Oropharyngeal Squamous Cell Carcinoma Patients Research Articles

Sex-Specific Survival and Treatment Delay in Oropharyngeal Squamous Cell Carcinoma.

As the majority of oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed in males, outcomes among females are not well-characterized. We identify sex-specific factors in OPSCC to refine female prognostication. Retrospective cohort. National Cancer Database (NCDB). OPSCC cases from the 2004 to 2019 NCDB were identified. Sociodemographic, clinical, and treatment characteristics (including timing between diagnosis and treatment administration) were compared between sexes. Multivariable Cox proportional hazard regression models were constructed to characterize survival in overall and female-only cohorts. Similar multivariable binomial logistic regression and survival models were constructed to assess odds of treatment delays and their effects on survival, respectively. A total of 192,973 OPSCC patients were identified; 36,695 (19%) were female. Females had more human papillomavirus (HPV) negative, lower clinical T and N stage, and higher comorbidity disease. Females experienced lower survival in HPV negative (hazard ratio, HR = 1.11, P < .001) but not HPV-positive disease. Females were more likely to have any treatment initiated over the median of 28 days (odds ratio, OR = 1.04, P = .014) or delays in adjuvant radiotherapy initiation over 6 weeks (OR = 1.11, P = .032). Treatment delay over 60 days (HR = 1.17, P = .016) and delay in adjuvant therapy initiation (HR = 1.24, P = .02) were associated with worse survival among females. In one of the largest analyses of OPSCC, females had poorer survival than males, specifically in HPV-negative disease, despite presentation with less advanced disease. Notably, delays in any treatment initiation and adjuvant radiotherapy initiation were more likely in HPV-negative women and associated with worse survival, highlighting potential systemic weaknesses contributing to poor prognosis among females.

Global DNA Methylation Level in Tumour and Margin Samples in Relation to Human Papilloma Virus and Epstein-Barr Virus in Patients with Oropharyngeal and Oral Squamous Cell Carcinomas.

Aberrant DNA methylation is a common epigenetic modification in cancers, including oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Therefore, the analysis of methylation levels appears necessary to improve cancer therapy and prognosis. The enzyme-linked immunosorbent assay (ELISA) was used to analyse global DNA methylation levels in OPSCC and OSCC tumours and the margin samples after DNA isolation. HPV detection was conducted by hybridisation using GenoFlow HPV Array Test Kits (DiagCor Bioscience Inc., Hong Kong, China). EBV detection was performed using real-time PCR with an EBV PCR Kit (EBV/ISEX/100, GeneProof, Brno, Czech Republic). OPSCC tumour samples obtained from women showed lower global DNA methylation levels than those from men (1.3% vs. 3.5%, p = 0.049). The margin samples from OPSCC patients with HPV and EBV coinfection showed global DNA methylation lower than those without coinfection (p = 0.042). G3 tumours from OSCC patients had significantly lower levels of global DNA methylation than G2 tumours (0.98% ± 0.74% vs. 3.77% ± 4.97%, p = 0.010). Additionally, tumours from HPV-positive OSCC patients had significantly lower global DNA methylation levels than those from HPV-negative patients (p = 0.013). In the margin samples, we observed a significant negative correlation between global DNA methylation and the N stage of OSCC patients (rS = -0.33, p = 0.039). HPV-positive OPSCC patients had higher global DNA methylation levels than HPV-positive OSCC patients (p = 0.015). We confirmed that methylation could be changed in relation to viral factors, such as HPV and EBV, as well as clinical and demographical parameters.

Treatment Delay and HPV Status on OPSCC With Upfront Surgery: Analysis of National Cancer Database.

Evaluate the effect of treatment delay on survival in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing primary surgical resection. Retrospective cohort study using the 2010-2017 National Cancer Database. Multicenter database study. Patients >18 years old with OPSCC and known HPV status, treated surgically with or without postoperative radiation/chemotherapy were included. Two cohorts based on HPV status were grouped by time to treatment initiation (TD-TI, ≤30, 31-60, ≥61 days) and surgery to radiotherapy (TS-RT, ≤42, 43-66, ≥67 days). Univariate, Kaplan-Meier, and multivariate analyses assessed correlations between demographic and clinical factors with overall survival in treatment delay groups. Included were 1643 HPV-positive OPSCC patients and 391 HPV-negative OPSCC patients. No associations between survival and gender, age, race, insurance, or radiotherapy length were observed. Regardless of HPV status, larger tumor size (>2 cm) and lymphovascular invasion predicted worse survival. HPV negative patients with >4 lymph nodes involved had 2.5×greater mortality risk (P = .039). Robotic surgery was associated with improved survival only in HPV positive patients (hazard ratio [HR]: 0.41, P < .001). In HPV positive patients, higher TD-TI related to lower mean survival, although this was not significant on multivariate analysis. HPV negative patients with >42 days of TS-RT had decreased survival (43-66 days, HR 1.63, P = .049; ≥67 days, HR 2.10, P = .032). Longer TS-RT was associated with lower overall survival in HPV negative patients. Treatment delay was not associated with survival in HPV positive OPSCC according to multivariate analysis. These findings enhance knowledge about treatment delay effects in OPSCC, aiding providers in decisions and patient communication.

Abstract 3683: Prognostic value and biological correlates of LINE1 hypomethylation in oropharyngeal cancer

Abstract Background. We have recently demonstrated that LINE-1 hypomethylation is a negative prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive patients with LINE-1 methylation &amp;lt;55% showed an almost 5-fold higher risk of death than hypermethylated once, with an overall survival as poor as HPV-negative patients. Somatic TP53 mutations are a common feature in HPV-negative OPSCC, whereas their presence has been reported in only a small subset of HPV-related OPSCC. At present, little is known about the correlation between LINE-1 methylation and p53 expression status and/or TP53 mutation in OPSCC. Methods. Since 2019, an ongoing prospective study has been enrolling patients with OPSCC in nine cancer centers in Northern Italy. HPV16 E6 DNA was quantified using real-time quantitative PCR (qPCR). LINE-1 methylation was evaluated by methylation-specific qPCR. p53 expression was detected by immunohistochemical staining. TP53 exon mutations were analyzed by Next Generation Sequencing. Results. Up to date, 134 OPSCC patients have been enrolled, including cancer of the tonsil (n=74; 55.2%), base of tongue (n=47; 35.1%), and other subsites (n=13; 9.7%). HPV16 DNA was found in 54.3% of cases: 65.7% in base of tongue, 57.1% in tonsil, and 16.7% in other subsites (p&amp;lt;0.001). LINE-1 methylation was higher in HPV16-positive patients (median: 55.8%, interquartile rage [IQR]: 42.5-68.5) than HPV16-negative ones (median: 40.7; IQR: 23.9-59.1; p=0.003). Nevertheless, the median LINE-1 methylation was lower (50.7%) among HPV-16 OPSCC patients who relapsed than those who did not (56.0%), thus confirming the findings previously reported. However, data from the present investigation are presently not mature to purse the study aims (median follow-up: 12.3 months). The correlation between LINE-1 hypomethylation and p53 expression has also been evaluated in OPSCC patients. p53 expression was categorized into three groups (0%, 1-49%, and ≥50%) based on the overall intensity of nuclear staining of the tumor cells. p53 was considered null, overexpressed, or wild type when its nuclear staining was 0 %, ≥50%, or ranged between 1% and 49%, respectively. Of note, the highest level of LINE-1 methylation was observed in OPSCC tissues with nuclear p53 staining between 1% and 49% (57.8%), whereas OPSCC patients with p53 expression ≥50% showed a decline of LINE-1 methylation levels (40.6; p=0.026). Interestingly, LINE-1 methylation was lower in OPSCC patients harboring TP53 mutations in both HPV16-negative (24.8%) and HPV16-positive (24.0%) OPSCC patients, even if statistical significance was reached only in the HPV-negative group (p=0.015). Conclusion. Preliminary results confirm the potential of LINE-1 methylation to identify HPV16-positive patients with poor prognosis. In addition, this study suggest that TP53 mutations might influence LINE-1 methylation, irrespective of HPV status. Citation Format: Mariateresa Casarotto, Roberto Guerrieri, Paolo Boscolo-Rizzo, Monica Schiappacassi, Sara D'Andrea, Valentina Lupato, Susanna Chiocca, Marta Tagliabue, Rita De Berardinis, Anna Menegaldo, Alice Piccinato, Paola Stritoni, Mohssen Ansarin, Doriano Politi, Giuseppe Fanetti, Giorgio Giurato, Jerry Polesel, Elisabetta Fratta. Prognostic value and biological correlates of LINE1 hypomethylation in oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3683.

Abstract 7382: Artificial intelligence derived features of collagen architecture identify high risk HPV associated oropharyngeal squamous cell carcinoma patients

Abstract Introduction: Human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) is a common subtype of head and neck carcinoma. Dysregulation of the extracellular matrix (ECM), an important part of the tumor microenvironment (TME), is shown in HPV related cancers. We studied collagen fibers (CF), the amplest component of the ECM, and evaluated whether their characteristics within the TME can offer a prognostic value in OPSCC. Methods: Whole slide images (WSIs) of OPSCC patients were obtained from Washington University (WU, n=107), Houston Veterans Administration Hospital (HV, n=94), Cleveland Clinic (CC, n=336), John Hopkins University (JH, n=121) and Vanderbilt Medical Centre (VM, n=158). For the identified CF in tumor-stroma regions of WSIs, the extracted CF features included: CF fragmentation measure, CF bundling percentage, CF rigidity measure, CF anisotropy index, and CF density index. For survival analysis using overall survival (OS) and Disease-Free Survival (DFS) as endpoints, the median risk score in the training set (WU) was applied for risk stratification in the validation sets (HV, CC, JH, VM) by means of a Least Absolute Shrinkage and Selection Operator-Cox regression model. Multivariable Cox Proportional Hazards Regression was done for both OS and DFS. Results: The patients defined as “high risk” had worse OS than those identified as “low risk” (HV(p=0.03), CC(p=0.03), JH(p=0.02), VM(p=0.04)). Multivariable analysis showed that CF features were prognostic independent of T/N stages, age, sex, and smoking status with HR=1.99 (95% CI=1.46-2.72, p=0.00001) for OS and HR=1.73 (95% CI=1.21-247, p=0.002) for DFS (Table 1). Table 1: Multivariable Survival Analysis for OS and DFS, HR=Hazard Ratio, CI=Confidence Interval Variable Overall Survival Disease Free Survival HR (95% CI) P value HR (95% CI) P value Age (&amp;lt;65 years vs. &amp;gt;=65 years) 0.99 (0.93-1.06) 0.78444 0.96 (0.82-1.12) 0.62864 Sex (Female vs. Male) 0.56 (0.29-1.10) 0.09042 0.50 (0.22-1.13) 0.09385 Smoking status (Yes vs. No) 1.85 (1.31-2.62) 0.00051 1.03 (0.72-1.47) 0.86871 T-stage (T3/4 vs T1/2) 1.86 (1.38-2.50) 0.00004 1.91 (1.36-2.69) 0.00018 N-stage (N+ vs N0) 1.76 (1.31-2.37) 0.00016 2.04 (1.46-2.86) 0.00003 Collagen fiber features (High risk vs low risk) 1.99 (1.46-2.72) 0.00001 1.73 (1.21-2.47) 0.00286 Conclusion: Artificial intelligence derived features of CF architecture can help identify high vs low risk patients in HPV related OPSCC. These findings deserve further confirmation in larger prospectively collected OPSCC data sets and could impact future treatment paradigms. Citation Format: Reetoja Nag, Haojia Li, Germán Corredor, Pingfu Fu, Nabil F. Saba, Mehmet A. Bilen, Tilak Pathak, Paula Toro, Mojgan Mokhtari, Krunal Pandav, Michael Gilkey, Shlomo Koyfman, Deborah Chute, Wade L. Thorstad, Mitra Mehrad, Patricia D. Castro, Andrew G. Sikora, Rebecca D. Chernock, Jingqin Luo, Mitchell Frederick, Vlad Sandulache, David J. Adelstein, James Lewis Jr., Anant Madabhushi. Artificial intelligence derived features of collagen architecture identify high risk HPV associated oropharyngeal squamous cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7382.

Abstract 1025: An AI based CT scan classifier for predicting extranodal extension and nodal metastasis of HPV-associated oropharyngeal carcinoma

Abstract Background: Pathologic extranodal extension (ENE) and nodal metastasis (NM) are of prognostic significance in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). The pretreatment identifications of these two factors through computed tomography (CT) imaging are of clinical importance since they could guide treatment de-escalation protocols and select candidates suitable for surgery. In an effort to enhance pretreatment decision making, we developed and validated an AI model (specifically a multi-layer perceptron (MLP)-based deep learning model) to predict radiologic NM and pathologic ENE in HPV-associated OPSCC patients. Methods: Radiographic CT scans for 290 OPSCC patients treated with definitive chemoradiation were acquired from The Cancer Imaging Archive (TCIA) and divided into training (D1) and validation (D2) cohorts for NM prediction. Radiologic NM for D1 and D2 were reviewed by two radiologists. Only nodes with concordant NM judgments from both radiologists were included for analysis. An additional 46 OPSCC patients treated with surgery at Emory Winship Cancer Institute were collected to form the test cohorts (D3) for ENE prediction. The largest metastatic or normal nodes were annotated for D1 and D2 while all visible nodes with pathology confirmation of ENE from D3 were annotated. We present a novel deep-learning model utilizing U-shaped multi-layer perceptron mixer (MLP-Mixer) to capture both global and local feature representations by spatially aggregating image patch information through a procedure called token-mixing. The model was trained for 20 epochs with learning rate of0.0001 and batch size of 64. The diagnostic performance of the AI model was evaluated on D2 and D3 using accuracy and area under the ROC curve (AUROC). Results: There were 121 NM negative and 130 NM positive nodes in D1, 14 NM negative and 25 NM positive nodes in D2 and 46 ENE negative and 20 ENE positive nodes in D3. On D2 for NM prediction, the AI model achieved overall accuracy of 0.77 and AUROC of 0.78. On D3 for ENE prediction, the AI model achieved overall accuracy of 0.71, AUROC of 0.69, positive predictive value of 0.52 and negative predictive value of 0.86. Conclusions: The new AI–based deep learning model was able to identify HPV-associated OPSCC NM and ENE with satisfactory diagnostic performance and shows promise to assist clinicians in treatment decision-making. Additional, multi-site prospective validation of the approach is warranted. Citation Format: Bolin Song, Kailin Yang, Shaoyan Pan, Liping Li, Qiyun Liu, Jonathan Lee, Sarah Stock, Nabil F. Saba, Mehmet Asim Bilen, Mihir R. Patel, Anant Madabhushi. An AI based CT scan classifier for predicting extranodal extension and nodal metastasis of HPV-associated oropharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1025.

Abstract 7661: Integrating radiomic features from primary tumor and lymph node for survival prediction of HPV-associated oropharyngeal squamous cell carcinoma

Abstract Background: HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is a unique disease with improved prognosis which could benefit from treatment de-escalation. Current radiographic-based biomarkers mainly focus on primary tumor (PT) alone, neglecting the potential prognostic value from the lymph node (LN). In this work, we constructed a radiomic model integrating texture features from both PT and LN to predict overall survival (OS) in HPV-associated OPSCC patients. Methods: Pretreatment CT scans for 647 OPSCC patients treated with definitive radiation with or without chemotherapy were acquired from The Cancer Imaging Archive (TCIA) and the Cleveland Clinic (CCF), which were divided into training set D1 (n=294) and test set D2 (n=353). PT and LN contours were annotated by three. 2045 texture radiomic features were extracted from both PT and LN and were concatenated as input to a LASSO Cox model to predict OS. We used the harrell’s concordance index (C-index) and hazard ratio (HR) to evaluate the prognostic performance. We also performed the multivariable cox proportional hazard analysis adjusting for clinicopathological variables to validate the independent prognostic significance. Results: Among the 647 patients, median follow-up time was 70.23 months, with 155 patients (24%) experienced death. 22.6%, 38.8%, 23.2% and 15.4% had T stage I, II, III and IV tumors, respectively. 203 patients (31.4%) were treated with radiation alone. The model integrating PT and LN (M_PTLN) yielded higher C-index compared to PT alone (M_PT) on D1 (0.74 vs 0.66) and on D2 (0.64 vs 0.61). In univariate analysis on D2, M_PTLN is prognostic of OS (HR, 2.26; 95% CI, 1.32 - 3.87; log rank p = 0.003). In multivariable analysis, M_PTLN is still statistically significant (p = 0.04) accounting for clinicopathologic factors (age, gender, smoking pack-year [PY], T stage, N stage and treatment modality). Conclusions: We developed and validated a CT-based survival prediction model for HPV-associated OPSCC patients with significant prognostic values, accounting for both primary tumor and lymph node. If prospectively validated, the model has the potential to inform trial eligibility and treatment-related decision making. Citation Format: Bolin Song, Amaury Leroy, Kailin Yang, Qiyun Liu, Xiao Li, Jonathan Lee, Sarah Stock, Nabil F. Saba, James S. Lewis, Eric Deutsch, Mehmet Asim Bilen, Shlomo A. Koyfman, Anant Madabhushi. Integrating radiomic features from primary tumor and lymph node for survival prediction of HPV-associated oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7661.

Characteristics and Management of Post Treatment Pharyngeal Ulceration in Oropharyngeal Squamous Cell Carcinoma Patients Treated with Definitive Radiation/Chemoradiation

Characteristics and Management of Post Treatment Pharyngeal Ulceration in Oropharyngeal Squamous Cell Carcinoma Patients Treated with Definitive Radiation/Chemoradiation

Human papillomavirus (HPV) load is higher in HPVDNA/p16 positive than in HPVDNA positive/p16 negative oropharyngeal squamous cell carcinoma but does not differ significantly between various subsites or correlate to survival

ObjectivePatients with human papillomavirus DNA positive (HPVDNA+) and p16ink4a overexpressing (p16+) oropharyngeal squamous cell carcinoma (OPSCC), especially those with cancer in the tonsillar and base of tongue subsites as compared to other OPSCC subsites have a better outcome than those with only HPVDNA+ or only p16+ cancer. Likewise having a high viral load has been suggested to be a positive prognostic factor. We therefore hypothesized, that HPV viral load could vary depending on OPSCC subsite, as well as with regard to whether the cancer was HPVDNA+ and p16+, or only HPVDNA+, or only p16+ and that this affected outcome. Material and methodsTo address these issues HPV viral load was determined by HPV digital droplet (dd) PCR in tumor biopsies with previously known HPVDNA/p16 status from 270 OPSCC patients diagnosed 2000–2016 in Stockholm, Sweden. More specifically, of these patients 235 had HPVDNA+/p16+, 10 had HPVDNA+/p16-, 13 had HPVDNA-/p16+ and 12 had HPVDNA-/p16- cancer. ResultsWe found that HPVDNA+/p16+ OPSCC had a significantly higher viral load than HPVDNA+/p16- OPSCC. Moreover, there was a tendency for a higher viral load in the tonsillar and base of tongue OPSCC subsites compared to the other subsites and for a low viral load to correlate to a better clinical outcome but none of these tendencies reached statistical significance. ConclusionTo conclude, the mean viral load in HPVDNA+/p16+ OPSCC was higher than in HPVDNA+/p16- OPSCC, but there was no statistically significant difference in viral load depending on OPSCC subsite or on clinical outcome.

Detection of antibody subclasses IgA, IgM and IgG against HPV L1 in HPV-positive oropharyngeal squamous cell carcinoma patients: a pilot study

PurposeDespite prognostic superiority of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), up to 25% of patients will suffer from recurrence within the first 5 years. Therefore, it is of great scientific interest to find relevant biomarkers to identify patients at risk. In this prospective observational study, we aimed to investigate the dynamics of HPV-L1 capsid protein specific antibody (AB) subclasses IgA, IgM, and IgG in HPV-positive OPSCC patients under therapy.MethodsSerum samples from HPV-positive OPSCC patients, identified by positive p16-immunohistochemistry, were collected before and during tumor-specific therapy and 3–6 months during follow-up. They were analyzed for the presence of HPV-L1 AB subclasses IgA, IgM, and IgG using an HPV-L1-specific immuno-assay. Additionally, a PCR-based HPV-DNA detection from the tumor tissue was performed.ResultsAltogether, 33 patients with a mean follow-up of 55 months were included. Analysis of a total of 226 serum samples revealed that the most common L1-AB-subclass pattern was characterized by IgG >  > IgA > IgM without significant fluctuation during the course of disease. Patients with excessive IgG levels tended to higher tumor stages and three out of three patients with disease recurrence showed increasing IgG AB titers beforehand. Seven patients showed an IgA dominance at diagnosis, which was associated with a better disease-free survival.ConclusionDespite limited cases, our prospective pilot study revealed promising trends in HPV L1 AB subclasses and may contribute useful information for future risk stratification and post-treatment monitoring in HPV-positive OPSCC patients.

Auto-segmentation of neck nodal metastases using self-distilled masked image transformer on longitudinal MR images.

Auto-segmentation promises greater speed and lower inter-reader variability than manual segmentations in radiation oncology clinical practice. This study aims to implement and evaluate the accuracy of the auto-segmentation algorithm, "Masked Image modeling using the vision Transformers (SMIT)," for neck nodal metastases on longitudinal T2-weighted (T2w) MR images in oropharyngeal squamous cell carcinoma (OPSCC) patients. This prospective clinical trial study included 123 human papillomaviruses (HPV-positive [+]) related OSPCC patients who received concurrent chemoradiotherapy. T2w MR images were acquired on 3 T at pre-treatment (Tx), week 0, and intra-Tx weeks (1-3). Manual delineations of metastatic neck nodes from 123 OPSCC patients were used for the SMIT auto-segmentation, and total tumor volumes were calculated. Standard statistical analyses compared contour volumes from SMIT vs manual segmentation (Wilcoxon signed-rank test [WSRT]), and Spearman's rank correlation coefficients (ρ) were computed. Segmentation accuracy was evaluated on the test data set using the dice similarity coefficient (DSC) metric value. P-values <0.05 were considered significant. No significant difference in manual and SMIT delineated tumor volume at pre-Tx (8.68 ± 7.15 vs 8.38 ± 7.01 cm3, P = 0.26 [WSRT]), and the Bland-Altman method established the limits of agreement as -1.71 to 2.31 cm3, with a mean difference of 0.30 cm3. SMIT model and manually delineated tumor volume estimates were highly correlated (ρ = 0.84-0.96, P < 0.001). The mean DSC metric values were 0.86, 0.85, 0.77, and 0.79 at the pre-Tx and intra-Tx weeks (1-3), respectively. The SMIT algorithm provides sufficient segmentation accuracy for oncological applications in HPV+ OPSCC. First evaluation of auto-segmentation with SMIT using longitudinal T2w MRI in HPV+ OPSCC.

Clinical and prognostic differences in oropharyngeal squamous cell carcinoma in USA and Denmark, two HPV high-prevalence areas

BackgroundUncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas. MethodsOPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015-2020, (n=2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1-2N0M0) and high-risk patients (UICC8 III-IV). ResultsThere were significantly more HPV-positive (88.2% vs. 63.1%), males (89.4% vs. 74.1%), never-smokers (52.1% vs. 23.7%), lower UICC8-stage (I/II: 79.3% vs. 68%), and fewer patients treated with radiotherapy (RT) alone (14.8% vs. 30.3%) in the UTMDACC cohort. No difference in the adjusted OS was observed (hazard ratio [HR] 1.21, p=0.23), but a significantly increased RFI HR was observed for the Copenhagen cohort (HR: 1.74, p=0.003). Subgroup analyses of low- and high-risk patients revealed significant clinical and treatment differences. No difference in prognosis was observed for low-risk patients, but the prognosis for high-risk patients in the Copenhagen cohort was worse (OS HR 2.20, p=0.004, RFI HR 2.80, p=0.002). ConclusionsWe identified significant differences in clinical characteristics, treatment modalities, and prognosis between a Northern European and Northern American OPSCC population. These differences are important to consider when comparing outcomes and for patient stratification in clinical trials, as reproducibility might be challenging.

Sarcopenia as a Predictor of Feeding Tube Placement in Individuals with Oropharyngeal Cancer

In oropharyngeal squamous cell carcinoma (OPSCC), systemic loss of skeletal muscle mass (SMM), or sarcopenia, is a strong prognostic predictor of survival outcomes. However, the relationship between sarcopenia and nutrition-related outcomes is not well understood. This investigation evaluated the prognostic significance of sarcopenia for feeding tube (FT) placement in a cohort of OPSCC patients. A retrospective cohort study was conducted with data collected from 194 OPSCC patients treated with definitive radiation therapy (RT) or chemoradiation therapy (CRT). Sarcopenia was assessed from computed tomography imaging at the level of the third cervical (C3) and fourth thoracic (T4) vertebrae. The prognostic nature of pretreatment sarcopenia and its relationship with FT placement was explored using logistic regression. The median age of patients included was 61.0 years, and the majority were male (83%). In this patient cohort, 87.6% underwent concurrent CRT, and 30.9% received a FT over the course of treatment. Sarcopenia was identified at baseline in 72.7% of patients based on C3 SMM measurements and in 41.7% based on measures at the level of T4. Based on measures at both C3 and T4, those with sarcopenia were significantly more likely to receive a FT and had significantly worse freedom from FT placement compared with patients without sarcopenia. Sarcopenia assessed at T4 was a significant predictor of FT placement. SMM measured at T4 may represent a novel and practical biomarker for sarcopenia detection that is associated with the need for FT placement. These findings suggest that the detection of baseline sarcopenia could guide decision-making related to the need for nutritional support in OPSCC patients undergoing RT/CRT.

INHBA is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression.

Patients with HPV-negative OPSCC have a poorer prognosis due to distinct molecular pathways. This study reveals significant transcriptomic differences between HPV-negative and HPV-positive OPSCC, identifying INHBA as a key upregulated gene in HPV-negative OPSCC's oncogenic pathways. INHBA is crucial in promoting EMT, cell proliferation, and an immunosuppressive tumor environment, suggesting its potential as a therapeutic target for HPV-negative OPSCC.

Could MMP3 and MMP9 Serve as Biomarkers in EBV-Related Oropharyngeal Cancer.

The high incidence of, and mortality from, head and neck cancers (HNCs), including those related to Epstein-Barr virus (EBV), constitute a major challenge for modern medicine, both in terms of diagnosis and treatment. Therefore, many researchers have made efforts to identify diagnostic and prognostic factors. The aim of this study was to evaluate the diagnostic usefulness of matrix metalloproteinase 3 (MMP 3) and matrix metalloproteinase 9 (MMP 9) in EBV positive oropharyngeal squamous cell carcinoma (OPSCC) patients. For this purpose, the level of these MMPs in the serum of patients with EBV-positive OPSCC was analyzed in relation to the degree of histological differentiation and TNM classification. Our research team's results indicate that the level of both MMPs is much higher in the EBV positive OPSCC patients compared to the EBV negative and control groups. Moreover, their levels were higher in more advanced clinical stages. Considering the possible correlation between the level of MMP 3, MMP 9 and anti-EBV antibodies, and also viral load, after statistical analysis using multiple linear regression, their high correlation was demonstrated. The obtained results confirm the diagnostic accuracy for MMP 3 and MMP 9. Both MMPs may be useful in the diagnosis of EBV positive OPSCC patients.

Association of circulating tumor HPV16DNA levels and quantitative PET parameters in patients with HPV-positive head and neck squamous cell carcinoma

Circulating tumor DNA (ctDNA), which circulates in the blood after being shed from cancer cells in the body, has recently gained attention as an excellent tumor marker. The purpose of this study was to evaluate whether ct human papillomavirus (HPV) 16 DNA (ctHPV16DNA) levels were associated with quantitative PET parameters in patients with HPV-positive head and neck (HN) squamous cell carcinoma (SCC). Fifty patients with oropharyngeal SCC (OPSCC) and 5 with SCC of unknown primary (SCCUP) before treatment were included. They all underwent blood sampling to test ctHPV16DNA levels and FDG PET-CT examinations. Quantitative PET parameters included SUVmax, metabolic tumor volume (MTV), MTV of whole-body lesions (wbMTV), and 56 texture features. ctHPV16DNA levels were compared to texture features of primary tumors in OPSCC patients (Group A) or the largest primary or metastatic lymph node lesions in OPSCC and SCCUP patients (Group B) and to other PET parameters. Spearman rank correlation test and multiple regression analysis were used to confirm the associations between ctHPV16DNA levels and PET parameters. ctHPV16DNA levels moderately correlated with wbMTV, but not with SUVmax or MTV in Groups A and B. ctHPV16DNA levels exhibited a weak negative correlation with low gray-level zone emphasis in Groups A and B. Multiple regression analysis revealed that wbMTV and high gray-level zone emphasis were the significant factors for ctHPV16DNA levels in Group B. These results were not observed in Group A. This study demonstrated that ctHPV16DNA levels correlated with the whole-body tumor burden and tumor heterogeneity visualized on FDG PET-CT in patients with HPV-positive HNSCC.

Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration. Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed. Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006). Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies.

Multi-Modal Ensemble Deep Learning in Head and Neck Cancer HPV Sub-Typing.

Oropharyngeal Squamous Cell Carcinoma (OPSCC) is one of the common forms of heterogeneity in head and neck cancer. Infection with human papillomavirus (HPV) has been identified as a major risk factor for OPSCC. Therefore, differentiating the HPV-positive and negative cases in OPSCC patients is an essential diagnostic factor influencing future treatment decisions. In this study, we investigated the accuracy of a deep learning-based method for image interpretation and automatically detected the HPV status of OPSCC in routinely acquired Computed Tomography (CT) and Positron Emission Tomography (PET) images. We introduce a 3D CNN-based multi-modal feature fusion architecture for HPV status prediction in primary tumor lesions. The architecture is composed of an ensemble of CNN networks and merges image features in a softmax classification layer. The pipeline separately learns the intensity, contrast variation, shape, texture heterogeneity, and metabolic assessment from CT and PET tumor volume regions and fuses those multi-modal features for final HPV status classification. The precision, recall, and AUC scores of the proposed method are computed, and the results are compared with other existing models. The experimental results demonstrate that the multi-modal ensemble model with soft voting outperformed single-modality PET/CT, with an AUC of 0.76 and F1 score of 0.746 on publicly available TCGA and MAASTRO datasets. In the MAASTRO dataset, our model achieved an AUC score of 0.74 over primary tumor volumes of interest (VOIs). In the future, more extensive cohort validation may suffice for better diagnostic accuracy and provide preliminary assessment before the biopsy.

PSMD1 as a prognostic marker and potential target in oropharyngeal cancer

BackgroundDespite 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.MethodsWe 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.ResultsH-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).ConclusionsIn 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.

A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas.

We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.