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Background: Head and neck (HN) gross tumor volume (GTV) auto‐segmentation is challenging due to the morphological complexity and low image contrast of targets. Multi‐modality images, including computed tomography (CT) and positron emission tomography (PET), are used in the routine clinic to assist radiation oncologists for accurate GTV delineation. However, the availability of PET imaging may not always be guaranteed. Purpose: To develop a deep learning segmentation framework for automated GTV delineation of HN cancers using a combination of PET/CT images, while addressing the challenge of missing PET data. Methods: Two datasets were included for this study: Dataset I: 524 (training) and 359 (testing) oropharyngeal cancer patients from different institutions with their PET/CT pairs provided by the HECKTOR Challenge; Dataset II: 90 HN patients(testing) from a local institution with their planning CT, PET/CT pairs. To handle potentially missing PET images, a model training strategy named the "Blank Channel" method was implemented. To simulate the absence of a PET image, a blank array with the same dimensions as the CT image was generated to meet the dual‐channel input requirement of the deep learning model. During the model training process, the model was randomly presented with either a real PET/CT pair or a blank/CT pair. This allowed the model to learn the relationship between the CT image and the corresponding GTV delineation based on available modalities. As a result, our model had the ability to handle flexible inputs during prediction, making it suitable for cases where PET images are missing. To evaluate the performance of our proposed model, we trained it using training patients from Dataset I and tested it with Dataset II. We compared our model (Model 1) with two other models which were trained for specific modality segmentations: Model 2 trained with only CT images, and Model 3 trained with real PET/CT pairs. The performance of the models was evaluated using quantitative metrics, including Dice similarity coefficient (DSC), mean surface distance (MSD), and 95% Hausdorff Distance (HD95). In addition, we evaluated our Model 1 and Model 3 using the 359 test cases in Dataset I. Results: Our proposed model(Model 1) achieved promising results for GTV auto‐segmentation using PET/CT images, with the flexibility of missing PET images. Specifically, when assessed with only CT images in Dataset II, Model 1 achieved DSC of 0.56 ± 0.16, MSD of 3.4 ± 2.1 mm, and HD95 of 13.9 ± 7.6 mm. When the PET images were included, the performance of our model was improved to DSC of 0.62 ± 0.14, MSD of 2.8 ± 1.7 mm, and HD95 of 10.5 ± 6.5 mm. These results are comparable to those achieved by Model 2 and Model 3, illustrating Model 1′s effectiveness in utilizing flexible input modalities. Further analysis using the test dataset from Dataset I showed that Model 1 achieved an average DSC of 0.77, surpassing the overall average DSC of 0.72 among all participants in the HECKTOR Challenge. Conclusions: We successfully refined a multi‐modal segmentation tool for accurate GTV delineation for HN cancer. Our method addressed the issue of missing PET images by allowing flexible data input, thereby providing a practical solution for clinical settings where access to PET imaging may be limited. [ABSTRACT FROM AUTHOR]

Background: Increased sexual activity is associated with higher human papillomavirus (HPV) rates; however, there is a lack of analysis comparing the sexual history of patients with HPV positive and HPV negative oropharyngeal cancer (OPC). Methods: In this meta‐analysis, PubMed, Scopus, and CINAHL were searched for articles that included patients with OPC and reported information regarding HPV status and either history of oral sex, number of sexual partners, or sexually transmitted infections (STI). Results: A total of 11 studies were included with 3296 patients with OPC. Patients with HPV positive OPC were more likely than patients with HPV negative OPC to report a history of oral sex (92%, 95% CI: 87.0–97.0 vs. 74.5%, 95% CI: 50.6–98.4, p < 0.0001), higher mean number of sexual partners (18.4 partners, 95% CI: 1.5–35.4 vs. 7.2 partners, 95% CI: 1.0–13.4, p < 0.0001), and more frequent history of STI (23.7%, 95% CI: 18.4–29.0 vs. 8.8%, 95% CI: 4.7–12.8, p = 0.0001). Conclusions: Compared to patients with HPV negative OPC, our analysis shows a larger proportion of patients with HPV positive OPC had participated in oral sex, had a higher number of sexual partners, and had a higher proportion of STI history. [ABSTRACT FROM AUTHOR]

Aims: To examine the prognostic value of F‐18 fluorodeoxyglucose (FDG) uptake in the bone marrow (BM) for disease recurrence and survival in patients with oropharyngeal squamous cell carcinoma (OP‐SCC). The secondary aims were to evaluate the prognostic value of PET/CT parameters for the primary oropharyngeal tumor and total tumor burden, and to assess the correlation between FDG uptake variables and serum inflammatory markers. Methods: This was an observational study of 91 patients with OP‐SCC who underwent pretreatment FDG‐PET/CT. The patients' blood samples were collected before treatment, and treatment was administered with the intention to cure. The median follow‐up time was 40 months. The PET parameters measured were SUVmeanBM for the assessment of BM FDG uptake, SUVmean, SUVmax, total lesion glycolysis (TLG), and metabolic tumor volume (MTV) for the evaluation of primary oropharyngeal tumor and total tumor burden. Blood samples were analyzed to determine each patient's white cell, red cell, and platelet cell counts, hemoglobin, and C‐reactive protein level. In a subgroup of 33 patients, blood serum was analyzed to evaluate the expression of serum immune proteins using a proximity extension assay (Olink Proteomics). Results: The univariate analysis revealed that SUVmeanBM and tumor‐specific parameters (SUVmaxtumor, SUVmeantotal, SUVmaxtotal, MTVtotal, TLGtotal) were significantly associated with recurrence‐free survival (RFS). After adjusting for age, sex, and stage only SUVmeanBM remained significantly associated with RFS. Spearman's correlation identified several correlations between PET parameters and inflammatory markers. Conclusions: Our results show that several FDG‐PET/CT parameters may have a prognostic value of treatment outcome in patients with OP‐SCC. However, SUVmeanBM was the only independent PET parameter that showed a prognostic value for RFS in the study cohort. Moreover, the study findings might suggest an association between systemic inflammation and the metabolic activity in the BM. [ABSTRACT FROM AUTHOR]

Simple Summary: When we consider nutrition in patients with head and neck cancer (HNC), we mostly focus on the type of nutrition; studies on the type of nutrition at different time points are sparse. This retrospective study analyzed patients with HNC according to their nutritional status and association with percutaneous endoscopic gastrostomy (PEG) from admission to six months after treatment at a tertiary hospital in Germany from 2017 to 2019. Results showed that 14.9% required PEG before starting therapy. The need for PEG increased to 22.7% at six weeks after therapy and remained stable at 23% six months later. PEG placement was more frequently required for alcohol or nicotine use, oropharyngeal and hypopharyngeal carcinoma, squamous cell carcinoma, cancer stage III/IV, chemotherapy and impaired feeding. There has been an increase in the percentage of PEG over the observation period. This retrospective monocentric cohort study analyzed patients with head and neck cancer according their nutritional status and association of percutaneous endoscopic gastrostomy (PEG) from admission to six months after treatment at a tertiary hospital in Germany from 2017 to 2019. A total of 289 patients (76.5% men; median age 62 years; 63.3% stage IV) were included. Univariate analyses and ANOVAs with repeated measures were performed to analyze differences over time. The percentage of patients requiring PEG was 14.9% (43 of 289 patients) before start of treatment (Z0), 14% (40 of 286 patients alive) after one week (Z1), 22.7% (58 of 255 patients) after six weeks (Z2) and 23% (53 of 230 patients) after six months (Z3) from the end of treatment. PEG placement was associated with alcohol or nicotine consumption, in oropharyngeal and hypopharyngeal carcinoma, squamous cell carcinoma, cancer stage III/IV, chemotherapy and impairment of food intake (all p < 0.05). Weight loss between Z1 and Z3 with PEG did not differ from patients without PEG at Z0 (p = 0.074), although patients with PEG at Z0 had a lower mean weight at the beginning. PEG was important for a quarter of the patients alive at Z3 and helped to prevent weight loss. [ABSTRACT FROM AUTHOR]

The impact of computed tomography-defined sarcopenia on outcomes in head and neck cancer has been well described. Sarcopenic obesity (SO) (depleted muscle mass combined with obesity) may pose a more serious risk than either condition alone. We investigated SO and its impact on survival and critical weight loss (≥ 5 %) in patients with head and neck cancer who received curative radiotherapy (± other modalities). Retrospective analysis of computed tomography cross-sectional muscle at cervical (C3), thoracic (T2) and lumbar (L3) regions was conducted. Patients were grouped by BMI and sarcopenia status based on established thresholds. A total of 413 patients were included for analysis, the majority having oropharyngeal carcinoma (52 %), and 56 % received primary concurrent chemoradiotherapy. The majority of the cohort (65 %) was overweight or obese (BMI ≥ 25 kg/m2). Sarcopenia was found in 43 %, with 65 % having SO (n 116), equating to 28 % of the whole cohort. Critical weight loss was experienced by 58 % (n 238). A significantly higher proportion of patients with SO experienced critical weight loss (n 70 v. 19, P < 0·001) and were four times more likely to do so during treatment (OR 4·1; 95 % CI 1·5, 7·1; P = 0·002). SO was not found to impact on overall or cancer-specific survival; however, in patients with sarcopenia, those with SO had better overall survival (median 9·1 v. 7·0 years; 95 % CI 5·2, 16·8; P = 0·021). SO at the time of presentation in patients with head and neck cancer is predictive of critical weight loss during treatment, and muscle evaluation can be useful in identifying patients at nutritional risk regardless of BMI and obvious signs of wasting. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal cancer (OPC) survivorship is a nursing priority because patients are living longer while significant short-term and long-term treatment complications that require nursing care are increasing. Hospital readmission is costly and reflects the quality of care patients receive. Objectives: This secondary analysis aimed to determine the prevalence of treatment complications resulting in hospital admissions among persons with OPC and examine the relationship between treatment complications resulting in hospital admission among persons with OPC and all other persons with head and neck cancer. Methods: Using the National Inpatient Survey 2008-2019 database, we identified persons with relevant head and neck cancer diagnoses using specific International Classification of Disease ICD-9 and ICD-10 codes. Complications were operationalized by diagnosis-related codes; persons with codes for major elective surgery were excluded as our focus was posttreatment symptoms requiring hospitalization. Descriptive statistics were used to characterize persons with OPC hospitalized between 2008 and 2019. Binary logistic regression was used to assess complications using crude comparisons. The Elixhauser Comorbidity Index was used for controlling for comorbidities. Results: The final analysis samples included 751,533: 164,770 persons with OPC and 586,763 with other head and cancers. Themost prevalent diagnoses observed in those with OPC were esophagitis, nutrition disorder, hematological disorder, and renal failure; the least common diagnoses were sepsis, respiratory tract infection, and pneumonia. Binary regression revealed that persons with OPC experienced significantly more esophagitis, nutrition disorders, hematological disorders, and renal failure compared to persons with other head and neck cancers. Discussion: Treatment of survivors of OPC requires more intensive monitoring for early symptoms associated with treatment, including esophagitis, nutrition disorders, bleeding disorders, and renal failure, than persons with other head and neck cancers. Monitoring laboratory values and clinical manifestations of these conditions is imperative. Nurses may encounter persons with OPC in emergency departments, outpatient radiology, or inpatient general medicine floors to manage swallowing difficulties, dehydration, malnutrition, and bleeding. Delayed or ineffective treatment of these conditions contributes to readmission, financial burden, and impairment of patient's quality of life. Future research should investigate the relationship between targeted treatment for expected complications and readmission rates in persons with OPC. [ABSTRACT FROM AUTHOR]

Kilovoltage computed tomography plays a crucial role in radiotherapy planning. However, the presence of high-density metallic objects can introduce streaking artifacts in CT scans, resulting in inaccurate dose calculations by the treatment planning software. Previous studies have explored manual density overrides and artifact reduction algorithms individually to enhance dose calculation accuracy, but their combined application on patient plans within a treatment planning system remains unexplored. This research aims to assess the necessity of manual density overrides when an artifact reduction algorithm is already employed to address dental artifacts in oropharyngeal cancer treatment plans. A total of 20 previously treated volumetric modulated arc therapy plans were collected, and manual density overrides were removed followed by plan recalculation. Dosimetric parameters were then compared between the original and modified plans. Statistical analysis revealed several dosimetric parameters for the planning target volume (PTV), clinical target volume (CTV), and oral cavity that exhibited statistically significant differences upon removing the manual density override. However, these differences were found to be small in absolute terms. No other organs evaluated demonstrated statistically significant differences in dose. The most significant disparity observed was an 8.26 cGy increase in mean dose to the CTV, which represents only 0.12% of the prescription dose. Based on these findings, it can be concluded that manual density overrides are likely unnecessary when an artifact reduction algorithm is employed in oropharyngeal cancer cases. [ABSTRACT FROM AUTHOR]

Background: The Australian Burden of Disease Study has shown that cancer is the single most important entity responsible for the greatest cause of health burden in Australia. Unfortunately, Aboriginal and Torres Strait Islander peoples experience a greater burden of this disease, with cancer of the lung, breast, bowel and prostrate being the most common. Lip, oral cavity and pharyngeal cancer incidence is rapidly rising globally and is now the sixth most common cancer in Australia. This paper aims to summarize, for the first time, the incidence and prevalence trends of lip, oral cavity and pharyngeal cancers in Aboriginal and Torres Strait Islander Australians. Methods: Data were obtained from the Australian Cancer Database (ACD), which is compiled at the Australian Institute of Health and Welfare (AIHW) from 1999 to 2018 to estimate the incidence and prevalence of certain head and neck cancers (ICD‐10 codes C00–C10, C14). The other variables requested were age groups and sex. Results: Results were stratified by ICD‐10 code, sex and age group at diagnosis and time period (i.e. grouped years of diagnosis). The total incidence of lip, oral cavity and pharyngeal cancers increased by 1.3 times from 1999 to 2008 (107/100 000) to 2009–2018 (135/100 000). The overall 5‐year prevalence of lip, oral cavity and pharyngeal cancers was 0.17% (0.24% for men and 0.09% for women). Conclusions: The significantly increased incidence of lip, oral cavity and pharyngeal cancers in Aboriginal and Torres Strait Islander peoples in Australia is concerning and should be explored. A targeted, comprehensive and culturally safe model of care for Aboriginal and Torres Strait Islander peoples with lip, oral cavity and pharyngeal cancers is imperative. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. Methods: The IARC‐ARCAGE European case–control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74–0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61–0.64). Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction. [ABSTRACT FROM AUTHOR]

Introduction: Head and neck cancer (HNC) is a complex disease, and multiple risk factors can lead to its progression. Observational studies indicated that herpes simplex virus (HSV) may be correlated with the risk of HNC. However, the causal effects and direction between them were still unclear. Methods: This study utilized a Mendelian randomization (MR) approach for causality assessment between HSV infection and Head and neck cancer based on the latest public health data and Genome-Wide Association Study (GWAS) data. The causal effects were estimated using IVW, weighted median, and MREgger. A reverse MR analysis was subsequently performed. Cochrans Q test, MREgger intercept test, leave one out analysis, and the funnel plot were all used in sensitivity analyses. Results: Genetically predicted higher level of HSV-1 IgG was causally related to HNC (OR=1.0019, 95%CI=1.0003-1.0036, p=0.0186, IVW) and oral and oropharyngeal cancer (OR=1.0018, 95%CI=1.0004-1.0033, p=0.0105, IVW). The reverse MR analysis did not demonstrate a reverse causal relationship between HSV and HNC. However, HSV-2 infection was not causally related to HNC data and oropharyngeal cancer data. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy. Conclusion: Collectively, a significant association was noted between HSV infection and increased risk of HNC, providing valuable insights into the etiology of this malignancy. Further in-depth study is needed to validate these findings and elucidate the underpinning mechanisms. [ABSTRACT FROM AUTHOR]

Background The impact of societal factors on the occurrence of head and neck cancers (HNCs) remains understudied, especially in the Nordic countries. Methods To quantify the association between socio-economic status (SES) and the occurrence of HNCs, this cohort study uses data from the Nordic Occupational Cancer project that combine occupational and cancer registry data from 1961 to 2005 of 14.9 million individuals aged between 30 and 64 years. Occupational categories were combined into seven socio-economic categories. Standardized incidence ratio (SIR) analyses were conducted with the cancer incidence rates for the entire national study populations used as reference rates. Results Altogether, 83 997 HNCs—72% in men and 28% in women—were recorded. Among men, a gradient of risk associated with SES was observed for cancers of the tongue, other oral cavity subsites, pharynx, oropharynx and larynx in groups with lower SES. Managers showed decreased SIRs of 0.50 to –0.90 also for cancers of the lip, tongue, other oral cavity subsites, oropharynx, nasopharynx, nose and larynx. In contrast, excess risks of tongue, other oral cavity subsites, pharyngeal, oropharyngeal and laryngeal cancers were observed among clerical (SIRs 1.05–1.16), skilled workers (1.04–1.14), unskilled workers (1.16–1.26) and economically inactive men (1.38–1.87). Among women, no risk gradient similar to that in men was revealed. Conclusions The current study underscores the influence of SES on the incidence of HNCs and highlights the need for targeted interventions, including tobacco and alcohol control policies, and improved access to healthcare services, particularly for socio-economically disadvantaged populations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess if multicriteria optimization could limit interoperator variability in radiation therapy planning and assess if this method could contribute to target volume coverage and sparing of organ at risk for intensity-modulated curative radiation therapy of head and neck cancers. We performed a retrospective analysis on 20 patients treated for an oropharyngeal or oral cavity squamous cell carcinoma. We carried out a comparative dosimetric study of manual plans produced with Precision® software, compared with the plans proposed using the multicriteria optimization method (RayStation®). We assessed interoperator reproducibility on the first six patients, and dosimetric contribution in sparing organs at risk using the multicriteria optimization method. Median age was 69 years, most lesions were oropharyngeal carcinoma (65%), and 35% lesions were stage T3. First, we obtained a high degree of similarity between the four operator measurements for each patient at the level of each organ. Intraclass correlation coefficients were greater than 0.85. Second, we observed a significant dosimetric benefit for contralateral parotid gland, homolateral and contralateral masseter muscles, homolateral and contralateral pterygoid muscles and for the larynx (P < 0.05). For the contralateral parotid gland, the mean dose difference between the multicriteria optimization and manual plans was −2.0 Gy (P = 0.01). Regarding the larynx, the mean dose difference between the two plans was −4.6 Gy (P < 0.001). Multicriteria optimization is a reproducible technique and faster than manual optimization. It allows dosimetric advantages on organs at risk, especially for those not usually taken into consideration in manual dosimetry. This may lead to improved quality of life. [ABSTRACT FROM AUTHOR]

To assess the exact role of high-risk HPV testing in patients of carcinoma unknown primary with secondary metastasis to the neck who underwent TORS and neck dissection for identification of the primary site. A prospective study was carried out at a tertiary care centre over one year. Patients with unilateral neck swelling, which was cytologically proven squamous cell carcinoma neck metastasis, were included in the study. After clinicopathological evaluation, they underwent TORS-assisted ipsilateral radical tonsillectomy, tongue base mucosal wedge biopsy for primary site identification, and ipsilateral neck dissection. They underwent HPV RNA ISH from the tonsil, the base of the tongue and blood. They also underwent HPV DNA testing from the blood. P16 was done in the base of tongue, tonsil, and lymph node specimens. In the study cohort of 18 patients who underwent ipsilateral radical tonsillectomy, mucosal tongue base wedge biopsy and neck dissection, p16 positivity was isolated in 5.56%, 0% and 2.78% of patients, respectively. (n = 1/18, 0/18, 5/18). Interestingly, HPV E7 mRNA expression was absent in the tonsil /base of tongue specimens, but metastatic lymph nodes displayed expression in 11.11%. HPV DNA was undetected in all analysed tissues and patients' blood. In the Indian subcontinent, it is not essential to do detailed high-risk HPV analysis in cases of carcinoma unknown primary with secondary metastasis to the neck. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based chemoradiation is a standard treatment for many patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), an etiologically distinct subset of head and neck cancer. Although associated with good long-term survival, clinical risk factors for ototoxicity have been understudied in this population. This study aimed to evaluate clinical predictors associated with ototoxicity in HPV-positive OPSCC patients treated with cisplatin chemoradiation. Methods: This retrospective case-control study included 201 adult patients (>18 years) with histologically confirmed HPV-positive OPSCC who received cisplatin chemoradiation as their primary treatment from 2001 and 2019 at a single tertiary cancer center. Ototoxicity was determined using baseline and follow-up audiometry and the Common Terminology Criteria for Adverse Events v5.0 grading criteria (Grade ≥2). Multivariable logistic regression [adjusted odds ratio (aOR)] identified significant predictors that increased the odds of ototoxicity. Results: A total of 201 patients [165 males; median (IQR) age, 57 (11) years] were included in the study. The incidence of ototoxicity in the worst ear was 56.2%, with the greatest hearing loss occurring at high frequencies (4-8 kHz), resulting in a loss of 12.5 dB at 4 to 6 kHz and 20 dB at 6 to 8 kHz. High-dose cisplatin administration compared to weekly administration [aOR 4.93 (95% CI: 1.84-14.99), P =.003], a higher mean cochlear radiation dose [aOR 1.58 (95% CI: 1.12-2.30), P =.01], smoking history [aOR 2.89 (95% CI: 1.51-5.63), P =.001], and a 10 year increase in age [aOR 2.07 (95% CI: 1.25-3.52), P =.006] were each independently associated with increased odds of ototoxicity. Conclusions: Clinical predictors of ototoxicity in HPV-positive OPSCC patients treated with cisplatin-based chemoradiation include the use of a high-dose cisplatin regimen, higher cochlear radiation doses, a history of smoking, and older age. With the rising incidence of this malignancy in Western countries and overall improved survivorship, our research motivates future studies into risk stratification and earlier interventions to mitigate and reduce the risk of ototoxicity. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the significance of positron emission tomography/computed tomography (PET/CT) in detecting recurrences or other primary malignancies in patients treated for oro- and hypopharyngeal squamous cell carcinoma. Method: A retrospective analysis of the follow up of 132 patients was performed and 370 PET/CT scans were assessed for their accuracy. Results: All asymptomatic clinical occult recurrences were detected by PET/CT and accounted for 28 per cent of recurrences. Asymptomatic patients with metastases detected by PET/CT had a significant survival benefit compared to patients diagnosed in a symptomatic stage. For locoregional recurrence, no significant difference in overall survival could be demonstrated. In total, 33 primary malignancies were discovered, of which 48 per cent were first detected by PET/CT. The specificity and negative predictive value of the PET/CT scans had ranges of 85–100 and 83–100 per cent, respectively. Conclusion: The role of PET/CT scans in detecting primary malignancies, clinical occult recurrences and especially asymptomatic metastases was observed. [ABSTRACT FROM AUTHOR]

Background: Tubarial glands are a new organ at risk for head and neck cancer radiation therapy (RT). We aimed to study the feasibility of sparing them using intensity‐modulated radiation therapy (IMRT). Methods: Tubarial glands were delineated for 17 patients with oropharyngeal carcinoma receiving definitive RT, and treatment plans were re‐optimized to spare dose to the tubarial glands while maintaining target coverage. A paired t test was performed to compare the mean dose of tubarial glands and target coverage. Results: The difference in mean doses was 4.9 and 7.0 Gy for the ipsilateral and contralateral tubarial glands, respectively (p < 0.01). The mean dose to tubarial gland was ≤39 Gy in 35% versus 47% (ipsilateral) and 70% versus 100% (contralateral) in clinical and re‐optimized plans, respectively. Re‐optimized ipsilateral tubarial gland mean ≤39 Gy was achieved more commonly in patients with base of tongue versus tonsil primaries (86% vs. 20%, p = 0.02). Conclusion: This pilot study demonstrates the dosimetric feasibility of tubarial gland sparing with IMRT. Dosimetric constraints need to be determined with larger studies. [ABSTRACT FROM AUTHOR]

Background: Despite the better prognosis associated with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), some patients experience relapse and succumb to the disease; thus, there is a need for biomarkers identifying these patients for intensified treatment. Leucine-rich repeats and immunoglobulin-like domain (LRIG) protein 1 is a negative regulator of receptor tyrosine kinase signaling and a positive prognostic factor in OPSCC. Studies indicate that LRIG1 interacts with the LIM domain 7 protein (LMO7), a stabilizer of adherence junctions. Its role in OPSCC has not been studied before. Methods: A total of 145 patients diagnosed with OPSCC were enrolled. Immunohistochemical LMO7 expression and staining intensity were evaluated in the tumors and correlated with known clinical and pathological prognostic factors, such as HPV status and LRIG1, CD44, Ki67, and p53 expression. Results: Our results show that high LMO7 expression is associated with significantly longer overall survival (OS) (p = 0.044). LMO7 was a positive prognostic factor for OS in univariate analysis (HR 0.515, 95% CI: 0.267–0.994, p = 0.048) but not in multivariate analysis. The LMO7 expression correlated with LRIG1 expression (p = 0.048), consistent with previous findings. Interestingly, strong LRIG1 staining intensity was an independent negative prognostic factor in the HPV-driven group of tumors (HR 2.847, 95% Cl: 1.036–7.825, p = 0.043). Conclusions: We show for the first time that high LMO7 expression is a positive prognostic factor in OPSCC, and we propose that LMO7 should be further explored as a biomarker. In contrast to previous reports, LRIG1 expression was shown to be an independent negative prognostic factor in HPV-driven OPSCC. [ABSTRACT FROM AUTHOR]

Background: Clinical diagnosis of the masses of the oropharynx and the oral cavity is usually straightforward; however, deep extension of lesions should be assessed by imaging. Thirty patients with suspected masses in oral cavity and oropharynx were enrolled in the present study. Contrast-enhanced CT and MRI were used for imaging of all patients, and superficial ultrasound was used as screening (whether the mass was accessible to ultrasound or not). The aim of this study was to evaluate clinical impact of combined imaging modalities for assessment of intraoral and oropharyngeal masses. Results: There was a statistically significant difference between CT and MRI regarding the detected tumor size, lymph node and adjacent structures. CT had a sensitivity of 77.78% and specificity of 75% in the detection of malignancy. A low apparent diffusion coefficient can detect malignancy with 61.11% sensitivity and 91.67% specificity. Conclusions: The radiographic diagnosis of the oral cavity presents a complex challenge. According to the unique presentation of each patient, combined CT and MRI imaging will enhance the identification and characterization of lesions in the oral cavity and oropharynx. There is a secondary, limited role for ultrasonography. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton therapy allows for more effective organs at risk avoidance than photon radiotherapy, thus reducing both radiation-induced toxicity and second cancer risk. The aim of the present paper is to compare protons and photons outcomes in the context of oropharyngeal and nasopharyngeal cancer and provide an updated comprehensive overview of the most promising new approaches and methodologies for treating head and neck cancer with protons. The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC. [ABSTRACT FROM AUTHOR]

Introduction: The profile and outcomes of head and neck cancer throughout Australia has changed over the past decade. The aim of this study was to perform a population‐based analysis of incidence, demographics, stage, treatments and outcomes of patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC), with a particular focus on HPV‐associated disease. Methods: This was a retrospective analysis of prospectively collected data within the Queensland Oncology Repository (QOR) and analysed by the Queensland Cancer Control Analysis Team. The cohort included patients diagnosed in Queensland between 1 January 2015 and 31 December 2019. Outcome measures included incidence of new OPSCC cases, age‐standardised rates (ASR) (3‐year average), demographics, p16 status, stage (8th Edition American Joint Commission on Cancer), treatments, and 2‐ and 5‐year overall survival. Results: There were 1527 newly diagnosed OPSCC, representing 96% (1527/1584) of all oropharyngeal cancers. It was the most common head and neck cancer diagnosed, with oral cavity cancer being the second most common (n = 1171). Seventy‐seven percent were p16 positive (1170/1527), of which 87% (1019/1170) were male. The median age was 61 years and 49% (568/1170) presented with Stage I disease. The ASR was 6.3/100,000, representing a 144% incidence increase since 1982 (2.6/100,000). Radiotherapy was utilised in 91% of p16+ cases with 2‐ and 5‐ year overall survival of 89% and 79%, respectively. Conclusion: OPSCC is now the most common mucosal head and neck cancer diagnosed in Queensland, having surpassed oral cavity cancer. The majority are HPV‐associated (p16+), presenting with early‐stage disease with a favourable prognosis. [ABSTRACT FROM AUTHOR]

The detection of the primary site in Carcinoma of Unknown Primary (CUP) is a challenging task which can significantly alter the course of management and also prognosis. Various modalities have been assessed with varying sensitivity and specificity. Imaging and cytological diagnosis have formed a key part of the diagnostic algorithm of CUP. Trans Oral Robotic Surgery offers the advantage of being both diagnostic as well as therapeutic with promising sensitivity and specificity and can form an integral part in the management of CUP. A prospective study was carried out at a tertiary care centre over a period of one year. Patients with unilateral neck swelling which was histopathologically proven squamous cell carcinoma neck metastasis were included in the study. They were evaluated with endoscopy and radiology according to the standard algorithm. When these failed to detect the primary, the patients underwent ipsilateral radical tonsillectomy and tongue base mucosal wedge biopsy via TORS. Post-operative histopathological examination was done on the resected specimens to detect the primary site. Transoral Robotic Surgery was able to localise primary in 50% of the patients enrolled in the study. Out of the primary site identified by TORS; 55.56% were located in the tonsil and 44.4% in the tongue base. TORS can offer promising detection rates of the occult primary in CUP and should form an integral part of the diagnostic algorithm. [ABSTRACT FROM AUTHOR]

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A. [ABSTRACT FROM AUTHOR]

Background: Massive oropharyngeal bleeding post‐chemoradiotherapy is a life‐threatening condition that requires emergent management. Methods: This retrospective case series included 11 patients with oropharyngeal squamous cell carcinoma who suffered from massive bleeding during or following treatment with definitive chemoradiotherapy. Details of acute and definitive management of oropharyngeal bleeding are reported. Results: Nine of 11 hemorrhagic events occurred a mean (SD) of 88.6 days (53.6) after radiotherapy. Airway intubation and embolization were performed in 10 of 11 patients, followed by surgery in 7 of 11 patients. The most commonly embolized vessels were the external carotid and lingual arteries. At the time of discharge, 3 of 11 patients had a tracheostomy, and 7 of 11 continued to use a gastrostomy tube. Four patients died. Conclusions: Hemorrhagic complications in oropharyngeal cancer treatment require emergent responses. Developing a workflow for coordination between multidisciplinary teams can maximize probability of survival and decrease morbidity. [ABSTRACT FROM AUTHOR]

Background: Aspirin intake might be inversely associated with head and neck cancer (HNC). Thus, we investigated this relationship within the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Methods: Four case–control studies within the INHANCE consortium were included (2024 cases, 4196 controls). Study‐specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression and subsequently pooled with DerSimonian‐Laird random‐effects model. Nonlinearity of the relationship between duration of intake and HNC was modeled with fractional polynomials. Results: Aspirin was inversely associated with HNC overall (OR = 0.48; 95% CI: 0.26, 0.91). Results for laryngeal cancer were similar (OR = 0.54; 95% CI: 0.30, 0.96). Analysis on duration of intake confirmed findings for HNC overall, showing also inverse associations for oropharyngeal and laryngeal cancer. Conclusions: This study suggests that aspirin intake may reduce the risk of HNC, driven mainly by decreases in risk for laryngeal and oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Convincing data have indicated that human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with much better locoregional control and survival than its HPV-unrelated counterparts. It is also worth noting that the distant metastases (DM) rate does not differ between HPV-related and HPV-unrelated OPSCC. Recently, the analysis of HPV in liquid biopsy (circulating tumor-related HPV DNA, ctHPV) has gained significant prognostic importance. Little is known about the importance of viral load (VL) levels of ctHPV16 in OPSCC on survival. Meanwhile, our results provide comprehensive data that the pretreatment ctHPV16 VL in liquid biopsy may be a biomarker of the risk of DM. Background: There are definite reasons to implement molecular diagnostics based on the measurement of human papillomavirus (HPV) DNA in liquid biopsy into clinical practice. It is a quick, repeatable, and health-safe test for cancer biomarkers in the blood. In this study, we investigated whether the circulating tumor-related HPV16 (ctHPV16) viral load (VL) in patients with oropharyngeal squamous cell carcinoma (OPSCC) was important for determining the risk of locoregional recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Methods: This study included 91 patients with ctHPV16-positive OPSCC who had been treated with radical radiotherapy and chemotherapy. The VL was measured using quantitative PCR (qPCR) and a probe specific for HPV16. Based on 10 years of follow-up, the 2-, 3-, 5-, and 9-year LRFS, MFS, and OS were estimated. Results: The 5-year actuarial LRFS, MFS, and OS rates of patients with ctHPV16-positive/OPSCC were 88%, 90%, and 81%, respectively. The VL was significantly higher in patients who subsequently developed distant metastases (DM) than in those who did not (VL 4.09 vs. 3.25; p = 0.009). In a Cox proportional hazards regression model for MFS, a higher ctHPV16 VL appeared to be a significant independent prognostic factor for the occurrence of DM (HR 2.22, p = 0.015). The ROC curve revealed a cutoff value of 3.556 for VL (p = 0.00001). Conclusions: A high VL before treatment indicates patients with a significant risk of DM, and should be used in OPSCC treatment stratification. [ABSTRACT FROM AUTHOR]

Background: This pilot study analyzed correlations between tongue electrical impedance myography (EIM), standard tongue electromyography (EMG), and tongue functional measures in N = 4 long‐term oropharyngeal cancer (OPC) survivors. Methods: Patients were screened for a supportive care trial (NCT04151082). Hypoglossal nerve function was evaluated with genioglossus needle EMG, functional measures with the Iowa oral performance instrument (IOPI), and multi‐frequency tissue composition with tongue EIM. Results: Tongue EIM conductivity was higher for patients with EMG‐confirmed cranial nerve XII neuropathy than those without (p = 0.005) and in patients with mild versus normal EMG reinnervation ratings (16 kHz EIM: p = 0.051). Tongue EIM correlated with IOPI strength measurements (e.g., anterior maximum isometric lingual strength: r2 = 0.62, p = 0.020). Conclusions: Tongue EIM measures related to tongue strength and the presence of XII neuropathy. Noninvasive tongue EIM may be a convenient adjunctive biomarker to assess tongue health in OPC survivors. [ABSTRACT FROM AUTHOR]

The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of CD66b+ neutrophil granulocytes separately in the stromal and epithelial compartments in cancer tissues from 397 patients with HNSCC. Tumor samples from six historical patient groups were processed into tissue microarrays and stained immunohistochemically. In total, 21.9% were HPV positive (p16+). Neutrophil counts were much lower in the stromal compartment (372 ± 812) than in the epithelial cancer compartment (1040 ± 1477) (p < 0.001), with large differences between groups. In three groups with high neutrophil infiltration, high rates were associated with a favorable prognosis, whereas in two groups, high rates were a negative prognostic factor. In p16- oropharyngeal and hypopharyngeal cancer high infiltration was associated with a favorable prognosis. Cancers with an exclusion of neutrophils in the epithelial compartment were associated with improved prognosis. In oropharyngeal and hypopharyngeal HPV-negative cancer high neutrophil infiltration rates were clearly associated with prolonged survival. Neutrophil granulocytes in HNSCC may contribute to a favorable or unfavorable prognosis. [ABSTRACT FROM AUTHOR]

Aims: The aim of this systematic literature review was to provide updated information on human papillomavirus (HPV) prevalence in locally and regionally advanced (LA) and recurrent/metastatic (RM) head and neck cancer (HNC) worldwide. Methods: Electronic searches were conducted on clinicaltrials.gov, MEDLINE/PubMed, Embase, and ASCO/ESMO journals of congresses for interventional studies (IS; Phase I–III trials) as well as MEDLINE and Embase for non‐interventional studies (NIS) of LA/RM HNC published between January 01, 2010 and December 31, 2020. Criteria for study selection included: availability of HPV prevalence data for LA/RM HNC patients, patient enrollment from January 01, 2010 onward, and oropharyngeal cancer (OPC) included among HNC types. HPV prevalence per study was calculated as proportion of HPV+ over total number of enrolled patients. For overall HPV prevalence across studies, mean of reported HPV prevalence rates across studies and pooled estimate (sum of all HPV+ patients over sum of all patients enrolled) were assessed. Results: Eighty‐one studies (62 IS; 19 NIS) were included, representing 9607 LA/RM HNC cases, with an overall mean (pooled) HPV prevalence of 32.6% (25.1%). HPV prevalence was 44.7% (44.0%) in LA and 24.3% (18.6%) in RM. Among 2714 LA/RM OPC patients from 52 studies with available data, mean (pooled) value was 55.8% (50.7%). The majority of data were derived from Northern America and Europe, with overall HPV prevalence of 46.0% (42.1%) and 24.7% (25.3%) across studies conducted exclusively in these geographic regions, respectively (Northern Europe: 31.9% [63.1%]). A "p16‐based" assay was the most frequently reported HPV detection methodology (58.0%). Conclusion: Over the last decade, at least one quarter of LA/RM HNC and half of OPC cases studied in IS and NIS were HPV+. This alarming burden is consistent with a potential implication of HPV in the pathogenesis of at least a subgroup of HNC, underscoring the relevance of HPV testing and prophylaxis to HNC prevention and management. [ABSTRACT FROM AUTHOR]

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV‐driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk‐factor analysis based on serology was conducted, comparing HPV‐driven to non‐HPV‐driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1‐88.3) and specificity of 91.2% (95% CI 88.6‐93.4) for HPV‐driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack‐years (72.1%). The risk‐factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack‐years, TNM‐T and TNM‐N stage. HPV serology is a robust biomarker for HPV‐driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels. [ABSTRACT FROM AUTHOR]

Background: To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). Methods: Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. Results: The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. Conclusion: Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events. [ABSTRACT FROM AUTHOR]

Purpose: Evaluate the occupational variation in incidence of oropharyngeal cancer (OPC). Methods: We calculated standardized incidence ratios (SIRs) of OPC in occupational categories in the Nordic countries relative to the entire national populations. The data covered 6155 OPC cases. Results: Among men high risk of OPC was observed, among else, in waiters (SIR 6.28, 95% CI 4.68–8.26), beverage workers (SIR 3.00, 95% CI 1.72–4.88), and artistic workers (SIR 2.97, 95% CI 2.31–3.76). Among women high risk of OPC was observed in waiters (SIR 2.02, 95% CI 1.41–2.81) and packers (SIR 1.73, 95% CI 1.07–2.64). The lowest SIRs were observed in female gardeners (SIR 0.27, 95% CI 0.12–0.51) and male farmers (SIR 0.30, 95% CI 0.25–0.35). Conclusion: The 20-fold variation in incidence of OPC between occupations needs further investigation in studies with detailed information on occupational and non-occupational risk factors. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is a common infection believed to cause 70% of oropharyngeal cancers, with incidence rising globally. Nurses play a critical role in providing care and education to patients with HPV-induced oropharyngeal squamous cell carcinoma (OPSCC). The etiology, diagnosis, and treatment of HPV-induced OPSCC are addressed. [ABSTRACT FROM AUTHOR]

Background: Despite the diverse genetic mutations in head and neck cancer, the chemotherapy outcome for this cancer has not improved for decades. It is urgent to select prognostic factors and therapeutic targets for oropharyngeal cancer to establish precision medicine. Recent studies have identified PSMD1 as a potential prognostic marker in several cancers. We aimed to assess the prognostic significance of PSMD1 expression in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry. Methods: We studied 64 individuals with OPSCC tissue from surgery at Seoul National University Bundang Hospital between April 2008 and August 2017. Immunostaining analysis was conducted on the tissue microarray (TMA) sections (4 μm) for p16 and PSMD1. H-score, which scale from 0 to 300, was calculated from each nucleus, cytoplasm, and cellular expression. Clinicopathological data were compared with Chi-squared test, Fisher's exact test, t-test, and logistic regression. Survival data until 2021 were achieved from national statistical office of Korea. Kaplan–Meier method and cox-regression model were used for disease-specific survival (DSS) analysis. Results: H-score of 90 in nucleus was appropriate cutoff value for 'High PSMD1 expression' in OPSCC. Tonsil was more frequent location in low PSMD1 group (42/52, 80.8%) than in high PSMD1 group (4/12, 33.3%; P =.002). Early-stage tumor was more frequent in in low PSMD1 group (45/52, 86.5%) than in high PSMD1 group (6/12, 50%; P =.005). HPV was more positive in low PSMD1 group (43/52, 82.7%) than in high PSMD1 group (5/12, 41.7%; P =.016). Patients with PSMD1 high expression showed poorer DSS than in patients with PSMD1 low expression (P =.006 in log rank test). In multivariate analysis, PSMD1 expression, pathologic T staging, and specimen age were found to be associated with DSS (P =.011, P =.025, P =.029, respectively). Conclusions: In our study, we established PSMD1 as a negative prognostic factor in oropharyngeal squamous cell carcinoma, indicating its potential as a target for targeted therapy and paving the way for future in vitro studies on drug repositioning. [ABSTRACT FROM AUTHOR]

Introduction: The following study aimed to answer the question if HPV-HNCUP and HPV-OPSCC are the same disease. Propensity score matching (PSM) was used to compare the oncological outcomes of both groups, in particular the 5-year overall survival rate (OS), the 5-year disease specific survival rate (DSS) and the 5-year progression free survival rate (PFS). Materials and methods: Firstly, between January 1st, 2007, and March 31st, 2020 a total of 131 patients were treated with HNCUP at our Department. Out of these, 21 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. Secondly, between January 1st, 2000, and January 31st, 2017, a total of 1596 patients were treated with an OPSSC at our Department. Out of these, 126 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. After PSM, 84 patients with HPV-OPSCC and 21 HPV-HNCUP remained in the study for further comparison. Results: The OS was 63.5% (95% CI 39.4–87.6) for HPV-HNCUP and 88.9% (95% CI 90.4–100.0) for HPV-OPSCC patients and therefore, significantly lower for the first mentioned (p = 0.013). The DSS was also significantly impaired for HPV-HNCUP (71.0%, 95% CI 46.3–95.7), in comparison with HPV-OPSCC patients (95.5%, 95% CI 90.4–100.0; p = 0.002). The PFS for HPV-HNCUP patients was lower (75.6%, 95% CI 54.0–97.2) yet not significantly different to HPV-OPSCC (90.4%, 95% CI 83.5–97.3; p = 0.067). Conclusions: The results presented demonstrate a significant reduced OS and DSS for HPV-HNCUP patients. Accordingly, in our study HPV-HNCUP and HPV-OPSCC are two different entities with a different oncological outcome. [ABSTRACT FROM AUTHOR]

Patients with HPV−-localized head and neck cancer (HNC) show inferior outcomes after surgery and radiochemotherapy compared to HPV-associated cancers. The underlying mechanisms remain elusive, but differences in immune status and immune activity may be implicated. In this study, we analyzed immune profiles of CD8+ T cells and myeloid-derived suppressor cells (MDSC) in HPV+ versus HPV− disease. The overall frequency of CD8+ T cells was reduced in HNC versus healthy donors but substantially increased after curative therapy (surgery and/or radiochemotherapy). In HPV+ patients, this increase was associated with significant induction of peripheral blood CD8+/CD45RA−/CD62L− effector memory cells. The frequency of HPV-antigen-specific CD8+ cells was low even in patients with virally associated tumors and dropped to background levels after curative therapy. Pre-therapeutic counts of circulating monocytic MDSC, but not PMN-MDSC, were increased in patients with HPV− disease. This increase was accompanied by reduced fractions of terminally differentiated CD8+ effector cells. HPV− tumors showed reduced infiltrates of CD8+ and CD45RO+ immune cells compared with HPV+ tumors. Importantly, frequencies of tumor tissue-infiltrating PMN-MDSC were increased, while percentages of Granzyme B+ and Ki-67+ CD8 T cells were reduced in patients with HPV− disease. We report differences in frequencies and relative ratios of MDSC and effector T cells in HPV− HNC compared with more immunogenic HPV-associated disease. Our data provide new insight into the immunological profiles of these two tumor entities and may be utilized for more tailored immunotherapeutic approaches in the future. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is a tumor occurring in various primary sites with limited chemotherapy options for its treatment. Recently, comprehensive genomic profiling (CGP) testing has become clinically widespread. In this study, we examined the utility of CGP in diagnosing and treating HNC. This study included 29 patients with HNC who underwent CGP testing at the Gifu University Hospital between December 2019 and April 2022. We analyzed the types of gene mutations and tumor mutational burden (TMB) based on the CGP results. Squamous cell carcinoma accounted for 55.2%, and other cancers accounted for 44.8%. And we investigated the correlation of prognosis with gene mutations and TMB. Gene mutations were detected in TP53(48.3%), CDKN2A (27.6%), CDKN2B (17.2%), NOTCH1 (17.2%), PIK3CA (17.2%), ARID1A (13.8%), and NF1 (13.8%). TP53, CDKN2A and CDKN2B mutations significantly decreased survival rate in HNC. Five cases (17.2%) were TMB-high and 82.8% were TMB-low. In SCC cases treated with immune checkpoint inhibitors, TMB-high had better Overall survival than TMB-low. And all patients with TMB-high were oropharyngeal cancer. Although there were no cases in which effective treatment was actually performed based on the results of CGP, many gene mutations have been detected and several gene mutations correlated with prognosis. Furthermore, TMB can be used as a biomarker to predict the therapeutic effects of immune checkpoint inhibitors in cases of SCC. [ABSTRACT FROM AUTHOR]

Background and purpose: The ability to determine the risk and predictors of lymphedema is vital in improving the quality of life for head and neck (HN) cancer patients. However, selecting robust features is challenging due to the multicollinearity and high dimensionality of radiotherapy (RT) data. This study aims to overcome these challenges using an ensemble feature selection technique with machine learning (ML). Materials and methods: Thirty organs-at-risk, including bilateral cervical lymph node levels, were contoured, and dose-volume data were extracted from 76 HN treatment plans. Clinicopathologic data was collected. Ensemble feature selection was used to reduce the number of features. Using the reduced features as input to ML and competing risk models, internal and external lymphedema prediction capability was evaluated with the ML models, and time to lymphedema event and risk stratification were estimated using the risk models. Results: Two ML models, XGBoost and random forest, exhibited robust prediction performance. They achieved average F1-scores and AUCs of 84 ± 3.3 % and 79 ± 11.9 % (external lymphedema), and 64 ± 12 % and 78 ± 7.9 % (internal lymphedema). Predictive ML and risk models identified common predictors, including bulky node involvement, high dose to various lymph node levels, and lymph nodes removed during surgery. At 180 days, removing 0–25, 26–50, and > 50 lymph nodes increased external lymphedema risk to 72.1 %, 95.6 %, and 57.7 % respectively (p = 0.01). Conclusion: Our approach, involving the reduction of HN RT data dimensionality, resulted in effective ML models for HN lymphedema prediction. Predictive dosimetric features emerged from both predictive and competing risk models. Consistency with clinicopathologic features from other studies supports our methodology.

AbstractMucoepidermoid carcinoma (MEC) is one of the most common histological malignant salivary gland tumors, it is most frequently diagnosed in the parotid gland. MEC is also diagnosed in the intra oral minor salivary glands. Only a few cases of tonsillar MEC have been reported. We present a rare case of mucoepidermoid carcinoma arising from the left pharyngeal tonsil. This case report shows that it is important to perform tonsillectomy when discovering neck metastasis of salivary gland tumors with unknown primary.

Abstract Introduction In the era of precision preventive medicine, susceptible genetic markers for oro‐/hypopharyngeal squamous cell carcinoma (OPSCC) have been investigated for genome‐wide associations. Materials and Methods A case–control study including 659 male head and neck squamous cell carcinoma (HNSCC) patients, including 331 oropharyngeal cancer, treated between March 1996 and December 2016 and 2400 normal controls was performed. A single‐nucleotide polymorphism (SNP) array was used to determine genetic loci that increase susceptibility to OPSCC. Results We analyzed the allele frequencies of 664,994 autosomal SNPs in 659 HNSCC cases; 7 SNPs scattered in loci of chromosomes 5, 7, 9, 11, and 19 were significant in genome‐wide association analysis (Pc

The incidence of head and neck cancer (HNC) which is the seventh most common cancer worldwide, continues to rise due to tobacco-derived carcinogens, excessive alcohol consumption, and common infection with oncogenic strains of human papillomavirus (HPV) [1,2]. The steady increase in the number of HPV-related oropharyngeal cancers makes the landscape of HNC more heterogeneous. Radiation therapy (RT) remains the mainstay of treatment as a sole modality, in combination with chemotherapy (chemoradiotherapy, CRT) or adjuvant after surgery. However, reliable predictive markers of response to conventional RT or CRT have not been found, despite established knowledge about the predictors of checkpoint inhibitors in metastatic disease. In view of the unsatisfactory results of clinical trials using concurrent RT/CRT with immunotherapy, increasing attention is being paid to the local effects of RT on the tumor microenvironment and systemic immune response. We hypothesized that the baseline expression of programmed death 1 ligand (PD-L1) and intratumoral infiltration with CD8+ lymphocytes (TILsCD8+) score in the non-metastatic oral cavity (OC) and oro-/hypopharynx (PX) cancers may correlate with RT response. It was a retrospective single-center analysis involving OC and PX patients who underwent radical RT (66Gy prescribed to the primary tumor, given in 30 fx/6 weeks) with or without concurrent chemotherapy (Cisplatin 100 mg/m2 i.v. every three weeks or 40 mg/m2 i.v weekly). We performed analysis of TILsCD8+ and PD-L1 expression status in the archival biospecimens of the treatment-naïve primary tumor. Tissue microarrays (TMA) were prepared using the Manual Tissue Arrayer MTA-1 (Beecher Instruments, Inc., USA). The TMA sections were first stained with hematoxylin and eosin to verify the invasive neoplastic content within each core. Next, consecutive sections were stained with IVD-grade antibodies, anti-PD-L1 (SP263) and anti-CD8 (SP57). PD-L1 expression was assessed in tumor cells, as TPS. For statistical analysis, the patients were divided into three groups: consistently negative (all cores with no positive cells), heterogeneous, and consistently PD-L1 high (const-high, all cores with >30% positive cells). Next, for each patient, the mean number of TILsCD8 per 1.76 mm2 of invasive tumor was calculated and recorded semi-quantitatively. Scores of <5, 6–50, 51–199, and ≥200 lymphocytes per core were rated as immunoscores (IMs) of 0, 1, 2, and 3, respectively. For statistical analyses, patients were divided into two groups: TILsCD8-negative (IM = 0) and TILsCD8-positive (IM ≥ 1). [Display omitted] The study group was compromised of 61 patients (OC, n=33; PX, n=28). The cumulative 5-year overall survival (5YOS) rate was 57.58% and 64.29%, respectively. Patients were treated between 2012 and 2018, postoperatively (PORT; n=26) or qualified for definitive CRT (n=35). HPV-positive cancers accounted for 3% of OC and 54% of PX. In the OC and PX groups, more patients were PD-L1 negative, 57% and 67%, respectively (Table 1). The univariate analysis showed no influence of PD-L1 expression values on long-term survival. However, the survival curves of patients with PX and PD-L1 expression ≥1% vs. <1% visibly separate (p=0.18) (Figure 1). Most of the examined patients with OC showed a positive TILsCD8 score, with longer 5YOS compared to patients with score 0, however the difference did not reach statistical significance (OC - 48.3% vs 25%; p=0.65). [Display omitted] In our analysis, no association of PD-L1 expression and TILsCD8+ score, and patient outcome can be found. In univariate analysis we did not find any predictive factors for RT response. The main limitation of our study was very small group sizes. [ABSTRACT FROM AUTHOR]

Background: Presently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique. This study aimed to assess the oncological outcomes of this population treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure. Material and methods: Between 2011 and 2019, 167 patients were included (40% of oropharyngeal cancers, and 60% of oral cavity cancers). The median age was 60 years. There was 64.2% of stage IV cancers. All patients had both T and N surgery. 34% had a R1 margin, 42% had perineural invasion. 72% had a positive neck dissection and 42% extranodal extension (ENE). All patients were treated with VMAT with simultaneous integrated boost with three dose levels: 66Gy in case of R1 margin and/or ENE, 59.4-60Gy on the tumor bed, and 54Gy on the prophylactic areas. Concomittant cisplatin was administrated concomitantly when feasible in case of R1 and/or ENE. Results: The 1- and 2-year loco-regional control rates were 88.6% and 85.6% respectively. Higher tumor stage (T3/T4), the presence of PNI, and time from surgery >45 days were significant predictive factors of worse loco-regional control in multivariate analysis (p=0.02, p=0.04, and p=0.02). There were 17 local recurrences: 11 (64%) were considered as infield, 4 (24%) as marginal, and 2 (12%) as outfield. There were 9 regional recurrences only, 8 (89%) were considered as infield, and 1 (11%) as outfield. The 1- and 2-year disease-free survival (DFS) rates were 78.9% and 71.8% respectively. The 1- and 2-year overall survival (OS) rates were 88.6% and 80% respectively. Higher tumor stage (T3/T4) and the presence of ENE were the two prognostic factors significantly associated with worse DFS and OS in multivariate analysis. Conclusion: Our outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are encouraging, with high rates of loco-regional control. However, the management of ENE still seems challenging. [ABSTRACT FROM AUTHOR]

Simple Summary: Oropharyngeal cancers may be difficult to detect with current clinical and radiographic examinations. This study explores whether a new transoral ultrasound technique using high-resolution, small-footprint ultrasound transducers can improve the detection and staging of oropharyngeal cancers in an outpatient setting. We found that clinicians can use transoral ultrasound to improve the diagnostic workup of oropharyngeal cancers with an accuracy comparable to magnetic resonance imaging. Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs. [ABSTRACT FROM AUTHOR]

Simple Summary: The impact of the relation of human papillomavirus (HPV) infection and smoking status of oropharyngeal squamous cell carcinoma (OPSCC) on overall survival (OS) was investigated in a retrospective population-based study in Thuringia, Germany. All patients with OPSCC (from 2018 to 2020) were included. OPSCC cases were 37.3% HPV-positive (+) (31.2% smokers; mean incidence: 2.91/100,000 population) and 57.8% HPV-negative (63.5% smokers; mean incidence: 4.50/100,000 population). HPV+ patients had significantly better OS than HPV-negative (−) patients. In multivariable analysis, HPV− patients had an increased 4.5-fold higher hazard of death, but the smoking status had no independent influence on risk of death. In binary logistic regression analysis, smokers showed a 4.5 increased odds ratio (OR) of being tested HPV− than for nonsmokers. HPV− smokers formed the majority in Thuringia. Optimizing OPSCC therapeutic strategies due to the dominance of HPV− is more important than discussing de-escalation strategies for HPV+ patients. The impact of the relation of human papillomavirus (HPV) and smoking status of oropharyngeal squamous cell carcinoma (OPSCC) on overall survival (OS) was investigated in a retrospective population-based study in Thuringia, Germany. A total of 498 patients with OPSCC (76.9% men; mean age 62.5 years) from 2018 to 2020 were included. OPSCC cases were 37.3% HPV-positive (+) (31.2% smokers; mean incidence: 2.91/100,000 population) and 57.8% HPV-negative (63.5% smokers; mean incidence: 4.50/100,000 population). Median follow-up was 20 months. HPV+ patients had significantly better OS than HPV-negative (−) patients (HPV+: 2-year OS: 90.9%; HPV−: 2-year OS: 73.6%; p < 0.001). In multivariable analysis, HPV− patients (hazard ratio (HR) = 4.5; 95% confidence interval (CI): 2.4–8.6), patients with higher N classification (N2: HR = 3.3; 95% CI: 1.71–6.20; N3: HR = 3.6; 95% CI: 1.75–7.31) and with a higher cancer staging (III: HR = 5.7; 95% CI: 1.8–17.6; IV: HR = 19.3; 95% CI: 6.3–57.3) had an increased hazard of death. HPV− smokers formed the majority in Thuringia. Nicotine and alcohol habits had no impact on OS. Optimizing OPSCC therapeutic strategies due to the dominance of HPV− is more important than discussing de-escalation strategies for HPV+ patients. [ABSTRACT FROM AUTHOR]

The prognosis after primary (chemo-)radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) is affected by Human Papillomavirus (HPV) status, with a better prognosis in HPV-positive OPSCC. HPV-status is routinely assessed by p16 immunohistochemistry (IHC), but additional HPV DNA testing is debated. Also, there are numerous HPV genotypes, which prognostic role may need clarification. The purpose of this study was: (1) to test a custom-made targeted HPV next generation sequencing (NGS) panel in OPSCC, (2) to determine correlation with p16 IHC, and (3) to assess the impact of HPV DNA testing on outcome in the prospectively randomized clinical trial DAHANCA 19. We included 271 patients with OPSCC treated with primary (chemo-)radiotherapy in the DAHANCA 19 trial. Of these, 199 (73%) were p16-positive. HPV-status was determined by targeted HPV next generation sequencing (NGS), using a custom-made HPV genotyping panel. HPV was detected in 194 tumor samples. p16 IHC and NGS HPV status were concordant in 265 (98%) of 271 patients, whereas we did not detect HPV DNA in 5 p16-positive tumors. HPV16 accounted for 169 of 194 HPV-positive cases (87%). HPV genotypes 18, 31, 33, 35, and 59 were also detected. Loco-regional failure and overall survival were similar whether patients were separated by p16 IHC, or HPV DNA status (p < 0.0001 for all) and did not depend on HPV genotype (p = 0.9 and p = 0.7). In the present study, HPV DNA testing or typing in a Danish OPSCC cohort did not add additional information to p16 IHC, the most widely used and accepted prognostic indicator. [ABSTRACT FROM AUTHOR]

The possibility of detecting circulating tumor HPV DNA (ctHPVDNA) in plasma in patients with oropharyngeal cancer has been demonstrated in several reports. However, these data are from small cohorts and available tests for detection of ctHPVDNA are not fully validated. The aim is to evaluate sensitivity, specificity, and accuracy of ctHPVDNA by ddPCR to define its efficacy in the clinical setting for the diagnosis of HPV + OPSCC. A comprehensive search of three different databases: MEDLINE, Embase, and Cochrane Library databases. A total of 998 patients were evaluated from the 13 studies. OPSSC p16+ were 729, while controls p16− were 269. The meta‐analytic study estimated the diagnostic performance of ctHPVDNA as follows: pooled sensitivity and specificity of 0.90 (95% CI: 0.82–0.94) and 0.94 (95% CI: 0.85–0.98), respectively; positive and negative likelihood ratios of 12.6 (95% CI: 4.9–32.1) and 0.05 (95% CI: 0.02–0.13), respectively. ddPCR for ctHPVDNA has good accuracy, sensitivity, and specificity for diagnosis of HPV + OPSCC. ctHPVDNA kinetic represents a great reliable opportunity to improve diagnostic and therapeutic management of cancer patients and could open new perspectives for understanding tumor biology. [ABSTRACT FROM AUTHOR]

Objective: Oropharyngeal cancer, a type of head and neck cancer (HNC), the incidence of which is increasing, often affects younger patients than traditional HNC, having distinct psychosocial consequences. Treatment side effects mean many rely on informal caregivers following (chemo)radiotherapy. The purpose of this review was to describe current understanding of the psychosocial experiences of these caregivers in the post‐treatment phase. Methods: A systematic search for relevant studies between January 2010 and October 2022 in three electronic databases (CINAHL, MEDLINE and PsycINFO) was followed by citation searching. Inclusion criteria were developed to ensure studies explored caregivers' experiences during the post‐treatment phase following oropharyngeal cancer (chemo)radiotherapy. Thematic analysis informed by the 'Cancer Family Caregiving Experience Model', identified stressors, appraisals and responses. Themes evolved through the synthesis of recurrent concepts across the studies and a narrative of psychosocial experiences and their impact upon caregiver well‐being was developed. Results: Fifteen HNC papers which included exploration of the psychosocial experiences of oropharyngeal cancer caregivers following (chemo)radiotherapy were selected. Findings were synthesised to develop five themes: an emotional struggle, supporting nutrition, altered lifestyles, changes within relationships and support needs. Conclusions: The completion of (chemo)radiotherapy signalled a transition for these caregivers as they undertook burdensome responsibilities. Experiences indicated that preparation for the role, assessment of needs, and targeted support is required. Additionally, caregivers' recognition by healthcare professionals as caring partners could help moderate this demanding experience. [ABSTRACT FROM AUTHOR]

Th e incidence of human papillomavirus (HPV)-associated head and neck cancer (HNC) has been rapidly increasing in developed countries, with HPV-associated HNC now accounting for 70% of all HNC cases. An increased incidence has been noted particularly among males. Th e disparities in HPV vaccine uptake rates and the increasing number of individuals with HPV-associated HNC suggest a lack of public awareness of both HPV sequelae and prevention options. Th is review highlights the importance of prophylactic HPV vaccination for preventing HPV-associated HNC, particularly in males. Current evidence substantiates the need for gender-neutral HPV vaccination programs and reinforces the recommendations made by the CDC. Th is article raises awareness of the association between HPV and HNC as well as the eff ectiveness of HPV vaccination in HNC prevention. [ABSTRACT FROM AUTHOR]