutaneous Radial Forearm Free Flaps.

OBJECTIVES: (1) Evaluate the association of flap type with late complications in patients undergoing osseous head and neck reconstruction with the fibula free flap (FFF), osteocutaneous radial forearm free flap (OCRFFF), and scapula free flap (SFF). (2) Compare the prevalence of late complications based on minimum duration of follow-up. STUDY DESIGN: Retrospective cohort study. SETTING: Multiple academic medical centers. METHODS: Patients undergoing FFF, OCRFFF, or SFF with ≥6-month follow-up were stratified by type of flap performed. The association of flap type with late complications was analyzed via univariable and multivariable logistic regression, controlling for relevant clinical risk factors. Additionally, the frequency of late complications by minimum duration of follow-up was assessed. RESULTS: A total of 617 patients were analyzed: 312 (50.6%) FFF, 230 (37.3%) OCRFFFF, and 75 (12.2%) SFF. As compared with the SFF, the FFF (adjusted odds ratio [aOR], 3.05; 95% CI, 1.61-5.80) and OCRFFF (aOR, 2.17; 95% CI, 1.12-4.22) were independently associated with greater odds of overall late recipient site wound complications. The SFF was independently associated with the lowest odds of hardware exposure when compared with the FFF (aOR, 2.61; 95% CI, 1.27-5.41) and OCRFFF (aOR, 2.38; 95% CI, 1.11-5.12). The frequency of late complications rose as minimum duration of follow-up increased until plateauing at 36 months. CONCLUSIONS: This multi-institutional study suggests that the long-term complication profile of the SFF and OCRFFF compares favorably to the FFF. The SFF may be associated with the fewest overall late recipient site complications and hardware exposure, while the FFF may be associated with the most of these 3 options.

Disparities in head and neck cancer incidence and trends by race/ethnicity and sex.

BACKGROUND: The epidemiology of head and neck cancer (HNC) sites differ substantially. This study compares HNC incidence trends by site and demographic subgroups. METHODS: We used the U.S. Cancer Statistics Public Use Database to calculate HNC incidence rates per 100 000. We assessed trends with annual percent change (APC) longitudinally from 2001 to 2017. RESULTS: The oropharyngeal cancer incidence APC decreased from 4.38% (95% CI: 3.6, 5.1) to 2.93% (2.5, 3.3) in 2008 among White males. Oral cavity cancer incidence rose in Other race males (APC 2.5% [1.6, 3.36]) and White females (APC: 0.96% [0.7, 1.2]). Although decreasing (APC: -1.15% [-1.48, -0.83]), laryngeal cancer incidence remained disproportionately high among Black males. CONCLUSIONS: Notable incidence trends occurred in non-White groups at non-oropharyngeal sites. With parity of smoking rates by race, differing sexual behaviors, and shifting demographics by race and sex, future studies of HNC trends should consider stratifying analyses to understand health disparities.

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.

Mesenchymal gene expression subtyping analysis for early-stage human papillomavirus-negative head and neck squamous cell carcinoma reveals prognostic and predictive applications.

Patients with oral cavity squamous cell carcinoma (OCSCC) are predominantly human papillomavirus (HPV)(-), and treatment typically involves surgical resection ± neck dissection, followed by radiation ± chemotherapy. We previously described four mRNA expression patterns (classical, atypical, basal, and mesenchymal), each with unique genomic features and prognosis. Here, we examine the clinical utility of gene expression subtyping in head and neck squamous cell carcinoma (HNSCC) and introduce potentially predictive applications in HPV(-) OCSCC. A retrospective genomic database analysis was performed including 562 HNSCC patients from MD Anderson (MDA-GSE41116) and The Cancer Genome Atlas (TCGA). Samples were assigned molecular subtypes (classical, atypical, basal, and mesenchymal) using an 88-gene classifier. HPV status was determined by gene expression. The clinical endpoint was overall survival censured at 36 months. The Kaplan-Meier plots and log-rank tests were used to investigate associations between clinical variables and survival. Of the 418 TCGA training patients who met analysis criteria, nearly 20% presented as stage I/II. Among node(-) OCSCC patients, the mesenchymal subtype is associated with worse survival (hazard ratio (HR) = 2.4, p = 0.021), offering a potentially actionable biomarker in otherwise early-stage, low-risk disease. This was confirmed in the MDA validation cohort. Node(-) non-mesenchymal OCSCC patients had far better survival compared to node(-) mesenchymal, and all node(+) patients had similarly poor survival. These findings suggest that the mesenchymal subtype is associated with poor survival in surgically resected, early-stage, node(-) OCSCC otherwise expected to have favorable outcomes. These findings highlight the potential value of gene expression subtyping as a pathology adjunct for prognostication and treatment decision-making in OCSCC patients.

Perioperative Outcomes in Patients Who Underwent Fibula, Osteocutaneous Radial Forearm, and Scapula Free Flaps: A Multicenter Study.

Importance: Studies comparing perioperative outcomes of fibula free flaps (FFFs), osteocutaneous radial forearm free flaps (OCRFFFs), and scapula free flaps (SFFs) have been limited by insufficient sample size. Objective: To compare the perioperative outcomes of patients who underwent FFFs, OCRFFFs, and SFFs. Design, Setting, and Participants: This cohort study assessed the outcomes of 1022 patients who underwent FFFs, OCRFFFs, or SFFs for head and neck reconstruction performed at 1 of 6 academic medical centers between January 2005 and December 2019. Data were analyzed from September 17, 2021, to June 9, 2022. Main Outcomes and Measures: Patients were stratified based on the flap performed. Evaluated perioperative outcomes included complications (overall acute wound complications, acute surgical site infection [SSI], fistula, hematoma, and flap failure), 30-day readmissions, operative time, and prolonged hospital length of stay (75th percentile, >13 days). Patients were excluded if data on flap type or clinical demographic characteristics were missing. Associations between flap type and perioperative outcomes were analyzed using logistic regression, after controlling for other clinically relevant variables. Adjusted odds ratios (aORs) with 95% CIs were generated. Results: Perioperative outcomes of 1022 patients (mean [SD] age, 60.7 [14.5] years; 676 [66.1%] men) who underwent major osseous head and neck reconstruction were analyzed; 510 FFFs (49.9%), 376 OCRFFFs (36.8%), and 136 SFFs (13.3%) were performed. Median (IQR) operative time differed among flap types (OCRFFF, 527 [467-591] minutes; FFF, 592 [507-714] minutes; SFF, 691 [610-816] minutes). When controlling for SSI, FFFs (aOR, 2.47; 95% CI, 1.36-4.51) and SFFs (aOR, 2.95; 95% CI, 1.37-6.34) were associated with a higher risk of flap loss than OCRFFFs. Compared with OCRFFFs, FFFs (aOR, 1.77; 95% CI, 1.07-2.91) were associated with a greater risk of fistula after controlling for the number of bone segments and SSI. Both FFFs (aOR, 1.77; 95% CI, 1.27-2.46) and SFFs (aOR, 1.68; 95% CI, 1.05-2.69) were associated with an increased risk of 30-day readmission compared with OCRFFFs after controlling for Charlson-Deyo comorbidity score and acute wound complications. Compared with OCRFFFs, FFFs (aOR, 1.78; 95% CI, 1.25-2.54) and SFFs (aOR, 1.96; 95% CI, 1.22-3.13) were associated with a higher risk of prolonged hospital length of stay after controlling for age and flap loss. Conclusions and Relevance: Findings of this cohort study suggest that perioperative outcomes associated with OCRFFFs compare favorably with those of FFFs and SFFs, with shorter operative times and lower rates of flap loss, 30-day readmissions, and prolonged hospital length of stay. However, patients undergoing SFFs represented a more medically and surgically complex population than those undergoing OCRFFFs or FFFs.

Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

Integrative genomic analysis reveals low T-cell infiltration as the primary feature of tobacco use in HPV-positive oropharyngeal cancer.

Although tobacco use is an independent adverse prognostic feature in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC), the biologic features associated with tobacco use have not been systematically investigated. We characterized genomic and immunologic features associated with tobacco use through whole exome sequencing, mRNA hybridization, and immunohistochemical staining in 47 HPV(+) OPSCC tumors. Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T > C substitutions and a lower proportion of expected mutational signatures, but not with increases in mutational burden or recurrent oncogenic mutations. Our findings suggest that rather than increased mutational burden, tobacco's primary and clinically relevant association in HPV(+) OPSCC is immunosuppression of the tumor immune microenvironment. Quantitative assays of T cell infiltration merit further study as prognostic markers in HPV(+) OPSCC.

Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration.

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.