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Penile squamous cell carcinoma (PSCC) is classified into 2 prognostically distinct types: human papillomavirus (HPV)-associated and HPV-independent. However, the impact of p53 status on prognosis remains controversial. We correlated HPV and p53 status with the prognosis of a large series of patients with PSCC. p53 was analyzed according to a recently described immunohistochemical (IHC) pattern-based framework that includes 2 normal and 4 abnormal patterns and closely correlates with TP53 mutational status. A total of 122 patients with surgically treated PSCC in 3 hospitals were included. Based on HPV in situ hybridization and p16 and p53 IHC, the tumors were classified into 3 subtypes: HPV-associated, HPV-independent/p53 normal, and HPV-independent/p53 abnormal. All patients were followed up for at least 22 months (median: 56.9 months). Thirty-six tumors (29%) were HPV-associated, 35 (29%) were HPV-independent/p53 normal, and 51 (42%) were HPV-independent/p53 abnormal. Disease-related deaths were observed in 3/36 (8%), 0/35 (0%) and 14/51 (27%) of the patients, respectively ( P < 0.001). A total of 7/14 deaths in the latter group were patients with tumors showing p53 abnormal patterns not recognized in the classic p53 IHC interpretation (basal, null, and cytoplasmic). According to our multivariate analysis, HPV-independent/p53 abnormal tumors and advanced stage were associated with impaired disease-specific survival (hazard ratio = 23.4, 95% CI = 2.7-3095.3; P = 0.001 and 16.3, 95% CI = 1.8-2151.5; P = 0.008, respectively). In conclusion, compared with patients with HPV-associated and HPV-independent/p53-normal PSCC, patients with HPV-independent/p53 abnormal PSCC have worse clinical outcomes. p53 IHC results define 2 prognostic categories in HPV-independent PSCC: HPV-independent/p53-normal tumors as low-risk tumors, whereas HPV-independent/p53-abnormal tumors as aggressive neoplasms., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

High-risk human papillomavirus (hrHPV) is an emerging risk factor for sinonasal squamous cell carcinoma (SNSCC). The goal of this study was to assess the prevalence of hrHPV and subtype distribution in SNSCC and correlation with patient and clinical characteristics. This retrospective cohort study included 43 cases diagnosed with incident primary SNSCC at the University of Cincinnati Medical Center from 2010 to 2015. The prevalence of hrHPV was interrogated using a multi-assay approach that included p16 immunohistochemistry (IHC), RNA in-situ hybridization (ISH), and hrHPV DNA sequencing. The association of hrHPV with 5-year overall survival (OS) and 2-year disease-free survival (DFS) was assessed. Fourteen cases (32.6 %) were classified as hrHPV positive, based on the a priori definition of having either a positive RNAScope™ ISH test or hrHPV DNA and p16-positive IHC; 9 cases (20.9 %) were positive for all three tests. All cases that arose from an inverted sinonasal papilloma (ex-ISP) were negative for hrHPV. HPV16 was the most common subtype among hrHPV positive cases (58.8 %), followed by HPV18 (17.6 %). No significant association was observed between hrHPV and OS or DFS after adjusting for potential confounding. hrHPV is prevalent in a sizable fraction of SNSCC. Additional studies are needed to better elucidate the relationship with patient survival outcomes and determine the optimal testing modality for prognostication., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Scott M Langevin reports financial support was provided by American Cancer Society. Scott M Langevin reports financial support was provided by Brandon C. Gromada Head & Neck Cancer Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Human papillomavirus (HPV) infection is a risk factor for the development of penile squamous cell carcinoma (PSCC). It remains inconclusive whether HPV-related PSCC has a different prognosis from non-HPV-related PSCC., Objective: To investigate the relationship between HPV status and survival as well as temporal changes in the proportion of HPV-related PSCC., Design, Setting, and Participants: A retrospective cohort of 277 patients treated in Norway between 1973 and 2022 was investigated for HPV DNA in tumor tissue. Clinicopathological variables and disease course were registered., Outcome Measurements and Statistical Analysis: Kaplan-Meier curves and Cox regression were used to investigate the determinants of cancer-specific survival (CSS). The chi-square test for trend in proportions enabled investigation of temporal changes in the HPV-related proportion of PSCC patients treated in Western Norway (n = 211)., Results and Limitations: HPV DNA was detected in tumor tissue from 131 (47%) patients. Stratified by HPV status, 5-yr CSS did not differ between groups (p = 0.37). When investigating only node-positive patients, however, presence of HPV DNA was an independent predictor of better survival in multivariable Cox regression after adjustment for age, nodal stage, and adjuvant therapy (hazard ratio 0.54, 95% confidence interval: [0.30-0.99], p = 0.04). In cases from Western Norway, an increasing proportion of HPV-related cases over time was found (p = 0.01). The main limitation is the retrospective study design., Conclusions: HPV DNA in tumor tissue was associated with significantly better CSS for node-positive patients. The proportion of HPV DNA-positive PSCC has increased significantly in Western Norway over the past 50 yr., Patient Summary: We investigated the impact of human papillomavirus (HPV) on the survival of penile cancer patients treated over a 50-yr period in Norway. We found that for patients with lymph node metastasis, survival was better for HPV-related cases. We also found that the proportion of cases due to HPV has increased in Western Norway., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite., Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival., Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m 2 was associated with improved survival, while BMI <18.5 kg/m 2 was associated with reduced survival, particularly in patients with HPV-positive oropharyngeal cancer tumors., Conclusions: This exploratory analysis suggests that pretreatment BMI could be an independent prognostic factor of survival outcomes in SCCHN patients, particularly in patients with HPV-positive oropharyngeal cancer tumors. Further prospective investigations are warranted., (© 2024 Wiley Periodicals LLC.)

Objective: While tobacco use is understood to negatively impact HPV+ oropharyngeal squamous cell carcinoma (OPSCC) outcomes, debate remains as to how this impact differs between cohorts. Multiple smoking metrics have been identified as having the greatest prognostic significance, and some recent works have found smoking to have no significant impact. Herein, we show through an analysis of four common smoking metrics that while smoking impacts overall survival (OS), it has a limited impact on recurrence-free survival (RFS) in our cohort., Methods: We conducted a retrospective review of patients treated for HPV+ OPSCC in our health system from 2012 to 2019. Patients with metastatic disease or concurrent second primaries were excluded. Four metrics of tobacco use were assessed: current/former/never smokers, ever/never smokers, and smokers with >10 or >20 pack-year (PY) smoking histories. Our main outcomes were 3-year RFS and OS., Results: Three hundred and sixty-seven patients met inclusion criteria. 37.3% of patients (137/367) were never-smokers; 13.8% of patients (51/367) were currently smoking at diagnosis and 48.8% of patients (179/367) were former smokers. No tobacco-use metric significantly impacted 3-year RFS. On univariate analysis, all smoking metrics yielded inferior OS. On multivariate analysis, current and ever smoking status significantly impacted 3-year OS., Conclusion: The impact of tobacco use on HPV+ OPSCC outcomes is not universal, but may instead be modulated by other cohort-specific factors. The impact of smoking may decrease as rates of tobacco use decline., Level of Evidence: 3 (Cohort and case-control studies) Laryngoscope, 134:3158-3164, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Studies have shown lower overall survival for patients with head and neck cancer treated at low-volume or community cancer centers. As the incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma steadily rises in the United States, we hypothesized that a greater proportion of patients with HPV-related oropharyngeal squamous cell carcinoma is being treated at community cancer centers, with a shift toward primary nonsurgical treatment., Methods: This cohort study included patients from the US National Cancer Database who received a diagnosis of HPV-related oropharyngeal squamous cell carcinoma from 2010 to 2019 and underwent treatment at a community cancer center or academic cancer center. The proportion of patients with HPV-related oropharyngeal squamous cell carcinoma treated at community cancer centers and receiving primary nonsurgical treatment was analyzed over time. Four-year overall survival was compared between community cancer centers and academic cancer centers., Results: The majority (67.4%) of 20 298 patients were treated at an academic cancer center, yet the proportion of patients treated at community cancer centers increased by 10% from 2010 to 2019 (P < .01 for trend). The proportion of patients undergoing primary nonsurgical treatment increased from 62.1% to 73.7% from 2010 to 2019 (P < .01 for trend), and patients were statistically significantly more likely to undergo nonsurgical treatment at community cancer centers than at academic cancer centers (adjusted odds ratio = 1.20, 95% confidence interval = 1.18 to 1.22). Treatment at community cancer centers was associated with worse survival overall (adjusted hazard ratio = 1.19, 95% confidence interval = 1.09 to 1.31), specifically for patients receiving primary nonsurgical treatment (adjusted hazard ratio = 1.22, 95% confidence interval = 1.11 to 1.34)., Conclusions: Treatment of HPV-related oropharyngeal squamous cell carcinoma has recently shifted to community cancer centers, with an increase in the proportion of nonsurgical treatment and worse overall survival at these centers compared with academic cancer centers. Concentration of care for HPV-related oropharyngeal squamous cell carcinoma at academic cancer centers and dedicated head and neck cancer centers may increase access to all available treatment modalities and improve survival., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility., Materials and Methods: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions., Results: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions., Conclusions: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC., Competing Interests: Declaration of competing interest The authors have no financial disclosures or conflicts of interests to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT)., Methods: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts., Results: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009)., Conclusion: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC)., Design: Meta-analysis and systematic evaluation., Data Sources: The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com., Eligibility Criteria for Selecting Studies: Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV + OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE)., Data Extraction and Synthesis: Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data., Results: A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV + OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV + OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], P = 0.0004; HR = 1.79, 95% CI [1.40-2.29], P < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], P < 0.0001; HR = 1.66, 95% CI [1.07-2.58], P = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], P = 0.28)., Conclusions: Cisplatin + radiotherapy remains the standard treatment for HPV + OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV + OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies., Prospero Registration Number: CRD42023445619., Competing Interests: The authors declare there are no competing interests., (©2024 Hu et al.)

Background: Human papillomavirus (HPV) causes several cancers such as cervical cancer and some head and neck (oral cavity, pharynx, and larynx), vulval, vaginal, anal, and penile cancers. As HPV vaccination is available, there is potential to prevent these cancers attributed to HPV and consequently the burden associated with them. The aim of this analysis was to estimate the number of HPV-related cancer deaths and the productivity costs due to years of life lost (YLL) in the United Kingdom (UK)., Method: A model was developed utilizing UK 2019 mortality data sourced from country-specific databases for England, Scotland, Wales, and Northern Ireland for the following HPV-related cancers: head and neck (ICD-10 C00-14 and C32), cervix uteri (C53), vaginal (C51), vulval (C52), anal (C21), and penile (C60). The proportion of deaths and years of life lost (YLL) due to HPV were estimated using HPV attributable fractions for each anatomic location from the published literature. Labor force participation, retirement ages, and mean annual earnings, discounted at 3.5% annually, were applied to YLL to calculate the present value of future lost productivity (PVFLP)., Results: A total of 1817 deaths due to HPV-related cancers were reported in the UK in 2019 resulting in 31,804 YLL. Restricting to only YLL that occurred prior to retirement age yielded a total YPLL of 11,765 and a total PVFLP of £187,764,978., Conclusions: There is a high disease burden in the UK for HPV-related cancers, with a large economic impact on the wider economy due to productivity losses. Implementing and reinforcing public health measures to maintain high HPV vaccination coverage in both males and females may further facilitate reduction of this burden.

The over expression of Indoleamine 2, 3-Dioxygenase (IDO1), an immune checkpoint inhibitor, is well known in cervical cancer. However, its association with chemokine signals promoting cellular infiltration in the cervical tumor microenvironment, is unknown. In the current study, we evaluated the expression and enzymatic activity of IDO1. We also profiled the expression of chemokine ligand-receptors- CCR4-CCL22, CXCR3-CXCL10, CXCR4-CXCL12, and CCR7-CCL19 using immunohistochemistry (IHC), and studied their association with IDO1, statistically. After getting an informed consent, punch biopsy samples were obtained from 105 patients diagnosed with cervical cancer. HPV typing by Sanger sequencing, realtime PCR for quantifying IDO1 mRNA expression, HPLC for determining the K/T ratio and IHC for all the above chemokine receptor-ligand pairs along with IDO1 were performed. We found a significant increase in the expression of IDO1 and K/T levels in early and locally advanced stages when compared to Stage IV disease. Among the chemokine ligand -receptor pairs profiled, we found that high CCL19 marker expression was a good prognostic indicator of patients' disease-free (p = 0.013) and overall survival (p = 0.043). Although we could not identify IDO1 as an independent prognostic factor, we found that high levels of IDO1 expression may further reduce survival outcomes in patients with low CCL19 expression. This could be vital for designing immuno therapeutic interventions targeting IDO1., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Backgroud: The pros and cons of tracheotomy, as a classic treatment of juvenile-onset recurrent respiratory papillomatosis (JORRP), have gradually been recognized, but the exact impact of tracheotomy on remission and demise is not clear., Objectives: To investigate the predicting influence of tracheotomy on prognosis for JORRP., Material and Methods: Three hundred forty two patients with JORRP treated in Beijing Tongren Hospital were retrospectively reviewed. The clinical characteristics and prognosis parameters were compared in the group of tracheotomy and non-tracheotomy., Results: The rate of tracheotomy was 24.6% (84/342). Among these patients, 68 (81.0%) developed the tracheal papillomatosis. The onset age of RRP occurred earlier in tracheostomized group, and patients performed tracheotomy needed a greater number of surgeries and developed distal spread more easily ( p  < .05). The remission rate was significantly lower (35.1 vs. 53.7%) and the mortality higher (13.1 vs. 1.2%) in patients with tracheotomy than non-tracheotomy. Tracheotomy decreased odds of remission (OR = 0.48; 95%CI: 0.28-0.83) and increased odds of demise (OR = 11.98; 95%CI: 3.21-44.65)., Conclusions: The age at diagnosis, the surgical frequency and the medical level of hospital are important factors affecting the occurrence of tracheotomy. Patients who had undergone tracheotomy are prone to possess the low remission rate and high mortality.

Background: Expression of killer cell lectin-like receptor B1 ( KLRB1 ), the gene encoding the cell surface molecule CD161, is associated with favorable prognosis in many cancers. CD161 is expressed by several lymphocyte populations, but its role and regulation on tumor-specific CD4+ T cells is unknown., Methods: We examined the clinical impact of CD4+CD161+ T cells in human papillomavirus (HPV)16+ oropharyngeal squamous cell carcinoma (OPSCC), analyzed their contribution in a cohort of therapeutically vaccinated patients and used HPV16-specific CD4+CD161+ tumor-infiltrating lymphocytes and T cell clones for in-depth mechanistic studies., Results: Central and effector memory CD4+ T cells express CD161, but only CD4+CD161+ effector memory T cells (Tem) are associated with improved survival in OPSCC. Therapeutic vaccination activates and expands type 1 cytokine-producing CD4+CD161+ effector T cells. The expression of CD161 is dynamic and follows a pattern opposite of the checkpoint molecules PD1 and CD39. CD161 did not function as an immune checkpoint molecule as demonstrated using multiple experimental approaches using antibodies to block CD161 and gene editing to knockout CD161 expression. Single-cell transcriptomics revealed KLRB1 expression in many T cell clusters suggesting differences in their activation. Indeed, CD4+CD161+ effector cells specifically expressed the transcriptional transactivator SOX4, known to enhance T cell receptor (TCR) signaling via CD3ε. Consistent with this observation, CD4+CD161+ cells respond more vigorously to limiting amounts of cognate antigen in presence of interleukin (IL)-12 and IL-18 compared to their CD161- counterparts. The expression of CD161/ KLRB1 and SOX4 was downregulated upon TCR stimulation and this effect was boosted by transforming growth factor (TGF)β1., Conclusion: High levels of CD4+CD161+ Tem are associated with improved survival and our data show that CD161 is dynamically regulated by cell intrinsic and extrinsic factors. CD161 expressing CD4+ T cells rapidly respond to suboptimal antigen stimulation suggesting that CD161, similar to SOX4, is involved in the amplification of TCR signals in CD4+ T cells., Competing Interests: Competing interests: GS reports personal fees from Pieris Pharmaceuticals GmbH outside the submitted work. FF has received honoraria for lecturing at the ESMO Virtual Advanced Course on Biomarkers for Precision Medicine 2021. PtD reports grants from Oncode Institute and Cancer Genomics Center Netherlands (CGC.NL). VMB reports funding from Centre National de la Recherche Scientifique, French Government (National Research Agency, ANR) through the 'Investments for the Future' programs LABEX SIGNALIFE ANR-11-LABX-0028 and IDEX UCAJedi ANR-15-IDEX-01, Cancéropole PACA and Fondation ARC pour la recherche sur le Cancer. SHvdB reports grants from IO Biotech and DC Prime for immunemonitoring of trials and personal consulting fees from ISA Pharmaceuticals, PCI Biotech, DC Prime, CHDR consultancy services and AGLAIA outside the submitted work. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC)., Study Design: Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017., Methods: Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments., Results: Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P < .001). Patients who initially received adjuvant chemoradiation and those suffering local, in-field, and/or retropharyngeal node recurrences had decreased disease control after salvage therapy., Conclusion: LRR rates are low for HPV+ OPSCCs completing TORS and guideline-compliant adjuvant therapy. Patients without indication for adjuvant therapy more often suffer LRR, but these recurrences are generally controllable by salvage therapy. Improved understanding of the patterns of recurrence most amenable to salvage therapy may guide treatment decisions, counseling, and adjuvant therapy de-escalation trials., Level of Evidence: 3 Laryngoscope, 131:E2865-E2873, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets (P = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy., (© 2021. The Author(s).)

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n = 304). For the first time to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set (n = 88) and within the HPV 16+ subset (n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53-p21. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy, and these patients may benefit from alternative treatment strategies.

Early studies estimate that 5% to 10% of oropharyngeal squamous cell carcinomas overexpress p16 but are unassociated with transcriptionally-active high-risk human papillomavirus (HPV). Patients with discordant HPV testing may experience clinical outcomes that differ from traditional expectations. To document the rate of p16 and HPV mRNA positivity, characterize patients with discordant testing, and identify features that may warrant selective use of HPV-specific testing after p16 IHC, a multi-institutional, retrospective review of oropharyngeal squamous cell carcinoma patients with p16 IHC and HPV mRNA testing by reverse transcriptase polymerase chain reaction was performed. Of the 467 patients, most had T1 or T2 tumors (71%), 82% were p16 positive, and 84% were HPV mRNA positive. Overall, most tumors were nonkeratinizing (378, 81%), which was strongly associated with p16 and HPV positivity (93% and 95%, respectively). Overall, 81% of patients were double positive, 14% double negative, and 4.9% discordant (3.4% p16 negative/HPV mRNA positive and 1.5% p16 positive/HPV mRNA negative). The survival rates of these discordant patient groups fell squarely between the 2 concordant groups, although in multivariate analysis for both disease-free survival and overall survival, discordant patients were not found to have statistically significantly different outcomes. Reclassifying patients by applying HPV mRNA testing when p16 results and morphology do not match, or when p16 results are equivocal, improved prognostication slightly over p16 or HPV mRNA testing alone. Patients with discordant testing demonstrate a borderline significant trend toward survival differences from those with concordant tests. When evaluated independently, patients who were p16 negative but HPV mRNA positive had a prognosis somewhat closer to double-positive patients, while those who were p16 positive, but HPV mRNA negative had a prognosis closer to that of double-negative patients. We suggest an algorithm whereby confirmatory HPV mRNA testing is performed in patients where p16 status is not consistent with tumor morphology. This captures a majority of discordant patients and improves, albeit modestly, the prognostication., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the NIH grant R01DE026471 (X.W.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To explore the survival implications of human papillomavirus (HPV) positivity and subtype in larynx cancer through a national cancer database. To investigate staging discrepancies in larynx cancer associated with HPV status., Study Design: Retrospective observational cohort study., Setting: National Cancer Database., Methods: Data were extracted concerning adults with known HPV status who were treated between 2010 and 2016 for laryngeal squamous cell carcinoma. Patients without known HPV subtype were excluded. Cox multivariable regression models were fit to evaluate the survival impact of HPV status, characterized as a binary variable (HPV+ vs HPV-) and by subtype. Two- and 5-year survival rates were calculated via the Kaplan-Meier method and compared by stage between the HPV+ and HPV- cohorts per the log-rank test., Results: Patients with HPV+ larynx cancer were younger (60.5 vs 64.3 years, P < .001), more likely to have private insurance (37.2% vs 31.2%, P < .001), more commonly White (84.6% vs 82.4%, P = .013), and more likely to present with nodal disease (42.6% vs 33.0%, P < .001). HPV positivity and HPV subtype 16 were associated with improved overall survival. One-stage discrepancies in 5-year survival were observed between the HPV+ and HPV- cohorts: stage II HPV+ (69.45%) vs stage I HPV- (65.77%); stage IV HPV+ (47.67%) vs stage III HPV- (46.80%)., Conclusions: HPV positivity and infection with HPV subtype 16 are correlated with improved overall survival in patients with laryngeal squamous cell carcinoma, manifesting with a 1-stage incremental survival advantage. Future prospective studies are indicated to corroborate the findings from this large-population database retrospective study.

Objective: To investigate the patterns of care and outcomes of treatment of early stage tonsil cancers, controlling for human papillomavirus (HPV) status., Study Design: Historical cohort study., Setting: National Cancer Database (NCDB)., Methods: Review of the NCDB between 2010 and 2017 for all T1-2N0M0 tonsillar squamous cell carcinoma (SCC). Demographics, clinical characteristics, HPV status, treatment regimens, and survival were analyzed., Results: A total of 4720 patients were identified with early stage SCC of the tonsil. Most were tested for HPV (2759 [58.5%]). Among tested patients, 1758 (63.7%) were positive for HPV and 1001 (36.3%) were negative for HPV. HPV-positive patients had higher 3-year survival compared to HPV-negative patients (93.2% vs 77.8%, P < .001). Among HPV-positive patients, there was no significant difference in survival between treatment cohorts. However, in the HPV-negative cohort, 3-year survival was higher in both bimodality surgical-based settings (tonsillectomy + neck dissection + radiotherapy, 86.0% vs chemoradiotherapy, 69.6%, P = .01) and for all surgical-based treatments when compared to nonsurgical management (84.6% vs 69.3%, P < .001). This difference was maintained in multivariable regression controlling for age, sex, comorbidities, clinical T stage, and treatments. In a subpopulation of HPV-negative patients propensity score matched by all factors significant in multivariable analysis, 3-year survival remained higher in the surgically treated group compared to the nonsurgically treated cohort (84.9% vs 67.1%, P < .001)., Conclusions: Surgical- or radiation-based treatment resulted in similar survival in early stage HPV-positive tonsil cancer. Surgical-based treatments were associated with longer survival in HPV-negative cancers. These findings should be further investigated in a randomized prospective trial.

Objective: To investigate the clinical characteristics and long-term outcomes of juvenile onset recurrent respiratory papillomatosis (JORRP) with or without pulmonary involvement., Methods: A group of patients with JORRP who had clinical course over an extended period of time (at least 5 years) in the Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital were included in this retrospective study. Lung/bronchus involvement was revealed by lung imaging. Data on mortality rate, frequency of surgical interventions, and age of disease onset were collected and analyzed., Results: The 192 patients (107 male and 85 female) included had a median [quartiles] age of JORRP onset of 2 [1, 4] years, and median follow-up duration of 10 [7, 13] years; 17 patients (8.9%) had papilloma with bronchial and pulmonary involvement 7.0 [4.0, 12.5] years after the onset of the disease. Compared to patients without lung involvement, patients with lung involvement had a younger age of disease onset (P = .001), higher frequency of surgical interventions (P < .001), higher mortality rate (OR = 94.909), and an increased risk of tracheotomy that could not be decannulated (P < .001). They also had a younger age of disease onset, and a higher frequency of surgical interventions and mortality compared to patients with tracheotomy but free from lung involvement (P < .001)., Conclusions: Children with JORRP and with pulmonary involvement have a higher average number of operations per year than those without pulmonary involvement, and pulmonary involvement indicates a higher incidence of tracheotomy that cannot be decannulated., Level of Evidence: 4 Laryngoscope, 131:E2277-E2283, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To determine the prognostic role of extranodal extension (ENE) among patients with human papilloma virus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) through a systematic review and meta-analysis of institutional studies., Data Sources: MEDLINE, Embase, Scopus, and PubMed., Review Methods: Two independent authors searched the databases on December 3, 2019, to identify studies of HPV+ OPSCC comparing prognostic outcomes stratified by ENE. The I 2 statistic was used to determine study heterogeneity. Fixed and random effects models were used to determine hazard ratios (HRs) with 95% CIs., Results: Eighteen observational studies met inclusion criteria, yielding 3603 patients with HPV+ OPSCC (1521 ENE+ and 2082 ENE-) with a median follow-up of 49 months. The presence of pathologic ENE (pENE) and radiologic ENE (rENE) was associated with decreased overall survival (pENE HR, 1.89 [95% CI, 1.15-3.13], I 2 = 35%; rENE HR, 2.64 [95% CI, 1.46-4.78], I 2 = 75%) and distant recurrence (pENE HR, 3.23 [95% CI, 1.25-8.33], I 2 = 0%; rENE HR, 3.83 [95% CI, 1.88-7.80], I 2 = 0%). Neither pENE nor rENE was associated with locoregional recurrence (pENE HR, 0.75 [95% CI, 0.20-2.84], I 2 = 0%; rENE HR, 2.03 [95% CI, 0.86-4.79], I 2 = 0%). pENE was not associated with disease-specific survival (pENE HR, 1.45 [95% CI, 0.84-2.49], I 2 = 0%)., Conclusion: pENE and rENE are moderately associated with an increased risk of all-cause mortality and recurrence with distant metastasis in a cohort of patients with HPV+ OPSCC. These findings may be used to inform exclusion criteria for deintensification trials and assist in refined risk stratification.

Objectives: The link between human papillomavirus (HPV) and oropharyngeal cancer (OPC) is well known. Locally advanced, HPV-positive OPC (HPV OPC) can be treated with either chemoradiation or primary surgery with or without adjuvant therapy. Head and neck cancer patients with government insurance or uninsured have been shown to have worse prognosis than similar patients with private insurance. In this study, we aimed to determine if insurance status would predict treatment modality in patients with HPV OPC., Study Design: A retrospective analysis using the National Cancer Database (NCDB)., Methods: The National Cancer Database was used to identify patients with HPV OPC who underwent primary surgery or primary chemoradiation from 2010-2015. Insurance status was categorized as government, private, or no insurance. The relationship between insurance status and treatment was investigated using Chi square and multivariate regression models. Kaplan-Meier analyses were performed comparing overall survival (OS) by insurance status., Results: There were 10,606 patients were included. There was a statistically significant correlation between insurance status and primary treatment modality for HPV OPC (P < .001). Patients with government insurance were 19.3% less likely to undergo surgery and uninsured patients were 36.9% less likely to undergo primary surgery when compared to those with private insurance (P < .001), even after correcting for TNM stage in multivariate analysis. There was an improved 5-year OS for patients with private insurance (86.6%) versus both government insurance (68.4%) and no insurance (69.9%) (P < .001)., Conclusions: Patients with private insurance are more likely to undergo primary surgery in HPV OPC and have improved overall survival., Level of Evidence: 4 Laryngoscope, 131:776-781, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Background: Patients with human papillomavirus (HPV+) head and neck squamous cell carcinoma (HNSCC) have superior prognoses compared with patients with HPV- HNSCC and strategies for treatment de-escalation are under investigation for the HPV+ setting. However, the survival advantage associated with HPV is not universal, and a subset of patients with HPV+ HNSCC fail definitive treatment and progress with metastatic/recurrent disease. Currently, no biomarker is available to distinguish aggressive from indolent HPV+ HNSCC. Immune dysfunction facilitates tumorigenesis and is associated with poor treatment response; therefore, we hypothesized that diminished intratumoral immune cell functionality may be attractive biomarkers to identify patients with HPV+ HNSCC at risk for early disease-specific mortality., Methods: This is a retrospective analysis of The Cancer Genome Atlas (TCGA) HPV+ HNSCC cohort., Results: Immunoglobulin J polypeptide (IGJ), uniquely expressed in plasma cells, showed a broad expression range in HPV+ HNSCC. Cox regression model, adjusting for clinical covariates, indicated that IGJ is an independent prognostic biomarker for disease-specific survival (DSS) and overall survival (OS). Patients with low IGJ had a 7.2-fold (p<0.001) increase in risk of disease-specific death with a median DSS of 13 months. Low IGJ showed an area under curve (AUC) of 0.89 with 91.0% sensitivity and 87.6% specificity to identify early disease-specific mortality (defined as DSS ≤12 months). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed a global dampening of immune pathways in low IGJ tumors., Conclusions: Our work showed that IGJ is a robust and independent prognostic biomarker for disease-specific mortality in HPV+ HNSCC. Patient with HPV+ HNSCC with limited adaptive immune functionality should not be candidates for treatment de-escalation modalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3' to a signal sequence and 5' to the HSP70 gene of Mycobacterium tuberculosis Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8 + T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8 + T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16 + cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody., (Copyright © 2021 Peng et al.)

Background: As a type of malignant tumor, head and neck squamous cell carcinoma (HNSCC) seriously threatens human health. This study is aimed at constructing a new, reliable prognostic model., Method: The gene expression profile data of HNSCC patients were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The immune-related differentially expressed genes (IRDEGs) related to HNSCC were identified. We then used Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis to explore IRDEGs related to the HNSCC prognosis and to construct and validate a risk scoring model and used ESTIMATE to evaluate tumor immune infiltration in HNSCC patients. Finally, we validated IGSF5 expression and function in HNSCC cells., Results: A total of 1,195 IRDEGs were found from the GSE65858 dataset. Thirty-one of the 1,195 IRDEGs were associated with the prognosis of HNSCC. Nine key IRDEGs were further selected using the LASSO method, and a risk scoring model was established for predicting the survival of HNSCC patients. According to the risk scoring model, the prognosis of patients in the high-risk group was worse than that of the low-risk group; the high-risk group had significantly higher immune scores than the low-risk group; and between the high- and low-risk samples, there were significant differences in the proportion of 10 types of cells, including naive cells, plasma cells, and resting CD4 + memory T cells. IGSF5 has low expression in HNSCC, and overexpression of IGSF5 significantly impaired HNSCC cell proliferation., Conclusion: This prognostic risk assessment model can help systematically evaluate the survival prognosis of HNSCC patients and provides a new research direction for the improvement of the survival prognosis of HNSCC patients in clinical practice., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yifei Chen et al.)

Objective: To evaluate the utility of lymph node ratio (LNR) as a prognostic factor for survival and recurrence in surgically treated patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC)., Study Design: Retrospective cohort study., Methods: In this retrospective cohort study of a tertiary healthcare system in a major metropolitan area, we reviewed 169 consecutive patients with HPV-related OPSCC treated using transoral robotic surgery. Univariable and multivariable Cox proportional hazards regression analysis with stratified models were used to compare LNR with other traditional clinicopathologic risk factors forrecurrence and survival. An LNR cutoff was found using the minimal P approach., Results: Multivariable Cox regression models showed that each additional percentage increase in LNR corresponded to an adjusted hazard ratio (HR) of 1.04 (confidence interval [CI] 1.02-1.07). LNR was more significant when adjusted for adequate lymph node yield of ≥ 18 nodes (HR 5.05, 95% confidence interval [CI] 1.38-18.47). The minimal P generated cutoff point at LNR ≥ 17% demonstrated a HR 4.34 (95% CI 1.24-15.2) for disease-free survival., Conclusion: For HPV-related OPSCC, continuous LNR and an LNR threshold of 17% could be helpful in identifying recurrent disease in addition to measures such as lymph node number alone., Level of Evidence: 4., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To investigate differences in epidemiology of oropharyngeal squamous cell carcinoma (OPSCC) with regards to human papillomavirus (HPV), race, and socioeconomic status (SES) using the National Cancer Database (NCDB)., Study Design: Population-based cohort study., Setting: Racial and socioeconomic disparities in survival of OPSCC have been previously acknowledged. However, the distribution of HPV-related cancers and its influence on survival in conjunction with race and SES remain unclear., Subjects and Methods: All patients with OPSCC in the NCDB with known HPV status from 2010 to 2016 were included. Differences in presentation, HPV status, treatment, and outcomes were compared along racial and socioeconomic lines. Univariable and multivariable Cox regression survival analyses were performed., Results: In total, 45,940 patients met criteria. Most were male (38,038, 82.8%), older than 60 years (23,456, 51.5%), and white (40,156, 87.4%), and lived in higher median income areas (>$48,000, 28,587, 62.2%). Two-thirds were HPV positive (31,007, 67.5%). HPV-negative disease was significantly more common in lower SES (<$38,000, 2937, 41.5%, P < .001) and among blacks (1784, 55.3%, P < .001). Median follow-up was 33 months. Five-year overall survival was 81.3% (95% CI, 80.5%-82.1%) and 59.6% (95% CI, 58.2%-61.0%) in HPV-positive and HPV-negative groups, respectively. In univariable and multivariable analyses controlling for HPV status, age, stage, and treatment, black race (hazard ratio [HR], 1.22; 95% CI, 1.11-1.34; P < .001) and low SES (HR, 1.58; 95% CI, 1.45-1.72; P < .001) were associated with worse survival., Conclusion: Significant differences in HPV status exist between socioeconomic and racial groups, with HPV-negative disease more common among blacks and lower SES. When controlling for HPV status, race and SES still influence outcomes in oropharyngeal cancers.

Objective: To investigate the adult outcomes of children with juvenile-onset recurrent respiratory papillomatosis via long-term follow-up., Study Design: Retrospective study., Setting: Beijing Tongren Hospital., Participants: The study includes 121 patients with recurrent respiratory papillomatosis., Main Outcome and Measure: We followed up respiratory papillomatosis patients aged least 14 years and analysed their clinical features based on recurrence-free time., Results: In total, 112 (92.6%) patients underwent three or more operations. The age at initial operation was 4.3 ± 2.9 years; 47.9% (58/121) experienced recurrence and underwent surgical treatment after age 14. At follow-up, 5% (6/121) had died, 41.3% (50/121) had been recurrence-free for 5 years or more (cured group), and 53.7% (65/121) had recurrence in the past 5 years (recurrent group). The age at the last operation was 9.2 ± 4.6 years in the cured group. The overall operation frequency was higher in the recurrence group than in the cured group (17.8 ± 11.9 vs 8.7 ± 6.5). Additionally, the human papillomavirus (HPV) infection and tracheal dissemination rates were higher in the recurrence group than in the cured group (90.8% [59/65] vs 54.0% [27/50] and 26.2% [17/65] vs 10% [5/50], respectively)., Conclusion: The mortality rate for juvenile-onset recurrent respiratory papillomatosis is 5%. Approximately 50% of children experience recurrence and require repeated operations in adulthood. No significant difference in sex, age at initial operation or adjuvant therapy between the cured and recurrent groups was observed; however, significant between-group differences were found in overall operation frequency, aggressive disease, tracheal dissemination of papilloma, and HPV infection., (© 2020 John Wiley & Sons Ltd.)

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known., Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery., Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020., Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73)., Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival., Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival., Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.

Objectives: (1) To estimate the association between neck dissection lymph node yield (LNY) and survival among patients with surgically treated human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). (2) To identify a clinically relevant quality metric for surgical treatment of HPV-related OPSCC., Study Design: Retrospective cohort study., Setting: National Cancer Database., Subjects and Methods: From the National Cancer Database, 4130 patients were identified with HPV-associated OPSCC treated with primary surgery from 2010 to 2016. Based on prior literature, an adequate neck dissection LNY was defined as ≥18 lymph nodes. To determine whether LNY is associated with survival, univariable and multivariable Cox proportional hazards regression was performed. Analysis was stratified by adjuvant therapy regimen., Results: A total of 2113 patients (51.2%) underwent surgery with or without adjuvant radiation (S ± RT), and 2017 patients (48.8%) underwent surgery with adjuvant chemoradiation. LNY ≥18 was associated with a 5-year survival benefit of 7.15% (91.7% for LNY ≥18, 84.5% for LNY <18, P = .004) for the S ± RT cohort on unadjusted survival analysis. For the S ± RT group, LNY ≥18 was associated with decreased hazard of death (hazard ratio, 0.45; 95% CI, 0.29-0.70; P < .001) after adjustment for patient characteristics, TNM staging, surgical margins, extranodal extension, and treating facility characteristics. For surgery with adjuvant chemoradiation, the adjusted hazard ratio estimate for LNY ≥18 was 0.64 (95% CI, 0.41-1.00), but the result was not statistically significant ( P = .052)., Conclusion: An adequate LNY from a neck dissection may affect survival when HPV-related OPSCC is treated with up-front surgery.

Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16 INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development., (© 2020 UICC.)

In a retrospective review, we identified 332 patients with 338 pathologically diagnosed primary oropharyngeal carcinomas (OPC) between January 2013 and March 2020 with known p16/HPV status from a tumor registry at Northwestern Memorial Hospital. The tumors predominantly involved the palatine tonsil (51 %) and the base of the tongue/lingual tonsil (38 %). The most common type of cancer was non-keratinizing squamous cell carcinoma (60 %), and the majority of primaries were p16 positive/HPV-mediated (86 %). A cohort of p16 positive/HPV mediated OPC (27/283, 9.5 %) presented with aggressive clinical behavior, including multiple distant metastases at unusual sites. Tumor size >2 cm and the presence of tumor anaplasia/multinucleation were significantly associated with an increased rate of distant metastases in p16 positive/HPV mediated cases, both in unadjusted and adjusted analyses (all P < 0.05). Of the 332 individuals in the overall cohort, 38 individuals died due to their disease within the observed follow-up time. Among the 283 patients with p16 positive/HPV mediated tumors, survival was estimated at 97 % (95 % CI 95 %, 100 %) at 1 year, 95 % (95 % CI 92 %, 98 %) at 2 years, and 80 % (95 % CI 72 %, 89 %) at 5 years. The presence of tumor anaplasia/multinucleation and distant metastasis were both significantly associated with poorer disease-specific survival in p16 positive/HPV mediated cases (both P < 0.05), with the survival effect of tumor anaplasia/multinucleation likely mediated in part through its association with distant metastasis. For p16 positive/HPV-mediated OPC, age, smoking status, tumor status, and lymph node status were not significantly associated with disease-specific survival in our study., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objective: Characterize the survival impact of smoking on HPV-related (human papillomavirus) oropharyngeal squamous cell carcinoma., Data Sources: Articles from 2000 to 2019 in the PubMed, Embase, and Cochrane Library databases were systematically reviewed for content and inclusion/exclusion criteria., Review Methods: Two reviewers independently analyzed the databases for eligibility and quality of the articles. Demographic data, smoking history, and survival outcomes were recorded. Hazard ratios and 95% CIs were collectively analyzed through a random effects meta-analysis model., Results: Fifteen articles were included in the meta-analysis for overall survival, disease-specific survival, disease-free survival, progression-free survival, and locoregional recurrence outcomes. The overall survival hazard ratio was 2.4 for ever having smoked (95% CI, 1.4-4.0; P = .0006, I 2 = .384) and 3.2 for current smoking (95% CI, 2.2-4.6; P < .0001, I 2 = 0). The hazard ratio for disease-specific survival in current smokers was 6.3 (95% CI, 1.3-29.3; P = .0194, I 2 = 0). Ever smoking had a larger impact on overall survival and disease-specific survival than the 10-pack year smoking threshold., Conclusion: Smoking negatively affects survival in patients with HPV-related oropharyngeal carcinoma across all outcomes. Current smoking during treatment is associated with the greatest reduction in survival, possibly secondary to diminished radiation therapy efficacy.

Importance: Although the survival impact of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is well known, there has been conflicting and scarce evidence on the role of HPV in non-OPSCC., Objective: To undertake a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of all published studies on the association between HPV status and survival outcomes in patients with non-OPSCC, analyzing each site separately., Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to December 16, 2019, for English-language articles., Study Selection: Analysis comprised randomized clinical trials or observational studies that each included at least 10 patients with non-OPSCC in which the presence of HPV was analyzed, survival outcomes were reported, and a clinical follow-up of 1 year or more was performed. Studies excluded were those in which data on OPSCC and non-OPSCC were not distinguished between both cohorts and studies on patients with distant metastatic tumors at diagnosis. Final analysis included outcomes that were analyzed in at least 3 studies., Data Extraction and Synthesis: Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model., Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points were disease-specific survival (DSS) and disease-free survival (DFS)., Results: Of the 3947 articles screened, a total of 22 observational and 2 randomized clinical trials were included in the analysis, representing 24 854 patients. In oral cavity locations, OS was not significantly associated with HPV positivity (hazard ratio [HR], 1.16; 95% CI, 0.83-1.61; I2 = 71%); however, HPV-positive tumors showed worse DFS (HR, 1.81; 95% CI, 1.12-2.91; I2 = 47%). Laryngeal and hypopharyngeal HPV-positive tumors were associated with improved OS (HR, 0.71; 95% CI, 0.54-0.92; I2 = 38% and HR, 0.60; 95% CI, 0.47-0.76; I2 = 0%), respectively, whereas, in nasopharyngeal locations HPV was not associated with OS (HR, 0.82; 95% CI, 0.49-1.38; I2 = 46%) or DSS (HR, 0.55; 95% CI, 0.22-1.42; I2 = 65%)., Conclusions and Relevance: In this meta-analysis of 24 studies, HPV was associated with improved OS in laryngeal and hypopharyngeal locations but not in the oral cavity and the nasopharynx. This information may be useful for future clinical studies of laryngeal and hypopharyngeal tumors and whether HPV status should be incorporated in prognostication of patients with these cancers.

Importance: While early epidemiologic studies ascribed increases in the incidence of human papillomavirus-associated oropharyngeal cancers to middle-aged patients, recent analyses have demonstrated an increasing median age of diagnosis. Treatment of patients older than 70 years is controversial as their inclusion in the practice-defining clinical trials has been limited and the survival benefit conferred by chemotherapy may be outweighed by treatment toxic effects., Objective: To assess the oncologic outcomes of older adults with human papillomavirus-associated oropharyngeal cancer who underwent upfront transoral robotic surgery and pathologic characteristics-guided adjuvant therapy in a large cohort of patients with close follow-up., Design, Setting, and Participants: A retrospective cohort analysis was conducted in a tertiary care academic medical center between January 1, 2010, and December 30, 2017. Patients aged 70 years or older at time of diagnosis with biopsy-proven and surgically resectable p16-positive oropharyngeal cancers were included. Data analysis was conducted from March 1 to June 1, 2020., Exposures: Transoral robotic surgery oropharyngeal resection and neck dissection with pathologic characteristic-guided adjuvant therapy., Main Outcomes and Measures: Three-year estimates of disease-specific survival, overall survival, and disease-free survival, as well as rates of adjuvant therapy (radiotherapy and chemoradiotherapy) and perioperative complications., Results: Seventy-seven patients were included (median age, 73.0; interquartile range, 71.0-76.0; range, 70-89 years); of these, 58 were men (75.3%). Perioperative mortality was 1.3% and the rate of oropharyngeal hemorrhage was 2.6%. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy. The median length of follow-up was 39.6 (range, 0.1-96.2) months, and the 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for disease-specific survival, 90.0% (95% CI, 79.4%-95.0%) for overall survival, and 84.3% (95% CI, 73.4%-91.0%) for disease-free survival., Conclusions and Relevance: The findings of this cohort study suggest that transoral robotic surgery and pathologic characteristic-guided adjuvant therapy can provide beneficial survival outcomes, infrequent perioperative mortality, and, for most carefully selected older adults, obviate the need for chemotherapy.

Several infectious agents are ascertained causes of cancer, but the burden of cancer mortality attributable to carcinogenic infections in Italy is still unknown. To tackle this issue, we calculated the rate and regional distribution of cancer deaths due to infections sustained by seven pathogens ranked as group 1 carcinogenic agents in humans by the International Agency for Research on Cancer. Population attributable fractions related to these agents were applied to annual statistics of cancer deaths coded according to the 10th International Classification of Diseases. The estimated burden of cancer mortality attributable to carcinogenic infections in Italy during the period 2011-2015 was 8.7% of all cancer deaths registered yearly, on average. Approximately 60% of deaths occurred in men, and almost the whole burden was due to four infectious agents ( Helicobacter pylori , hepatitis C virus, high-risk human papillomavirus, and hepatitis B virus). The analysis of regional distribution showed a higher number of infection-related cancer deaths in the northern regions, where the estimates reached 30 (Liguria) and 28 (Friuli Venezia Giulia) deaths per 100,000 inhabitants in 2015. Since one-twelfth of cancer deaths were attributable to these modifiable risk factors, the implementation of appropriate prevention and treatment interventions may help to reduce the impact of these infections on cancer mortality.

Oncology is a highly siloed field of research in which sub-disciplinary specialization has limited the amount of information shared between researchers of distinct cancer types. This can be attributed to legitimate differences in the physiology and carcinogenesis of cancers affecting distinct anatomical sites. However, underlying processes that are shared across seemingly disparate cancers probably affect prognosis. The objective of the current study is to investigate whether multitask learning improves 5-year survival cancer patient survival prediction by leveraging information across anatomically distinct HPV related cancers. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program database. The study cohort consisted of 29,768 primary cancer cases diagnosed in the United States between 2004 and 2015. Ten different cancer diagnoses were selected, all with a known association with HPV risk. In the analysis, the cancer diagnoses were categorized into three distinct topography groups of varying specificity. The most specific topography grouping consisted of 10 original cancer diagnoses differentiated by the first two digits of the ICD-O-3 topography code. The second topography grouping consisted of cancer diagnoses categorized into six distinct organ groups. Finally, the third topography grouping consisted of just two groups, head-neck cancers and ano-genital cancers. The tasks were to predict 5-year survival for patients within the different topography groups using 14 predictive features which were selected among descriptive variables available in the SEER database. The information from the predictive features was shared between tasks in three different ways, resulting in three distinct predictive models: 1) Information was not shared between patients assigned to different tasks (single task learning); 2) Information was shared between all patients, regardless of task (pooled model); 3) Only relevant information was shared between patients grouped to different tasks (multitask learning). Prediction performance was evaluated with Brier scores. All three models were evaluated against one another on each of the three distinct topography-defined tasks. The results showed that multitask classifiers achieved relative improvement for the majority of the scenarios studied compared to single task learning and pooled baseline methods. In this study, we have demonstrated that sharing information among anatomically distinct cancer types can lead to improved predictive survival models., Competing Interests: The authors have declared that no competing interests exist.

We assessed the prevalence of HPV DNA in a large series of Chinese penile cancer and examine its association with the histological subtype, p16 INK4a expression, and prognosis. We pathologically categorized 226 invasive penile squamous cell carcinomas and assessed HPV genotyping by real-time PCR and p16 INK4a immunohistochemistry. The results were correlated with histopathological and clinical parameters and disease-specific survival (DSS). HPV DNA was detected in 32.7% (74/226) of penile cancer cases. The most frequent genotype was HPV 16 (64/74, 86.5%), followed by HPV 18 (6/74, 8.1%). Fifty-nine (26.1%) cases were positive for the p16 INK4a expression, and p16 INK4a expression had a sensitivity of 56.8% (95% CI, 45.2-68.3%) and a specificity of 88.8% (95% CI, 83.8-93.9%) for defining HPV status. HPV DNA (P = 0.019), p16 INK4a (P = 0.038), age (P = 0.018), grade of differentiation (P = 0.001), lymph nodes (P < 0.001), T stage (P < 0.001), M stage (P < 0.001), and lymphovascular invasion (LVI, P = 0.001) were prognostic factors for DSS. HPV-positivity (HR 0.334; 95% CI, 0.158-0.705, P = 0.004) was still a significant prognostic factor for DSS in the multivariate Cox regression model. HPV DNA was observed in one third of Chinese penile carcinoma cases. The p16INK4a expression can indicate high-risk human papillomavirus (HR-HPV). HPV-positive penile tumors confer a survival benefit over HPV-negative tumors.

Cervical cancer (CC) has a high incidence and mortality rate, with a low 5-year survival rate, and human papillomavirus (HPV) is one of its carcinogenic risks. However, little evidence exists on the impact of HPV infection on the survival of patients with CC. In the present study, the CC cohort and immune genes were downloaded from the TCGA database and the ImmPort database, respectively. Subsequently, the Gene Set Enrichment Analysis was performed and found that HPV status was involved in multiple immune signaling pathways, which revealed that HPV infection might play critical roles in the immune response. Then seven prognostic immune genes were identified according to HPV status in CC. Using the seven immune genes, we established an immune risk score (IRS) signature and the Kaplan-Meier curve showed that high IRS was significantly correlated with poor prognosis of CC in both the training sets (HR = 2.32, 95% CI = 1.66-3.33; AUC = 0.712) and the validation sets (HR = 1.38, 95% CI = 1.02-1.85 and AUC = 0.583 in TCGA-HNSCC; HR = 2.58, 95% CI = 1.364-4.893, AUC = 0.676 in GSE44001). A nomogram of IRS combined with clinical features was established, and further analyses demonstrated that the power of the nomogram to predict the prognosis of CC was more reliable than that of a single independent factor. In conclusion, this study provided a more comprehensive understanding of the correlation between HPV and immune mechanisms as well as a novel signature that can effectively predict the prognosis of CC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients., Methods: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05)., Results: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively., Conclusions: Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Background: Human papillomavirus (HPV) is associated with a substantial percentage of cervical cancer, and a significant percentage of anal, penile, vaginal, vulvar, oral cavity, oropharyngeal, and laryngeal cancers. Understanding the burden and trends of HPV-attributable cancers is crucial to HPV prevention strategies. In the current study, the authors estimated the latest burden and trends of HPV-attributable cancers in China., Methods: Data from the following sources were used. The number of new cancer cases and cancer deaths in China were estimated based on the China Cancer Registry Annual Report. The population-attributable fraction was estimated using pooled high-risk HPV prevalence and biomarker-positive rates, which were calculated using random effects meta-analyses. Cancer burden estimates were stratified by anatomic site, sex, and age., Results: In 2015, a total of 110,650 new cancer cases and 36,714 cancer deaths attributable to HPV infection were estimated to have occurred in China, of which cervical cancer accounted for 85.6% and 78.1%, respectively. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of HPV-attributable cancers were 5.63 and 1.81 per 100,000 person-years, respectively. The ASIR and ASMR both varied by anatomic site, with the highest rates noted for cervical cancer at 4.83 and 1.42 per 100,000 person-years, respectively. Between 2005 and 2015, the ASIR and ASMR demonstrated significant upward trends for all HPV-attributable cancers combined., Conclusions: Between 2005 and 2015, cervical cancer accounted for the vast majority of HPV-attributable cancers and its incidence and mortality increased rapidly in China. The comprehensive prevention of cervical cancer remains the most important target in the prevention of HPV-attributable cancers., (© 2020 American Cancer Society.)

Objective: To determine the prognostic significance of smoking in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) when considering American Joint Committee on Cancer eighth edition (AJCC-8) stage., Study Design: Retrospective cohort study., Methods: Three hundred seventeen HPV-positive OPSCC patients with known AJCC-8 stage and smoking status (<10 or ≥10 pack-years) seen at a tertiary center from 1997 to 2017 were studied. We used the Kaplan-Meier method to compare 5-year overall survival (OS) by smoking status and by clinical AJCC-8 stage and smoking status combined. Hazard ratios (HRs) were estimated with Cox proportional hazard regression for the independent effects of smoking and AJCC-8 stage. We also studied pathologic stage and estimated the combined effects of smoking and clinical stage., Results: The ≥10 pack-years smokers had worse 5-year OS than <10 pack-years smokers (93.6%; 95% confidence interval (CI): 89.7-97.8 vs. 82.3%; 95% CI: 76.0%-89.1%). When stratified by AJCC-8 clinical stage, only stage I <10 pack-years smokers (98.7%; 95% CI: 96.3%-100.0%) had significantly better 5-year OS than their ≥10 pack-years (84.8%; 95% CI: 76.4%-94.1%) counterparts. In a multivariable analysis, ≥10 pack-years smoking was associated with increased hazard of death when adjusting for AJCC-8 clinical (HR: 2.52; 95% CI: 1.16-5.46) and pathologic (HR: 5.21; 95% CI: 1.47-18.5) stage. In both analyses, stage III patients demonstrated worse survival than stage I, and smoking had greater impact at lower stages., Conclusions: Smoking is a negative prognosticator in HPV-positive OPSCC and interacts with AJCC-8 clinical stage. It is important to understand the impact of smoking in HPV-positive disease when considering treatment plans and deintensification trials., Level of Evidence: 2b Laryngoscope, 130: 1961-1966, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To analyze survival outcomes in patients with oropharygeal cancer treated with primary intensity modulated radiotherapy (IMRT) using decision tree algorithms., Methods: A total of 273 patients with newly diagnosed oropharyngeal cancer were identified between March 2010 and December 2016. The data set contained nine predictor variables and a dependent variable (overall survival (OS) status). The open-source R software was used. Survival outcomes were estimated by Kaplan-Meier method. Important explanatory variables were selected using the random forest approach. A classification tree that optimally partitioned patients with different OS rates was then built., Results: The 5 year OS for the entire population was 78.1%. The top three important variables identified were HPV status , N stage and early complete response to treatment. Patients were partitioned in five groups on the basis of these explanatory variables., Conclusion: The proposed classification tree could help to guide future research in oropharyngeal cancer field., Advances in Knowledge: Decision tree method seems to be an appropriate tool to partition oropharyngeal cancer patients.

Background and Objective: Different studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection., Material and Methods: Retrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990-2016 for whom information on HPV status was available., Results: 14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours., Conclusions: Regional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas., (Copyright © 2019 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: Survival outcomes for human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC) treated with surgery alone are unclear. To increase understanding, we assessed overall survival (OS) outcomes using the national cancer database (NCDB)., Methods: We conducted a retrospective analysis of OS of 736 NCDB HPV + OPSCC patients who underwent surgery alone from 2010 to 2014 using univariate and multivariate analyses and the Kaplan-Meir method., Results: Multivariable analysis found the following independent risk factors for death: American Joint Commission on Cancer (AJCC) 8th edition pathologic stage(p)N2 versus pN0 disease (hazard ratio [HR], 5.5; P = 0.000006), macroscopic extranodal extension (ENE) versus non-ENE (HR, 4.9; P < 0.02), a positive lymph nodes (LN) percentage of ≥10% (HR, 4.2; P = 0.0002), and five or more positive LNs (HR, 4.9; P = 0.00004). Three-year OS was significantly worse for AJCC 8th edition pN2 versus pN0 but not for 7th edition pN2 versus pN0 disease. Five-year OS was significantly worse for positive versus negative surgical margins, AJCC 8th edition stage II versus I, and either microscopic or macroscopic ENE versus non-ENE positive LNs. For 523 (71%) AJCC 8th edition stage I patients and for 283 (38%) patients who were pT1-T2, with negative margins, pN0-N1, with ≤4 pathologic LNs, without ENE, and with >20 LNs removed during neck dissection, the 3-year OS rates were 93% and 95%, respectively, and the 5-year OS rates were 91% and 95%, respectively., Conclusion: In the context of the lack of detail and possible inaccuracies found in the NCDB, surgery alone for AJCC 8th edition stage I HPV + OPSCC, particularly pT1-T2, pN0-N1 with ≤4 pathologic LNs, without ENE, and with negative surgical margins has a high OS., Level of Evidence: 4 Laryngoscope, 130:E423-E435, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To investigate the incidence and survival of Vulvar Squamous Cell Carcinoma (VSCC) by etiology over a 27 year period., Method: Retrospective case-note and pathology slide review of 390 consecutive VSCC, treated at a Centralized Cancer Centre covering half New Zealand's population, 1990-2016. Incidence was calculated in 5-6 year cohorts and correlated with precursor of the VSCC, age and stage., Results: Age-standardized incidence of all VSCC did not change significantly, however age standardized incidence of HPV-dependent VSCC increased significantly, from 0.55/100,000 (95% CI 0.38-0.72) in 1991-2000 to 0.83/100,000 (95% CI 0.68-0.97) in 2001-2016, with a significant decrease in the incidence of HPV-independent VSCC, from 0.76/100,000 (95% CI 0.58-0.95) to 0.54/100,000 (95%CI 0.43-0.65). HPV-dependent VSCC in women ≥50 years increased significantly from 0.75/100,000 (95% CI 0.45-1.17) to 1.43/100,000 (95% CI 1.14-1.77), with no significant change seen in younger women. HPV-independent VSCC in women ≥50 years has decreased significantly from 2.53/100,000 (95% CI 1.95-3.23) to 1.62/100,000 (95% CI 1.31-1.98) with no change in younger women. The proportion of HPV-dependent VSCC has increased from 25% to 50%. Age standardized death rate from VSCC has not changed significantly from 0.22/100,000 (95% CI 0.10-0.34) in 2001-5 to 0.27/100,000 (95% CI 0.15-0.40) in 2011-16. Five year survival for HPV-dependent VSCC was 93% and 68% for HPV-independent VSCC (p < .0001)., Conclusions: HPV-dependent VSCC incidence has increased significantly and now accounts for half of VSCC, with a significant rise in women over 50. HPV-dependent and independent VSCC have different prognoses and should be registered and investigated separately., (Copyright © 2020 Elsevier Inc. All rights reserved.)