Systematic evaluation and meta-analysis of the prognosis of down-staging human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma using cetuximab combined with radiotherapy instead of cisplatin combined with radiotherapy.

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.

Upfront surgery versus definitive radiotherapy: competing risk analyses for cancer-specific and noncancer mortality in oropharyngeal cancer.

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.

Predictors of short-term mortality in HIV-infected patients admitted to intensive care unit / Fatores preditores de mortalidade de curto prazo em pacientes infectados com HIV admitidos em unidade de terapia intensiva

INTRODUCTIONn: Historically, complications of HIV infection have been related to admissions to the Intensive Care Unit (ICU). Despite therapeutic advances, the results of the analysis of prognostic factors in patients with HIV/AIDS have varied, including late diagnosis and failure to adhere to antiretroviral treatment. OBJECTIVE: To evaluate the predictors of short-term mortality in HIV-infected patients admitted to the ICU, as well as their sociodemographic and clinical characteristics. METHODS: A retrospective cohort study including patients admitted to the ICU of a teaching hospital from 2003 through 2012. Data were collected from medical records after the Institutional Review Board approval. RESULTS: 148 HIV-infected patients were identified and 131 were eligible. Among included patients, 42.75% were HIV new diagnoses and 5.34% had no information about the time of diagnosis. The main reasons for admission to the ICU were respiratory failure and sepsis while mortality was 70.23% between 2003 and 2012. Among the risk factors for mortality were low albumin, high APACHE, low CD4+ T lymphocyte count, and not using antiretroviral therapy. CONCLUSION: Despite the availability of diagnosis and treatment for HIV-infected individuals, the number of new cases of advanced Aids diagnosed in high-complexity services such as ICU is high, as well as the non-use of combination antiretroviral therapy. It is necessary to strengthen anti-HIV screening to detect and treat more cases in the early stages.

INTRODUÇÃO: Historicamente, as complicações da infecção pelo HIV estavam relacionadas às internações em Unidade de Terapia Intensiva (UTI). Apesar dos avanços terapêuticos, os fatores prognósticos em pacientes com HIV/AIDS têm variado, incluindo diagnóstico tardio e não adesão ao tratamento antirretroviral. OBJETIVO: Avaliar os fatores preditores de mortalidade a curto prazo em pacientes infectados pelo HIV internados em UTI, bem como suas características sociodemográficas e clínicas. MÉTODOS: Estudo de coorte retrospectivo incluindo pacientes internados na UTI de um hospital universitário entre 2003 a 2012. Os dados foram coletados dos prontuários médicos após a aprovação pelo Comitê de Ética em Pesquisa com Seres Humanos. RESULTADOS: 148 pacientes infectados pelo HIV foram identificados e 131 eram elegíveis. Entre os pacientes incluídos, 42,75% possuíam diagnósticos recente de HIV e 5,34% não possuíam informação sobre o momento do diagnóstico. Os principais motivos de admissão na UTI foram insuficiência respiratória e sepse, enquanto a mortalidade foi 70,23% entre 2003 e 2012. Entre os fatores de risco para mortalidade identificou-se albumina baixa, APACHE alto, baixa contagem de linfócitos T CD4+ e não uso de terapia antirretroviral. CONCLUSÃO: Apesar da disponibilidade de diagnóstico e tratamento para indivíduos infectados pelo HIV, é elevado o número de casos novos em estágio avançado de Aids diagnosticados em serviços de alta complexidade, como UTI, e o não uso de terapia antirretroviral combinada. É necessário fortalecer a triagem anti-HIV, bem como aumentar a repetição da testagem anti-HIV para detectar e tratar mais casos em estágios iniciais.

CD161 expression and regulation defines rapidly responding effector CD4+ T cells associated with improved survival in HPV16-associated tumors.

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)ß1. 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.

Combination of IDO1high and CCL19low expression in the tumor tissue reduces survival in HPV positive cervical cancer.

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.

Tracheotomy as a predictor of remission and demise for juvenile-onset recurrent respiratory papillomatosis.

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.

TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer.

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.

HPV transcript expression affects cervical cancer response to chemoradiation.

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.

Immunotherapy Advances in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Its Relationship With Human Papillomavirus.

Head and neck cancer (HNC) is the sixth most common malignancy worldwide; head and neck squamous cell carcinoma (HNSCC) account for the most cases of HNC. Past smoking and alcohol consumption are common risk factors of HNSCC; however, an increasing number of cases associated with human papillomavirus (HPV) infection have been reported in recent years. The treatment of HNSCC is integrated and multimodal including traditional surgery, radiotherapy, chemotherapy, and targeted therapy. Since pembrolizumab was approved in 2016, an increasing number of studies have focused on immunotherapy. However, not all of HNSCC patients have a better outcome on immunotherapy. Immunotherapy has been reported to be more effective in HPV-positive patients, but its molecular mechanism is still unclear. Some researchers have proposed that the high proportion of infiltrating immune cells in HPV-positive tumors and the difference in immune checkpoint expression level may be the reasons for their better response. As a result, a series of individualized immunotherapy trials have also been conducted in HPV-positive patients. This paper summarizes the current status of HNSCC immunotherapy, individualized immunotherapy in HPV-positive patients, and immune differences in HPV-positive tumors to provide new insights into HNSCC immunotherapy and try to identify patients who may benefit from immunotherapy.

Locoregional Recurrence in p16-Positive Oropharyngeal Squamous Cell Carcinoma After TORS.

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.

Oropharyngeal Squamous Cell Carcinoma With Discordant p16 and HPV mRNA Results: Incidence and Characterization in a Large, Contemporary United States Cohort.

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.

Plasma cell marker, immunoglobulin J polypeptide, predicts early disease-specific mortality in HPV+ HNSCC.

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.

Identification of Immune-Related Prognostic Biomarkers Associated with HPV-Positive Head and Neck Squamous Cell Carcinoma.

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.

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody.

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.

Long-term Outcomes of Juvenile Onset Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

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.

Long-term outcomes of juvenile-onset recurrent respiratory papillomatosis.

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.

Insurance Status as a Predictor of Treatment in Human Papillomavirus Positive Oropharyngeal Cancer.

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.

Prognostic Significance of Extranodal Extension in HPV-Mediated Oropharyngeal Carcinoma: A Systematic Review and Meta-analysis.

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 I2 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], I2 = 35%; rENE HR, 2.64 [95% CI, 1.46-4.78], I2 = 75%) and distant recurrence (pENE HR, 3.23 [95% CI, 1.25-8.33], I2 = 0%; rENE HR, 3.83 [95% CI, 1.88-7.80], I2 = 0%). Neither pENE nor rENE was associated with locoregional recurrence (pENE HR, 0.75 [95% CI, 0.20-2.84], I2 = 0%; rENE HR, 2.03 [95% CI, 0.86-4.79], I2 = 0%). pENE was not associated with disease-specific survival (pENE HR, 1.45 [95% CI, 0.84-2.49], I2 = 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.

Lymph Node Ratio in HPV-Associated Oropharyngeal Cancer: Identification of a Prognostic Threshold.

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.