Oropharyngeal Carcinoma Research Articles

Malignancy Associated with Low-Risk HPV6 and HPV11: A Systematic Review and Implications for Cancer Prevention.

High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0-5.5% for penile and 0-87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV.

Analysis of the anatomical distribution of HPV genotypes in head and neck squamous papillomas.

Squamous papillomas (SPs) of the head and neck are usually benign lesions associated with human papilloma virus (HPV) infection. However, the reported HPV detection rates vary widely, especially with respect to anatomical distribution. The etiology of SPs in the head and neck remains unclear; analyzing HPV genotypes of SPs based on anatomical sites could assist in clarifying the pathogenesis of SPs in the head and neck. Therefore, the aim of this study was to review the prevalence, subtypes, and anatomical distribution of HPV in head and neck SPs at a hospital in China; we also investigated whether p16, a marker of HPV infection in oropharyngeal carcinoma, could serve as a surrogate marker for HPV in head and neck SPs. The presence of HPV DNA of 23 types (5 low-risk HPV and 18 high-risk HPV types) was detected via real-time PCR. p16 immunohistochemistry was performed using SP sections. Age, sex, anatomical location, and HPV subtype were recorded for each case. In total, 105 SPs were identified, including 47 in the larynx, 42 in the pharynx, 6 in the external auditory canal (EAC), 5 in the oral cavity, and 5 in the nasal cavity. HPV was found in 57 (54.3%) cases, with the highest positivity rate in the larynx (46/47; 97.9%). Only 5/42 (11.9%) patients showed HPV positivity in the pharynx. HPV incidence was highly dependent on the anatomical site. SPs in the larynx and EAC were more likely to carry HPV than those in other anatomical sites. High-risk HPV infections were rarely associated with SPs in the head and neck region. The sensitivity and specificity of p16 immunohistochemistry for HPV infection were 88% and 96%, respectively. There may be an association between p16 and HPV infection in head and neck SPs, but further studies are needed to validate this assertion.

De-escalated radiation for human papillomavirus virus-related oropharyngeal cancer: evolving paradigms and future strategies.

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma has increased dramatically in recent years reaching epidemic-like proportions. Data has emerged not only showing that these cancers are a unique entity with distinct molecular characteristics but that they also have a significantly improved prognosis as a result of their exquisite radiosensitivity compared to their HPV-negative counterparts. This, it has been increasingly suggested that these tumors can be targeted with de-escalated approaches using reduced doses of radiation. The overriding goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain the high rates of cure and preserve quality of life for appropriately selected patients with this disease. However, these studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in treatment, inclusion criteria, and follow-up. As the data continues to mature on de-escalation, it is unquestionable that treatment paradigms for this disease will evolve. The ongoing quest to define a standard regimen comprises the subject of this review.

The Diagnostic and Prognostic Value of EBUS-TBNA for Intrathoracic Metastasis in Previously Treated Patients With Head and Neck Cancer.

The present study assessed the diagnostic and prognostic significance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for suspected intrathoracic metastasis after HNC treatment. A retrospective analysis was conducted on 75 patients with a prior history of head and neck cancer treatment who underwent EBUS-TBNA for suspected intrathoracic metastases between March 2012 and December 2021. A total of 126 targeted lesions, including 107 mediastinal/hilar lymph nodes and 19 intrapulmonary/mediastinal masses, were sampled. The metastatic head and neck cancer (HNC) cases detected by EBUS-TBNA consisted of nasopharyngeal carcinoma (n = 24), oropharyngeal carcinoma (n = 3), hypopharynx carcinoma (n = 6), laryngeal carcinoma (n = 6), and oral cavity carcinoma (n = 6). Cases with negative EBUS-TBNA results consisted of tuberculosis (n = 9), sarcoidosis (n = 3), anthracosis (n = 9), and reactive lymphadenitis (n = 9). Six false-negative cases were found among the 75 patients with suspected intrathoracic metastases. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the EBUS-TBNA procedure for metastatic HNC were 88.2, 100.0, 100.0, 80, and 92.0%, respectively. The diagnosis of HNC intrathoracic metastasis by EBUS-TBNA correlated with an adverse prognosis in terms of overall survival (OS) (P = .008). The log-rank univariate analysis and Cox regression multivariate analysis results indicated that the detection of metastatic HNC through EBUS-TBNA was a significant independent prognostic factor for patients with HNC who had received prior treatment. Endobronchial ultrasound-guided transbronchial needle aspiration is a safe, effective, and minimally invasive procedure for assessing suspected intrathoracic metastasis in HNC patients after treatment. The intrathoracic metastasis detected by EBUS-TBNA has crucial prognostic significance in previously treated HNC patients.

Dental hygienists and dentists as providers of brush biopsies for oral mucosa screening.

Oral cancer is a severe and potentially fatal disease usually starting in the squamous epithelium lining the oral cavity. Together with oropharyngeal carcinoma, it is the fifth to sixth most common malignancy worldwide. To limit the increase in the global oral cancer incidence over the past two decades, the World Health Assembly adopted a resolution urging member states to integrate preventive measures such as engagement and training of dental personnel in screening, early diagnosis, and treatment into their national cancer control programs. The aim of this study was to investigate if dental hygienists (DHs) and dentists (Ds) in general dental practice care can be entrusted to perform brush sampling of oral potentially malignant disorders (OPMDs), and to evaluate their level of comfort in performing brush biopsies. Participants were five DHs and five Ds who received one day of theoretical and clinical training in oral pathology to identify OPMDs (leukoplakia [LP], erythroplakia [EP], and oral lichen planus [OLP]), and perform brush sampling for PAP cytology and high-risk human papillomavirus (hrHPV) analysis. Out of 222 collected samples, 215 were adequate for morphological assessment and hrHPV analysis. All the participants agreed that sample collection can be incorporated in DHs and Ds routine clinical duties, and most of them reported that sample collection and processing was easy/quite easy. Dentists and DHs are capable of collecting satisfactory material for cytology and hrHPV analysis. All the participating DHs and Ds were of the opinion that brush sampling could be handled routinely by DHs and Ds in GDP.

Forecasting Rural and Urban Otolaryngologists, Radiation Oncologists, and Oropharyngeal Carcinoma.

To forecast oropharyngeal carcinoma (OPC) incidence with otolaryngologist and radiation oncologist numbers per population by rural and urban counties through 2030. Incident OPC cases were abstracted from the Surveillance, Epidemiology, and End Results 19 database, and otolaryngologists and radiation oncologists from the Area Health Resources File by county from 2000 to 2018. Variables were analyzed by metropolitan counties with over 1,000,000 people (large metros), rural counties adjacent to a metro (rural adjacent), and rural counties not adjacent to a metro (rural not adjacent). Data were forecasted via an unobserved components model with regression slope comparisons. Per 100,000 population, forecasted OPC incidence increased from 2000 to 2030 (large metro: 3.6 to 10.6 cases; rural adjacent: 4.2 to 11.9; rural not adjacent: 4.3 to 10.1). Otolaryngologists remained stable for large metros (2.9 to 2.9) but declined in rural adjacent (0.7 to 0.2) and rural not adjacent (0.8 to 0.7). Radiation oncologists increased from 1.0 to 1.3 in large metros, while rural adjacent remained similar (0.2 to 0.2) and rural not adjacent increased (0.2 to 0.6). Compared to large metros, regression slope comparisons indicated similar forecasted OPC incidence for rural not adjacent (p = 0.58), but greater for rural adjacent (p < 0.001, r = 0.96). Otolaryngologists declined for rural regions (p < 0.001 and p < 0.001, r = -0.56, and r = -0.58 for rural adjacent and not adjacent, respectively). Radiation oncologists declined in rural adjacent (p < 0.001, r = -0.61), while increasing at a lesser rate for rural not adjacent (p = 0.002, r = 0.96). Rural OPC incidence disparities will grow while the relevant, rural health care workforce declines. NA Laryngoscope, 134:136-142, 2024.

Oncological results of salvage treatment in patients with oropharynx carcinoma treated with radiotherapy

ObjectiveTo evaluate the possibilities of salvage after local recurrence in patients with oropharyngeal carcinomas treated with radiotherapy, and to analyse the prognostic factors related to the final control of the disease. MethodsRetrospective study of 596 patients with oropharyngeal carcinoma treated with radiotherapy during the period 1991–2018. ResultsOne hundred and eighty-one patients (30.4%) had a local recurrence. Of the patients with a local recurrence, 51 (28.2%) were treated with salvage surgery. Variables that were associated with the patient not receiving salvage surgery were age greater than 75 years, tumour location in the posterior hypopharyngeal wall, an initial tumour extent cT4, and a recurrence-free interval of less than 6 months. Five-year specific survival of patients treated with salvage surgery was 19.1% (95% CI: 7.3%–30.9%). Variables that were related to specific survival were extent of recurrence and status of resection margins. Final tumour control was not achieved in any of the patients with extensive recurrence (rpT3−4, n = 25) or positive resection margins (n = 22). ConclusionPatients with oropharyngeal carcinomas treated with radiotherapy with local tumour recurrence have a limited prognosis. Most patients (71.8%) were not considered candidates for salvage surgery. The 5-year specific survival of patients treated with salvage surgery was 19.1%.

Spatially-aware clustering improves AJCC-8 risk stratification performance in oropharyngeal carcinomas

ObjectiveEvaluate the effectiveness of machine learning tools that incorporate spatial information such as disease location and lymph node metastatic patterns-of-spread, for prediction of survival and toxicity in HPV+ oropharyngeal cancer (OPC). Materials & methods675 HPV+ OPC patients that were treated at MD Anderson Cancer Center between 2005 and 2013 with curative intent IMRT were retrospectively collected under IRB approval. Risk stratifications incorporating patient radiometric data and lymph node metastasis patterns via an anatomically-adjacent representation with hierarchical clustering were identified. These clusterings were combined into a 3-level patient stratification and included along with other known clinical features in a Cox model for predicting survival outcomes, and logistic regression for toxicity, using independent subsets for training and validation. ResultsFour groups were identified and combined into a 3-level stratification. The inclusion of patient stratifications in predictive models for 5-yr Overall survival (OS), 5-year recurrence free survival, (RFS) and Radiation-associated dysphagia (RAD) consistently improved model performance measured using the area under the curve (AUC). Test set AUC improvements over models with clinical covariates, was 9 % for predicting OS, and 18 % for predicting RFS, and 7 % for predicting RAD. For models with both clinical and AJCC covariates, AUC improvement was 7 %, 9 %, and 2 % for OS, RFS, and RAD, respectively. ConclusionIncluding data-driven patient stratifications considerably improve prognosis for survival and toxicity outcomes over the performance achieved by clinical staging and clinical covariates alone. These stratifications generalize well to across cohorts, and sufficient information for reproducing these clusters is included.

Circulating tumour HPV16 DNA quantification – A prognostic tool for progression-free survival in patients with HPV-related oropharyngeal carcinoma receiving curative chemoradiotherapy

Background and PurposeCirculating tumour (ct) human papillomavirus (HPV) DNA is detectable in HPV-related oropharyngeal carcinoma (OPSCC) patients and has the potential to become an important clinical tool. This study aimed to evaluate the prognostic significance of ctHPV16-DNA kinetics during treatment with chemoradiotherapy in HPV-related OPSCC. Patients with p16-positive OPSCC recruited to the ARTSCAN III trial, comparing radiotherapy plus cisplatin with radiotherapy plus cetuximab, constituted the study cohort. Materials and methodsBlood samples before start and at the end of treatment of 136 patients were analysed. ctHPV16-DNA was quantified by real-time (q)PCR. The correlation between ctHPV16-DNA levels and tumour burden was investigated with Pearson regression analysis. The prognostic value of ctHPV16-DNA levels at baseline and decline during treatment was evaluated by area-under-the-curve (AUC) calculations and analysed with univariable and multivariable Cox proportional hazards models. ResultsctHPV16-DNA was detectable with qPCR in 108/136 patients before start of treatment and cleared in 74% of these patients at the end of treatment. Disease burden was significantly correlated with baseline ctHPV16-DNA levels (R = 0.39, p=<0.001). Both lower baseline levels and AUC-ctHPV16DNA were associated with improved progression-free survival (p = 0.01 and p < 0.001), overall survival (p = 0.013 and p = 0.002), but not local tumour control (p = 0.12 and p = 0.2, respectively), with a stronger association for AUC-ctHPV16DNA (likelihood ratio test 10.5 vs 6.5 in Cox regression analyses of progression-free survival). In multivariable analysis including tumour volume (GTV-T) and treatment allocation (cisplatin vs cetuximab), AUC-ctHPV16DNA remained a significant prognostic marker of progression-free survival. ConclusionctHPV16-DNA is an independent prognostic factor in HPV-related OPSCC.

Data from the 2022 ASCO Annual Meeting on surgical therapy

Last year, studies on immuno-oncologic treatment approaches for recurrent or metastatic head and neck cancer were the main focus at the two major international cancer congresses of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). The success of these therapeutic strategies has led to many new studies, including their use in the neoadjuvant setting. This review article summarizes presented studies from ASCO 2022 in which surgical therapy is the focus of the study protocol and also includes study results on neoadjuvant treatment strategies. No surgical trials were presented at ESMO 2022. At ASCO 2022 as well as in previous years, it became increasingly clear that treatment de-escalation in the context of human papillomavirus (HPV)-associated oropharyngeal carcinoma treatment involving surgical measures appears to be oncologically safe and functionally beneficial. In addition, anumber of studies indicate that in the setting of neoadjuvant administration of immuno-oncologic agents, aproportion of patients have pathologic complete remission. In this fraction of patients, which is usually significantly smaller than 50%, survival data are better than in those who have already failed to respond to neoadjuvant therapy. Unfortunately, however, significant toxicities or tumor progression with the risk of inoperability were also seen under these current therapeutic regimens, leading to discontinuation of therapy in 5-20% of cases. It remains to be seen whether neoadjuvancy with immune checkpoint inhibitors can establish itself, in contrast to the failed attempts of the past with the use of cytostatics.

Oral cavity and oropharyngeal carcinoma disparities in age and survival in Indigenous and non-Indigenous populations of Queensland

ObjectivesTo investigate the risk and prognosis of oral squamous cell carcinoma (SCC) between Indigenous and non-Indigenous populations of Queensland.Materials and methodsRetrospective analysis of data from the Queensland Cancer Registry (QCR) between the years 1982–2018. Main outcome measures were age at diagnosis and cumulative survival to compare the risk and prognosis of oral SCC between the populations.Results9424 patients with self-declared ethnicity were identified with oral SCC from the QCR, with a male to female ratio of 2.56:1. Of these patients, 9132 were non-Indigenous (96.9%) and 292 Indigenous (3.1%). Indigenous people were significantly younger at diagnosis (mean (SD) age 54.3 (10.1) years), compared to 62.0 (12.1) years in non-Indigenous people. Mean survival in the full cohort was 4.3 years (SD: 5.6), with Indigenous people presenting a significant shorter mean survival of 2.0 years (SD: 3.5) when compared with 4.4 years (SD: 5.7) in non-Indigenous people (p < 0.001).ConclusionsIndigenous Australians are diagnosed at a significantly younger age and present with worse survival and poorer prognosis. Due to missing variables in the Queensland Cancer Registry, it is not possible in the current study to ascertain the scientific or social reasons behind these disparities.Clinical relevanceResults from this study can inform public policy and raise awareness in Queensland regarding disparity in oral cancer prognosis.

CT radiomic signature predicts survival and chemotherapy benefit in stage I and II HPV-associated oropharyngeal carcinoma

Chemoradiation is a common therapeutic regimen for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients benefit from chemotherapy, especially patients with low-risk characteristics. We aim to develop and validate a prognostic and predictive radiomic image signature (pRiS) to inform survival and chemotherapy benefit using computed tomography (CT) scans from 491 stage I and II HPV-associated OPSCC, which were divided into three cohorts D1–D3. The prognostic performance of pRiS was evaluated on two test sets (D2, n = 162; D3, n = 269) using concordance index. Patients from D2 and D3 who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Seven features were selected to construct pRiS, which was found to be prognostic of overall survival (OS) on univariate analysis in D2 (hazard ratio [HR] = 2.14, 95% confidence interval [CI], 1.1–4.16, p = 0.02) and D3 (HR = 2.74, 95% CI, 1.34–5.62, p = 0.006). Chemotherapy was associated with improved OS for high-pRiS patients in D2 (radiation vs chemoradiation, HR = 4.47, 95% CI, 1.73–11.6, p = 0.002) and D3 (radiation vs chemoradiation, HR = 2.99, 95% CI, 1.04–8.63, p = 0.04). In contrast, chemotherapy did not improve OS for low-pRiS patients, which indicates these patients did not derive additional benefit from chemotherapy and could be considered for treatment de-escalation. The proposed radiomic signature was prognostic of patient survival and informed benefit from chemotherapy for stage I and II HPV-associated OPSCC patients.

Incidence and survival of oropharyngeal carcinoma patients and the development of HPV-testing prevalence in North Rhine-Westphalia: A Cancer Registry analysis from 2008-2018.

e18070 Background: Oropharyngeal cancer (OPC) is caused by tobacco and alcohol or by HPV infection, which is associated with a better overall survival. A growing incidence of OPC with a decrease in other risk factors suggests a rising proportion of HPV-associated oropharyngeal carcinomas. However, regional differences exist and require further analyses. Therefore we analysed the incidence and the survival of OPC-patients and the test-rate for HPV in the largest European cancer registry in North-Rhine Westphalia (NRW), Germany. Methods: All patients diagnosed with oropharyngeal cancer (ICD-10: C01; C02.4; C05.1; C05.2; C09.0-9; C10.0-9) during 2008-2018 were included in the study. We assumed a carcinoma to be HPV-associated if either p16-IHC-test and/or HPV-DNA-PCR test was positive. In this retrospective study we analysed pseudonymized individual pathology and incidence reports collected by the cancer registry to extract our data. Five-year survival was calculated with the Kaplan-Meier Estimator. Results: A total of 10.652 cases of oropharyngeal cancer were reported in the study period. Age standardized incidence rate was 4.1 (SE 0.041) and constant over time. The majority (M:71.9%;n = 7663/W:28.1%n = 2989) of all cases were men, which is comparable to the distribution for HPV-associated OPC (M:70,3%;n = 786/W:29,7%;n = 332). 1,866 (17.5%) of OPC were tested for HPV. (M:70,4%;1314/W29,6%;552) In 2008 the test rate was 2.3% (n = 20), which increased steadily to 49.3% (n = 490) in 2018. HPV detection rate was 59,9% (n = 1118) in tested cases, which remained stable during the observation period.(M:59,8%; W:60,1%) Five-year survival was better for HPV-associated OPC (0.656; SE 0.023) than for non-HPV-associated OPC (0.430; SE 0.026) and not-HPV-tested OPC (0.468; SE 0.006). Five-year survival was slightly worse for men with OPC (0.466; SE 0.007) than for women (0.531; SE 0.011). The mean age was 63.0 (n = 10,652; HPV+Ø = 62,5; HPV-Ø = 62,7). Conclusions: In line with existing data, HPV-associated OPC achieved a better prognosis in NRW. HPV test rate increased in OPC recently, however, about 50% were still not tested. With relatively constant fractions of HPV-positive OPC in the tested group over the timespan our data does not suggest a rise in the fraction of HPV-associated OPC, which is in contrast to published data. The retrospective analyses, variance in HPV testing as well as the lack of occupational or behavioural hazards captured in the registry limit the interpretation of our data.

CT radiomic signature to predict overall survival and chemotherapy benefit in stage I and II HPV-associated oropharyngeal carcinoma.

6073 Background: Chemoradiation is the standard of care for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients would benefit from chemotherapy, especially patients with low-risk characteristics. We aim to develop and validate a prognostic and predictive radiomic image signature (pRiS) to inform survival and chemotherapy benefit in stage I and stage II HPV-associated OPSCC. Methods: Radiographic scans for 491 patients with stage I and stage II HPV-associated OPSCC were acquired from 4 independent sources and divided into three cohorts D1-D3. D1 comprised computed tomography (CT) scans from 60 radiotherapy treated patients and was used to identify prognostic features via a LASSO Cox model to predict overall and disease-free survival. The prognostic performance of pRiS was evaluated on two test sets (D2, n = 162; D3, n = 269) using concordance index (C-index). An integrated nomogram was developed to demonstrate the incremental value of the pRiS to the existing clinical factors for individualized survival estimation. Patients from D2 and D3 who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Results: Seven radiomic features were selected to construct the image biomarker pRiS, which was found to be prognostic of overall survival (OS) on univariate analysis in D2 (hazard ratio [HR] = 2.14, 95% confidence interval [CI], 1.1–4.16, p = 0.02) and D3 (HR = 2.74, 95% CI, 1.34–5.62, p = 0.006). Chemotherapy was associated with improved OS for high-pRiS patients in both D2 (radiation vs chemoradiation, HR = 4.47, 95% CI, 1.73–11.6, p = 0.002) and D3 (radiation vs chemoradiation, HR = 2.99, 95% CI, 1.04–8.63, p = 0.04). In contrast, chemotherapy did not improve OS for low-pRiS patients, which indicates these patients did not derive additional benefit from chemotherapy and could be considered for treatment de-escalation. Conclusions: The proposed radiomic signature was prognostic of patient survival and the binary pRiS group informed chemotherapy benefit for stage I and II HPV-associated OPSCC patients. [Table: see text]

Clinical validity of TTMV-HPV DNA liquid biopsies for the diagnosis and surveillance of HPV-associated oropharyngeal carcinoma.

6060 Background: While there are several HPV biomarker assays, a commercially available assay evaluating tumor tissue modified viral DNA (TTMV-HPV DNA) (NavDx, Naveris Inc, Natick, MA) has shown impressive results in clinical trials and small cohort studies. Our aim was to establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary, real-world clinical setting. Methods: In this retrospective analysis, we evaluated the accuracy of the TTMV-HPV DNA assay in detecting HPVOPSCC in the diagnostic (pre-treatment) and surveillance phases of care between April 2020 and October 2022. For the diagnostic cohort, patients with OPSCC and at least one TTMV-HPV DNA measurement prior to initiation of primary therapy were included in the analysis. For the surveillance cohort, all TTMV-HPV DNA tests performed 3 months after completion of primary therapy for pathologically confirmed HPV-associated OPSCC were evaluated, regardless of pre-treatment TTMV-HPV DNA testing. Patients with suspected recurrence, but without pathologic confirmation, were excluded. HPV status was defined utilizing positive p16 staining on immunohistochemistry (93.2% diagnosis; 97.9% surveillance) or HPV polymerase chain reaction/in situ hybridization (79.6% diagnosis; 89.7% surveillance). Results: In the diagnostic cohort, 163 patients were included. The cohort included mostly men (87%) with median age 63, of which 93.3% had HPVOPSCC versus 6.7% had HPV negative OPSCC. The sensitivity in pre-treatment diagnosis was 91.5%; its specificity was 100%. In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. 23 patients had pathologically confirmed recurrences. The assay demonstrated 79.2% sensitivity and 100% specificity in detecting the recurrences. Positive predictive value was 100% and negative predictive value was 98.2%. The median lead time from positive test to pathologic confirmation was 28 days, 6/18 (30%) had lead time &gt;50 days (maximum 507 days). Conclusions: The commercially available NavDx TTMV-HPV DNA assay demonstrated 100% specificity, and therefore excellent positive predictive value, in both diagnosis and surveillance. However, the sensitivity was lower, 91.5% for the diagnosis cohort and 79.2% for the surveillance cohort, signifying that a negative value may require further work-up. Further studies will be required to determine the optimal timing of testing and how results should inform treatment decisions. [Table: see text]

Development and validation of an HPV infection knowledge assessment scale among Aboriginal and Torres Strait Islander Peoples

BackgroundAn increased incidence of Human Papillomavirus (HPV) infection and its related cancers has been observed in recent years. Correct knowledge about HPV infection can lead to a significant decrease in transmission and a subsequent increase in vaccine uptake. Awareness and behavioural perception towards HPV infections are critical for improving HPV vaccination rates among Aboriginal and/or Torres Strait Islander Peoples. However, to the best of our knowledge, there has been no instrument designed to measure knowledge about HPV infection that is culturally appropriate and validated among Aboriginal and/or Torres Strait Islander People. AimTo address this research gap, this paper aims to examine the psychometric properties of the HPV Knowledge Tool (HPV-KT) in an Indigenous population sample from South Australia. MethodologyData from 747 Indigenous Australian Adults who participated in the 12-month follow-up of the HPV and Oropharyngeal Carcinoma in Indigenous Australians Study was utilised for this study. The psychometric properties examined included1) dimensionality and item redundancy; (2) network loadings; (3) model fit; (4) criterion validity; and (5) reliability. The network model was estimated using the Graphical Least Absolute Shrinkage and Selector Operator (GLASSO). Evaluation of the HPV-KT (10 items) dimensionality and item redundancy was conducted within the framework of Exploratory Graph Analysis (EGA). Reliability was evaluated with the McDonald’s Omega (ω) coefficient. ResultsAfter the exclusion of two items, the HPV-KT exhibited good psychometric properties for Aboriginal and/or Torres Strait Islander Peoples. The two dimensions of “General HPV Knowledge” and “Commonness of HPV” were identified. The dimension of “Commonness of HPV” displayed poor reliability, so a sum score for this subscale is not recommended (i.e. the items can still be used individually) The network model of the 7-item HPV-KT was fitted in the validation sample and model fit was adequate (x2 (7) = 17.17, p < 0.016; CFI = 0.980; TLI = 0.94; RMSEA = 0.063, 90% CI = 0.025–0.010). Furthermore, the reliability of the “General HPV Knowledge” subscale (ω = 0.76, 95% CI: 0.72–0.79), while the reliability of the “Commonness of HPV” subscale (ω = 0.58, 95% CI0.58–0.88) was poor. ConclusionThe HPV-KT was adapted for an Aboriginal and/or Torres Strait Islander population and is readily available for future use in Australia. The addition of items assessing specifications of HPV infection, natural history and behaviour will improve the reliability and usability to assess the level of accurate knowledge about HPV infection. Future studies should investigate the possibility of developing new items for the dimension ‘Commonness of HPV’.

A costimulatory chimeric antigen receptor targeting TROP2 enhances the cytotoxicity of NK cells expressing a T cell receptor reactive to human papillomavirus type 16 E7

Immune cells modified to express a tumor-reactive T cell receptor (TCR) have shown limited efficacy as stand-alone therapy against solid tumors. Genital and oropharyngeal carcinomas induced by human papillomavirus (HPV) type 16 express constitutively its E6 and E7 oncoproteins, which makes them convenient targets for adoptive cell immunotherapy. However, viral antigen presentation by tumor cells is low and limits the anti-tumor efficacy of CD8+ T cells. To enhance the functionality of immune effector cells, we have devised a strategy combining a costimulatory chimeric antigen receptor (CAR) with a TCR. We used a clinically tested TCR specific to E7 (E7-TCR) of HPV16 and a newly constructed CAR targeting the trophoblast cell surface antigen 2 (TROP2), which carried the intracellular costimulatory domains CD28 and 4-1BB, but was devoid of the CD3ζ domain. Flow cytometry analyses showed a notable upregulation of activation markers and of cytolytic molecule release by NK-92 cells genetically engineered to express CD3, CD8 and both E7-TCR and TROP2-CAR, after co-incubation with HPV16+ cervical cancer cells. Furthermore, the E7-TCR/TROP2-CAR NK-92 cells demonstrated enhanced antigen-specific activation and augmented cytotoxicity against tumor cells compared with NK-92 cells expressing the E7-TCR alone. A costimulatory TROP2-CAR can synergistically cooperate with the E7-TCR in NK cells thereby enhancing their signaling strength and antigen-specific cytotoxicity. This approach might improve the outcome of adoptive cell immunotherapies for HPV16+ cancer patients that are currently under investigation.

Resultados oncológicos del tratamiento de rescate en pacientes con carcinomas de orofaringe tratados con radioterapia

ObjectiveTo evaluate the possibilities of salvage after local recurrence in patients with oropharyngeal carcinomas treated with radiotherapy, and to analyze the prognostic factors related to the final control of the disease. MethodsRetrospective study of 596 patients with oropharyngeal carcinoma treated with radiotherapy during the period 1991–2018. ResultsOne hundred and eighty-one patients (30.4%) had a local recurrence. Of the patients with a local recurrence, 51 (28.2%) were treated with salvage surgery. Variables that were associated with the patient not receiving salvage surgery were age greater than 75 years, tumor location in the posterior hypopharyngeal wall, an initial tumor extent cT4, and a recurrence-free interval of less than 6 months. Five-year specific survival of patients treated with salvage surgery was 19.1% (95% CI: 7.3%–30.9%). Variables that were related to specific survival were extent of recurrence and status of resection margins. Final tumor control was not achieved in any of the patients with extensive recurrence (rpT3-4, n=25) or positive resection margins (n=22). ConclusionPatients with oropharyngeal carcinomas treated with radiotherapy with local tumor recurrence have a limited prognosis. Most patients (71.8%) were not considered candidates for salvage surgery. The 5-year specific survival of patients treated with salvage surgery was 19.1%.

Association between maximum standarised uptake value (SUV) and local control in patients with oropharyngeal carcinoma treated with radiotherapy

ObjectiveTo analyse the prognostic ability of the maximum standardised uptake value (SUVmax) on local disease control in patients with oropharyngeal carcinoma treated with radiotherapy. Material and methodsRetrospective study of 105 patients with oropharyngeal carcinomas treated with radiotherapy, including chemo- and bio-radiotherapy, and who had a PET-CT scan prior to the start of treatment. ResultPatients with a SUVmax value higher than 17.2 at the primary tumour site had a significantly higher risk of local recurrence. The 5-year local recurrence-free survival for patients with SUVmax less than or equal to 17.2 (n = 71) was 86.5% (95% CI 78.2–94.7 %), and for patients with SUVmax greater than 17.2 (n = 34) it was 55.8% (95% CI 36.0–75.6 %) (P = 0.0001). This difference in local control was maintained regardless of patients' HPV status. Specific survival was similarly lower for patients with a SUV greater than 17.2. The 5-year specific survival for patients with SUVmax greater than 17.2 was 39.5% (95% CI: 20.6–58.3 %), significantly shorter than that of patients with SUVmax equal to or less than 17.2, which was 77.3% (95% CI: 66.9–87.6 %) (P = 0.0001). ConclusionsPatients with oropharyngeal carcinomas treated with radiotherapy with a SUVmax greater than 17.2 at the level of the primary tumour site had a significantly higher risk of local recurrence.

High Recurrence for HPV-Positive Oropharyngeal Cancer With Neoadjuvant Radiation Therapy to Gross Disease Plus Immunotherapy: Analysis From a Prospective Phase Ib/II Clinical Trial

Moderate reduction of radiation to elective volumes has demonstrated encouraging results for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPSCC). However, it remains unknown whether omitting elective volume radiation completely can maintain adequate locoregional control. This trial (NCTXXX) assessed outcomes of Stereotactic Body Radiation Therapy (SBRT) to the gross disease without elective volume irradiation combined with durvalumab and tremelimumab before surgery in patients with HPV+ OPSCC. This phase Ib/II trial included patients with previously untreated locally advanced HPV+ OPSCC from September 2019 to March 2021. Patients received neoadjuvant durvalumab±tremelimumab for 2 doses, with the first dose concurrent with SBRT of 25 Gy in 5 fractions to gross disease only, prior to TransOral Robotic Surgery, followed by adjuvant durvalumab for up to 4 cycles. The primary endpoint was safety/efficacy for the phase Ib portion; and two-year progression-free survival for the phase II portion. This report describes patterns of failure after early closure of the trial following a separate study demonstrating a lack of efficacy of durvalumab±tremelimumab in the metastatic/recurrent setting. Nineteen patients were enrolled (phase Ib: 6; phase II: 13). Three were treated with durvalumab only while 16 with durvalumab+tremelimumab. Median follow-up was 12.7 months. No safety signals were seen. Overall, 18 out of 19 (95%) achieved a clinical to pathological downstaging, and 9 (47%) had a pathological complete response (pCR). Five patients (26%) developed locoregional recurrence, with a median time to recurrence was 3 months. Failing to achieve pCR was significantly associated with locoregional recurrence (p=0.033). None developed distant metastasis. Neoadjuvant SBRT delivered only to the gross tumor before surgery is associated with a high early risk of lymph node recurrence in HPV+ OPSCC despite concurrent/adjuvant immunotherapy. The results caution against omitting elective volume irradiation even in this group of patients with relatively favorable prognosis.