Head And Neck Squamous Cell Cancer Patients Research Articles

EZH2 Expression in Head-and-Neck Squamous Cell Cancer in Young Patients.

EZH2 (Enhancer of zeste homolog 2) promotes tumor growth and survival through numerous mechanisms and is a promising target for novel therapeutic approaches. We aimed to characterize the expression of EZH2 in the tumors of young head-and-neck squamous cell cancer (HNSCC) patients in comparison with the general HNSCC patient population. We used formalin-fixed, paraffin-embedded tissue blocks from 68 random young HNSCC patients (≤39 years, median age: 36 years; diagnosed between 2000 and 2018), which were compared with the samples of 58 age- and gender-matched general HNSCC subjects (median age: 62 years; all diagnosed in the year 2014). EZH2 and p53 expression of the tumors was detected using immunohistochemical staining. Lower EZH2 expression was found to be characteristic of the tumors of young HNSCC patients as opposed to the general population (median EZH2 staining intensity: 1 vs. 1.5 respectively, p < 0.001; median fraction of EZH2 positive tumor cells: 40% vs. 60%, respectively, p = 0.003, Mann-Whitney). Cox analysis identified a more advanced T status (T3-4 vs. T1-2), a positive nodal status, and alcohol consumption, but neither intratumoral EZH2 nor p53 were identified as predictors of mortality in the young patient group. The lower EZH2 expression of young HNSCC patients' tumors discourages speculations of a more malignant phenotype of early-onset tumors and suggests the dominant role of patient characteristics. Furthermore, our results might indicate the possibility of an altered efficacy of the novel anti-EZH2 therapies in this patient subgroup.

Sarcopenia accompanied by systemic inflammation can predict clinical outcomes in patients with head and neck cancer undergoing curative therapy.

Evaluation of sarcopenia accompanied by systemic inflammation status is a more beneficial prognostic marker than sarcopenia alone in various cancers. However, few studies have focused on this combination in patients with head and neck squamous cell cancer (HNSCC). In this study, we investigated how the combination of sarcopenia and systemic inflammation could affect survival in patients with HNSCC. Moreover, we explored which systemic inflammation markers could be better prognostic indicators when accompanied by sarcopenia. We retrospectively reviewed the medical records of patients with HNSCC treated between 2012 and 2016. Sarcopenia was defined by the skeletal muscle area measured on a computed tomography image slice at the level of the third cervical vertebra. The neutrophil/lymphocyte, platelet/lymphocyte, and lymphocyte/monocyte ratios (NLR, PLR, and LMR, respectively) were used as systemic inflammation markers that were combined with sarcopenia to evaluate prognosis. A total of 100 patients were enrolled, and 71 patients were considered sarcopenia. Patients with sarcopenia had significantly lower LMR and higher NLR and PLR. They also showed worse overall survival (OS) and progression-free survival (PFS). The comparative assessment of multiple combination patterns of sarcopenia and systemic inflammation indices proved that sarcopenia plus LMR considered as most reliable indicator for prognosis in HNSCC patients. Sarcopenia plus low LMR was a significantly poor prognostic factor both for OS and PFS with greater HR values than sarcopenia alone. The combination of sarcopenia and LMR was considered the most sensitive prognostic factor in patients with HNSCC, suggesting it might be beneficial for identifying poor outcome risks.

Safety outcomes of pembrolizumab with platinum agent chemotherapy combined with 5-fluorouracil or taxane derivative in head and neck cancer.

For patients with metastatic head and neck squamous cell cancer (HNSCC), the outcomes of pembrolizumab in combination with a platinum agent and taxane as first-line therapy remain unknown. The purpose of this study is to characterize the impact of substituting the 5-fluorouracil (5-FU) backbone for a taxane in this chemoimmunotherapy regimen on safety/tolerability and survival outcomes. This was an IRB-approved, single-center, retrospective, active comparator, new-user design study in adult patients with HNSCC treated between January 2018 and September 2021. The primary objective was to assess safety and tolerability of pembrolizumab in combination with a platinum agent and taxane against an active comparator arm of pembrolizumab in combination with a platinum agent and 5-FU. Safety and tolerability were evaluated by assessing differences in overall toxicities, with further secondary analysis evaluating differences in hematologic toxicities and pre-defined non-hematologic toxicities. There was no statistical difference demonstrated with the primary endpoint between the cohorts. Reduced toxicity rates were found in the taxane arm for mucositis and creatinine levels. No grade 4 non-hematologic toxicities were reported. Patients receiving 5-FU were more likely to have dose reductions upfront, discontinue treatment due to intolerances and had significantly higher mucositis. This study helps to characterize the safety profile and activity of pembrolizumab in combination with a platinum agent and taxane derivative in HNSCC patients. Within our study, substitution of 5-FU with a taxane did not show an increased risk of toxicities, worsened survival, or decreased odds of achieving a response. Mucositis and elevated creatinine rates were significantly reduced within the taxane arm.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model, cellular platform, and clinical human data.

Head and neck squamous cell cancer (HNSCC) is a leading global malignancy. Every year, More than 830 000 people are diagnosed with HNSCC globally, with more than 430 000 fatalities. HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics. It originates from the squamous epithelium of the oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. The most frequently impacted regions are the tongue and larynx. Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC. Despite the advances in our knowledge, the improved survival rate of HNSCC patients over the last 40 years has been limited. Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods. These results indicate a need to identify more genetic factors underlying this complex disease, which can be better used in early detection and prevention strategies. The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors. In this report, we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes (e.g. Smad4 and P53 genes) to identify genetic factors affecting the development of this complex disease using genome-wide association studies, epigenetics, microRNA, long noncoding RNA, lncRNA, histone modifications, methylation, phosphorylation, and proteomics.

Circular RNA from Tyrosylprotein Sulfotransferase 2 Gene Inhibits Cisplatin Sensitivity in Head and Neck Squamous Cell Carcinoma by Sponging miR-770-5p and Interacting with Nucleolin.

Chemoresistance poses a significant challenge in the treatment of advanced head and neck squamous cell cancer (HNSCC). The role and mechanism of circular RNAs (circRNAs) in HNSCC chemoresistance remain understudied. We conducted circRNA microarray analysis to identify differentially expressed circRNAs in HNSCC. The expression of circRNAs from the tyrosylprotein sulfotransferase 2 (TPST2) gene and miRNAs was evaluated through qPCR, while the circular structure of circTPST2 was verified using Sanger sequencing and RNase R. Through Western blotting, biotin-labeled RNA pulldown, RNA immunoprecipitation, mass spectrometry, and rescue experiments, we discovered miR-770-5p and nucleolin as downstream targets of circTPST2. Functional tests, including CCK8 assays and flow cytometry, assessed the chemoresistance ability of circTPST2, miR-770-5p, and Nucleolin. Additionally, FISH assays determined the subcellular localization of circTPST2, miR-770-5p, and Nucleolin. IHC staining was employed to detect circTPST2 and Nucleolin expression in HNSCC patients. circTPST2 expression was inversely correlated with cisplatin sensitivity in HNSCC cell lines. Remarkably, high circTPST2 expression correlated with lower overall survival rates in chemotherapeutic HNSCC patients. Mechanistically, circTPST2 reduced chemosensitivity through sponge-like adsorption of miR-770-5p and upregulation of the downstream protein Nucleolin in HNSCC cells. The TCGA database revealed improved prognosis for patients with low circTPST2 expression after chemotherapy. Moreover, analysis of HNSCC cohorts demonstrated better prognosis for patients with low Nucleolin protein expression after chemotherapy. We unveil circTPST2 as a circRNA associated with chemoresistance in HNSCC, suggesting its potential as a marker for selecting chemotherapy regimens in HNSCC patients. Further exploration of the downstream targets of circTPST2 advanced our understanding and improved treatment strategies for HNSCC.

Timely Initiation of Radiation Treatment for Primary Head and Neck Squamous Cell Carcinoma in an Urban Safety Net Hospital during the COVID-19 Pandemic

Delayed initiation of radiation treatment for head and neck squamous cell cancer (HNSCC) may lead to worse survival, higher recurrence, and increased financial burden on patients. In times of limited resources, timely treating underserved population of HNSCC patients pose a special challenge to a safety net setting. This single-institutional study aims to characterize and compare treatment delays in HNSCC before and during the COVID-19 pandemic at an urban safety net hospital in Los Angeles to assess the success of efforts made to deliver timely care. Patients who received definitive or post-operative radiotherapy for treatment of primary HNSCC at LAC+USC Medical Center between 2010-2021 were retrospectively reviewed. Time to treatment initiation (TTI) was defined as date of histopathological diagnosis to date of first radiation treatment for definitive and date of surgery to date of first radiation treatment for post-operative patients. Among 70 patients with HNSCC (mean age at diagnosis 55 years, 79% male), 31 patients (18 pre-pandemic, 13 peri-pandemic) were treated definitively with chemoradiation, and 39 patients (24 pre-pandemic, 15 peri-pandemic) were treated post-operatively. Overall, the median TTI was 50 days (interquartile range, IQR 42-74 days); median TTI for pre-pandemic HNSCC patients was 49 days (IQR 43-70 days) and median TTI for peri-pandemic HNSCC patients was 51 days (IQR 43-75 days). The median TTI for definitive radiation was 52 days (IQR 42-93) for pre-pandemic and 52 days (IQR 44-61) for peri-pandemic patients. The median TTI for post-operative radiation was 47 days (IQR 41-75) for pre-pandemic and 50 days (IQR 48-73) for peri-pandemic patients. During the pandemic, there were fewer (38% vs 44%) definitive patients whose TTI exceeded 60 days, whereas more (40% vs 33%) post-operative patients had TTI >60 days. By prioritizing treatment of definitive and high-risk post-operative HNSCC patients according to ASTRO-ESTRO consensus guidelines, expanding the use of telephone follow-up to ensure continuity of care, teleconferencing for multidisciplinary tumor board discussions, and initiating COVID-19 protocols in which mildly symptomatic patients were treated at the end of the day, we were able to maintain timely initiation of radiation treatment not compromised by the pandemic.

Impact of radiation dose on patient-reported acute taste alteration in a prospective observational study cohort in head and neck squamous cell cancer (HNSCC)

PurposeTaste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in relation to patient-assessed taste impairment in a prospective cohort treated with intensity-modulated radiotherapy.MethodsAll patients with locally advanced HNSCC and amenable to radical treatment were included. Chemotherapy-induced taste alteration scale (CITAS), EORTC QLQ-C30 and QLQ-HN43 questionnaires at baseline (T0), 3 weeks (T1) and 3 months (T2) after radiotherapy conclusion were used to assess taste impairment. Base of tongue, submandibular glands (SG), parotid glands (PG) and taste buds, along with anterior and medium third of the tongue, were considered as organs at risk and thus delineated according to consensus guidelines. The mean dose to the above-mentioned structures was correlated with patient-reported outcomes.ResultsBetween September 2019 and November 2020, 33 patients were recruited, 31 of which analyzed. 71% had oropharyngeal carcinoma, mostly HPV-related (60%). All were treated with tomotherapy. 77.4% had concurrent cisplatin. Mean scores of general taste alterations, global health status and dry mouth and sticky saliva were assessed. The mean doses to the anterior third, medium third and base of the tongue were 23.85, 35.50 and 47.67 Gy, respectively. Taste buds received 32.72 Gy; right and left parotid 25 and 23 Gy; right and left submandibular glands 47.8 and 39.4 Gy. At univariate analysis, dysgeusia correlated with SG mean dose (95% CI 0–0.02 p = 0.05) and PG mean dose (95% CI 0–0.02 p = 0.05); dry mouth with mean dose to anterior (95% CI 0.03–1.47 p = 0.04) and medium third (95% CI 0.02–0.93 p = 0.04) of the tongue, to taste buds (95% CI 0.06–0.96 p = 0.03) and to SGs (95% CI 0.06–0.63 p = 0.02); pain mouth with mean dose to taste buds (95% CI 0–0.02 p = 0.04), to SGs (95% CI 0–0.03 p = 0.03) and to base tongue (95% CI 0–0.02 p = 0.02).ConclusionsOur analysis supports the influence of dose distribution on the development of TA in HNSCC patients. The contribution of dose to taste buds and tongue subvolumes remains unclear and worthy of further investigation.

CT-Based Screening for Pulmonary Metastases in Head and Neck Squamous Cell Cancers: Diagnostic Accuracy and Cost Comparison with PET-CECT.

This study's objective was to compare detection rates of radiograph, computed tomography (CT), and positron emission tomography-contrast-enhanced computed tomography (PET-CECT) for pulmonary metastasis/synchronous primary lung tumors in head and neck squamous cell cancer (HNSCC) and its association with clinico-radio-pathological factors. Our retrospective study included 837 HNSCC patients from January 2012 to December 2017. Lung nodules were characterized on CT as benign, indeterminate, and metastatic. The true detection rate and statistical significance of associated risk factors were calculated. Risk factors for metastasis were determined using univariate and multivariate logistic regression models. Seventy-five (8.9%) patients had pulmonary metastasis and 3 (0.3%) had second lung primary. Detection rate of pulmonary metastasis by CT was higher (sensitivity-97.3%, specificity-97.2%) as compared to radiograph (sensitivity 49% and specificity 89%). Correlation was found between pulmonary and extra-pulmonary metastasis and N classification (P = 0.01, P = 0.02) and positive low jugular node (P = 0.001, P = 0.001). Using PET-CECT in place of CT costed an extra outlay of 7,033,805 INR (95,551.85 USD) while detecting distant metastasis in only 4 (0.47%) extra cases. Chest CT is a useful pulmonary metastases screening tool in advanced HNSCC patients with reasonable imaging cost as compared to PET-CT.

High 4-1BB Expression in PBMCs and Tumor Infiltrating Lymphocytes (TILs) in Patients with Head and Neck Squamous Cell Carcinoma.

4-1BB is a costimulatory immune-activating molecule. Increased amounts of this protein have previously been found in the plasma of patients with oropharyngeal and oral cancer. Here, we focused on this molecule that functions as part of the immune system. We investigated 4-1BB in the peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) of patients with head and neck squamous cell cancer (HNSCC). The expression level of 4-1BB in the PBMCs was determined using real-time polymerase chain reaction (PCR). The TIMER (Tumor Immune Estimation Resource) web server was utilized to approximate the 4-1BB level in HNSCC TILs. Moreover, 4-1BB immunohistochemistry (IHC) was used to validate TILs in four organs of HNSCC, including oral cancer (OC), oropharyngeal cancer (OPC), sinonasal cancer (SNC), and laryngeal cancer (LC), in both the tumor area and adjacent normal epithelium. The difference in 4-1BB expression levels in various groups was assessed using a Kruskal-Wallis test and an independent sample t-test. The level of 4-1BB expression in PBMCs was highest in OPC, followed by OC and healthy controls (HC). Significant differences were discovered between HC and OPC and between OC and OPC. Bioinformatics revealed a substantial correlation between 4-1BB expression level and lymphocyte infiltration in HNSCC, including B cells, CD8+ T cells, and CD4+ T cells. IHC validation in HNSCC tissue revealed that the average number of 4-1BB positive TILs in all four HNSCC subtypes was considerably greater than the number of lymphocytes seen in adjacent normal tissue. Interestingly, the number of lymphocytes that were 4-1BB positive increased in relation to the TIL level. A higher number of 4-1BB expression levels were found in the PBMCs and TILs of HNSCC patients, implying that 4-1BB may be a promising approach for HNSCC patients to improve their immune function. It is important to study and create a treatment that uses 4-1BB medicine as well as existing drugs.

Diagnostic performance of FDG PET/MRI for cervical lymph node metastasis in patients with clinically N0 head and neck cancer.

Treatment management in cases of head and neck squamous cell cancer (HNSCC) that are clinically negative for lymph node metastases (cN0) is still an important topic of discussion. There is increasing interest in sensitive imaging modalities that can detect the risk of occult metastases at levels below 20%. This study aimed to examine the efficacy of integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) in determining neck nodal metastasis status in cN0 patients with HNSCC. In this retrospective study, 44 patients who underwent neck dissection with the diagnosis of HNSCC between January 2018 and August 2020 were analyzed. Clinical examinations, including ultrasonography, were performed to identify cervical metastases in HNSCC patients with preoperative cN0. A nuclear medicine specialist visually evaluated the MRI, PET, and PET/MRI results. Histopathologically, 86.4% of patients were classified as N0. According to the histopathological results, MRI showed 50% sensitivity, 89.5% specificity, 91.8% negative predictive value (NPV), 42.8% positive predictive value (PPV) and 84% accuracy, while PET showed 83.3% sensitivity, 68.4% specificity, 96.2% NPV, 29.4% PPV and 70.4% accuracy. PET/MRI was more successful in distinguishing pathological N0 and N+ patients (83.3% sensitivity, 92.1% specificity, 97.2% NPV, 62.5% PPV and 90.9% accuracy). PET/MRI is more sensitive and has a higher NPV compared to MRI alone, while its sensitivity was found to be comparable to that of PET. In addition, with its ability to detect pathological N0 patients, PET/MRI may significantly decrease the number of unnecessary neck dissections.

Synergistic Interaction of the Class IIa HDAC Inhibitor CHDI0039 with Bortezomib in Head and Neck Cancer Cells.

In contrast to class I/IIb/pan histone deacetylase inhibitors (HDACi), the role of class IIa HDACi as anti-cancer chemosensitizing agents is less well understood. Here, we studied the effects of HDAC4 in particular and the class IIa HDACi CHDI0039 on proliferation and chemosensitivity in Cal27 and cisplatin-resistant Cal27CisR head and neck squamous cell cancer (HNSCC). HDAC4 and HDAC5 overexpression clones were generated. HDAC4 overexpression (Cal27_HDAC4) increased proliferation significantly compared to vector control cells (Cal27_VC). Chicken chorioallantoic membrane (CAM) studies confirmed the in vitro results: Cal27_HDAC4 tumors were slightly larger than tumors from Cal27_VC, and treatment with CHDI0039 resulted in a significant decrease in tumor size and weight of Cal27_HDAC4 but not Cal27_VC. Unlike class I/pan-HDACi, treatment with CHDI0039 had only a marginal impact on cisplatin cytotoxicity irrespective of HDAC4 and HDAC5 expression. In contrast, the combination of CHDI0039 with bortezomib was synergistic (Chou-Talalay) in MTT and caspase 3/7 activation experiments. RNAseq indicated that treatment with CHDI0039 alters the expression of genes whose up- or downregulation is associated with increased survival in HNSCC patients according to Kaplan-Meier data. We conclude that the combination of class IIa HDACi with proteasome inhibitors constitutes an effective treatment option for HNSCC, particularly for platinum-resistant cancers.

Marathi translation, linguistic validation, and cross-cultural adaptation of M.D. Anderson dysphagia inventory in patients of head and neck squamous cell cancer.

Self-reported treatment outcome is a better way to measure patient's quality of life (QOL). This study was undertaken to translate dysphagia-specific QOL questionnaire M. D. Anderson Dysphagia Inventory (MDADI) in Marathi language, its linguistic validation, and cross-cultural adaptation in patients of head and neck squamous cell cancer (HNSCC). After Institutional ethics committee approval, MDADI was translated into Marathi with prior permission from the author of original English questionnaire (AOEQ). The translation procedure included - two forward translations (English to Marathi), formation of first intermediate Marathi translation (FIMT), two back translations (BT) (Marathi to English) of FIMT and interim Marathi translation (IMT) formation. Second intermediate Marathi translation (SIMT) was prepared after face validation of IMT by Marathi subject expert. Pretesting of SIMT was done in 10 patients of HNSCC for linguistic validation and cross-cultural adaptation. After incorporating the patients' suggestions, final Marathi translation was formulated and forwarded to primary author for approval. The grammatically acceptable and conceptually equivalent face-validated SIMT was prepared and given to HNSCC patients. The questionnaire was well understood and unobjectionable reflecting its linguistic validity and cross-cultural adaptation. Some of the patients suggested changes in a few words which were then rectified, rechecked with BT, and the final Marathi translated questionnaire was prepared. The credit statement for AOEQ was used as a footnote in the translated questionnaire. Marathi translation of MDADI is well accepted and comprehensible. It can be used for future studies.

Serum 25-hydroxy vitamin-D levels in head and neck cancer chemoradiation therapy: Potential in cancer therapeutics.

To evaluate the relation between serum-25-hydroxy Vitamin-D levels (S25OHVDL) and concurrent chemoradiation therapy (CTRT) toxicities in patients of head and neck squamous cell cancer (HNSCC). After an institutional ethics committee approval, consecutive HNSCC patients who received radical/adjuvant CTRT were prospectively evaluated. Patients were assessed for CTRT toxicities using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE-v5.0) and the response was evaluated according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST-1.1). S25OHVDL was assessed at the time of the first follow-up. Patients were divided into group A (Optimal) and group B (suboptimal) according to S25OHVDL. The treatment toxicities were correlated with S25OHVDL. Twenty-eight patients were evaluated for the study. S25OHVDL was optimal in eight (28.57%) and suboptimal in 20 patients (71.42%). Mucositis and radiation dermatitis were significantly more in subgroup B (P-value 0.0011 and 0.0505, respectively). Relatively lower but nonsignificant hemoglobin and peripheral white blood cell counts were observed in subgroup B. Suboptimal S25OHVDL was associated with significantly more skin and mucosal toxicities in HNSCC patients treated with CTRT.

Subjective and perceptive assessment of speech/voice and swallowing function before and after radiation therapy in patients of head-and-neck squamous cell cancer.

To prospectively assess subjective and perceptive speech/voice and swallowing function before and after radiation therapy (RT) in patients of head-and-neck squamous cell cancer (HNSCC). The study cohort comprised eligible consecutive HNSCC patients planned for curative RT from April 2018 to July 2018 who consented for the study. Prospective evaluation of speech/voice and swallowing function was done before and after RT. For subjective and perceptive evaluation of speech/voice, speech handicap index (SHI) and Grade, Roughness, Asthenia, Breathiness, and Strain (GRABS) Scale was used, respectively. For subjective and perceptive evaluation of swallowing, M D Anderson Dysphagia Inventory (MDADI) and Performance Status Scale for head and neck (PSSHN) were used, respectively. All patients were taught speech/voice and swallowing exercises before RT. Statistical analysis was performed using SYSTAT version-12 (Cranes software, Bengaluru). The study cohort comprised 30 patients of HNSCC with a median age of 57 years and male-to-female ratio of 4:1. The most common subsite was the oral cavity (43.33%) and a majority (76.66%) presented in the locally advanced stage. Post-RT there was significant improvement in speech/voice function (SHI P = 0.0006, GRABS score P = 0.003). Perceptive assessment of swallowing function by PSSHN showed significant improvement (P = 0.0032), but subjective assessment by MDADI showed no significant (P = 0.394) improvement until the first follow-up. Speech/voice function improved significantly after radiotherapy when combined with rehabilitation exercises. Swallowing function did not improve till the first follow-up. Future studies with the large number of patients and long-term follow-up are needed to document the changes in organ function.

Human Immunodeficiency Virus Is Associated With Poor Overall Survival Among Patients With Head and Neck Cancer.

Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV. Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1. HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18-84] vs 94 [86-103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32-2.97; P < .001). PWH with human papillomavirus (HPV)-positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV- HPV+ tumors (P = .04). HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials.

Aberrant inactivation of SCNN1G promotes the motility of head and neck squamous cell carcinoma.

The sodium channel epithelial 1 subunit gamma (SCNN1G) is mainly responsible for sodium entry and absorption. The dysfunction of SCNN1G has been widely studied in kidney-related diseases and chronic heart failure. However, its role in cancer remains unclear. Here, we found that SCNN1G was aberrantly downregulated in head and neck squamous cell cancer (HNSCC) tissues, which showed an efficifent diagnostic value according to the ROC curve analysis. The lower expression of SCNN1G was significantly correlated with lymphatic metastasis and a worse outcome of HNSCC patients. Ectopic overexpressing SCNN1G inhibited the invasive and migratory abilities of HNSCC cells, while knocking down SCNN1G showed an opposite effect. A positive correlation between SCNN1G and CDH1 expression was observed, which suggested that SCNN1G might impede HNSCC metastasis via strengthing cell-cell adherin. In addition, RAS signaling and ion channel transport signaling were enriched by SCNN1G in HNSCC using GSEA analysis, indicating that these signaling pathways might be the underlying mechanisms for SCNN1G as well. In addition, six sorts of immune infiltrate subtype cells were associated with SCNN1G expression. Our findings support that SCNN1G inactivation contributes to the metastasis of HNSCC. SCNN1G could serves as a valuable diagnostic and prognostic marker for HNSCC.

Sex-Specific Cut-Off Values for Low Skeletal Muscle Mass to Identify Patients at Risk for Treatment-Related Adverse Events in Head and Neck Cancer.

A low skeletal muscle index (SMI), defined with cut-off values, is a promising predictor for adverse events (AEs) in head and neck squamous cell cancer (HNSCC) patients. The aim was to generate sex-specific SMI cut-off values based on AE to diagnose low SMI and to analyse the relationship between low SMI and AEs in HNSCC patients. In this present study, HNSCC patients were prospectively included in a large oncological data-biobank and SMI was retrospectively measured using baseline neck scans. In total, 193 patients were included and were stratified according to treatment modality: (chemo-)radiotherapy ((C)RT) (n = 135) and surgery (n = 61). AE endpoints were based on the occurrence of clinically relevant toxicities (Common Terminology Criteria for Adverse Events grade ≥ III) and postoperative complications (Clavien–Dindo Classification grade ≥ II). Sex-specific SMI cut-off values were generated with receiver operating characteristic curves, based on the AE endpoints. The relationship of the baseline characteristics and AEs was analysed with logistic regression analysis, with AEs as the endpoint. Multivariable logistic analysis showed that low SMI (OR 3.33, 95%CI 1.41–7.85) and tumour stage (OR 3.45, 95%CI 1.28–9.29) were significantly and independently associated to (C)RT toxicity. Low SMI was not related to postoperative complications. To conclude, sex-specific SMI cut-off values, were generated based on the occurrence of AEs. Low SMI and tumour stage were independently related to (C)RT toxicity in HNSCC patients.

Impacts of hepatitis b infection in patients with head and neck squamous carcinoma.

e18051 Background: Hepatitis B Virus (HBV) infection was known to be have impacts of occurrence and survival in different malignancies. We aim to evaluate the clinical association with head and neck squamous cell cancer (HNSCC) and HBV infection. Methods: A retrospective review was conducted on the medical records and cancer registry database at the Taichung Veterans General Hospital (Taichung, Taiwan) between January 2007 and December 2015. Patients with histologically proven squamous cell carcinoma of oral cavity, oropharynx, hypopharynx and larynx were enrolled in the study. HBV infection was defined as HBsAg seropositivity. Clinical features, hepatic function test and five-year overall survival (OS) were compared between patients with and without HBV infection. Results: A total of 1826 HNSCC patients were analyzed. 225 of them (12.3%) were proved HBV-infected. The HBV-infected patients was diagnosed at younger age (&lt; 65 years; 76.1% vs. 65.5%, p&lt; 0.012) and had a higher proportion of initial liver cirrhosis (11.6% vs. 3.6%, p&lt; 0.001) and hepatic dysfunction (10.7% vs. 6.1%, p= 0.009) included elevation of alanine transaminase (ALT), aspartate transaminase (AST) and prothrombin time expressed as international normalized ratio (INR). The other baseline characteristics were similar. The five-year OS were 52.9% and 48.6% in the HNSCC patients with or without HBV infection, respectively ( p= 0.341). The incidence of later founded hepatic dysfunction during follow-up was similar (31.1% vs 26.2%, p= 0.122). Conclusions: Information from this study indicated that HBV-infected HNSCC patients may present in younger age, more initial liver cirrhosis, and hepatic dysfunction. However, HBV infection did not have negative impacts on survival outcome and later founded hepatic dysfunction in those patients. Characteristics and survival of HBsAg (+) vs. HBsAg (-) HNSCC Patients[Table: see text]

Development of a Hypoxia-Immune Prognostic Classifier for Head-and-Neck Cancer Patients Undergoing Radiotherapy ― Results From a Prospective Imaging Trial

Tumor-infiltrating lymphocytes (TILs) correlate with an improved outcome of head-and-neck squamous cell cancer (HNSCC) patients undergoing radiotherapy and are influenced by the tumor microenvironment and tumor-associated hypoxia. The present analysis is based on a prospective imaging trial and analyzes the value of TILs and tumor-associated hypoxia to stratify HNSCC patients according to their response to radiotherapy.A total of 49 patients with locoregionally advanced HNSCCs were prospectively enrolled in this trial and underwent longitudinal hypoxia PET imaging using fluoro-18 misonidazole ([18F]FMISO) in weeks 0, 2 and 5 during chemoradiation. Tumor hypoxia was assumed for a tumor-to-background SUV (contralateral sternocleidomastoid muscle) exceeding 1.4, and an early hypoxia response was defined as a decrease in the normalized maximum intratumoral SUV (FMISO-SUVindex) between weeks 0 and 2. Pre-treatment tumor biopsies were analyzed for TILs and the hypoxia tissue marker carbonic anhydrase IX (CAIX). Trial patients were stratified into 4 subgroups based on their TIL numbers (> 100 vs. < 100 TILs/HPF) and expression of CAIX (above vs. below median H-score), and locoregional control (LRC) and progression-free survival (PFS) rates for all subgroups were assessed using Cox and subsequent concordance analyses (Harrell's C).High TIL levels correlated with improved LRC (HR = 0.279, P = 0.011) and PFS (HR = 0.276, P = 0.006). Similarly, a decrease in the FMISO-SUVindex within the first 2 weeks of treatment corresponded with better LRC (HR = 0.321, P = 0.015) and PFS (HR = 0.402, P = 0.043). Harrell's C was 0.68, when TILs and early hypoxia PET response were combined. The hypoxia PET-based hypoxia-immune classifier separated 3 distinct prognostic patient subgroups, a favorable (TILhigh/ early PET response), and intermediate (TILhigh/no early PET response or TILlow/early PET response) and a poor (TILlow/no early PET response) prognostic group with 2-year LRC of 71%, 33% and 0%, respectively. Low pre-treatment tissue levels of CAIX were also prognostic for improved LRC (HR = 0.352, P = 0.050) but not PFS (HR = 0,468, P = 0,087). Harrell's C was 0.66 for CAIX and TILs separately and 0.71 for the combination. The immunohistochemistry-based immune-hypoxia classifier similarly stratified between a favorable (CAIXlow/TILhigh), an intermediate (CAIXlow/TILlow or CAIXhigh/TILhigh) and a poor (CAIXhigh/TILlow) subgroup with 2-year LRC rates of 73%, 62% and 11%, respectively.We developed a hypoxia PET-based hypoxia-immune classifier that was able to separate HNSCC patients into 3 distinct prognostic subgroups based on their tumor biology. These subgroups could also be stratified in a clinically feasible, immunohistochemistry-based classifier with comparable model accuracy. Therefore, this hypoxia-immune classifier could help to stratify prognoses of HNSCC patients undergoing radiotherapy pending validation in an external cohort.

Subtyping of head and neck squamous cell cancers based on immune signatures

Although head and neck squamous cell cancer (HNSCC) is one of the cancer types in which immune checkpoint inhibitors (ICIs) has achieved a certain success, only a subset of HNSCC patients respond to ICIs. Thus, identification of HNSCC subtypes responsive to ICIs is crucial. Using hierarchical clustering, we identified three subtypes of HNSCC, termed Immunity-H, Immunity-M, and Immunity-L, based on the enrichment scores of 28 immune cells generated by the single-sample gene-set enrichment analysis of transcriptome data. We demonstrated that this subtyping method was stable and producible in four different HNSCC cohorts. Immunity-H had the highest levels of immune infiltrates and PD-L1 expression, lowest levels of stemness, intratumor heterogeneity and genomic instability, and favorable prognosis. In contrast, Immunity-L had the lowest levels of immune infiltrates and PD-L1 expression, highest levels of stemness, intratumor heterogeneity and genomic instability, and unfavorable prognosis. We found that somatic copy number alteration had a significant negative association with anti-tumor immunity in HNSCC, while tumor mutation burden showed no significant association. TP53, COL11A1, NSD1, and PKHD1L1 were more frequently mutated in Immunity-H versus Immunity-L, and their mutations were associated with increased immune signatures in HNSCC. Besides immune-related pathways, many stromal and oncogenic pathways were highly enriched in Immunity-H, including cell adhesion molecules, focal adhesion, ECM-receptor interaction, calcium signaling, MAPK signaling, apoptosis, VEGF signaling, and PPAR signaling. The high levels of PD-L1 expression and immune infiltration in Immunity-H indicate that this subtype responds best to ICIs. Our study recaptures the immunological heterogeneity in HNSCC and provide clinical implications for the immunotherapy of HNSCC.