Positive Squamous Cell Carcinoma Research Articles

Triple Positive Oral Squamous Cell Carcinoma Patients Predict Poor Survival Outcomes: Multiple Factor Positivity Warrants the Need for Modified Treatment Approaches

Triple Positive Oral Squamous Cell Carcinoma Patients Predict Poor Survival Outcomes: Multiple Factor Positivity Warrants the Need for Modified Treatment Approaches

The molecular characteristics of recurrent/metastatic HPV-positive head and neck squamous cell carcinoma: A systematic review of the literature.

About 17% of patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), which is mainly comprised of oropharyngeal SCC (OPSCC), will experience disease recurrence, which is often considered incurable when manifested at a metastatic and/or recurrent stage. We conducted a critical qualitative systematic review. Our objectives were to provide an overview of the molecular landscape of recurrent/metastatic HPV-positive HNSCC as well as novel molecular biomarkers. A literature review was conducted to identify studies reporting on the molecular characteristics of recurrent/metastatic HPV-positive HNSCC, novel molecular biomarkers and treatment options. The reviews of abstracts, full articles, and revision of the included studies, followed by data extraction and quality assessment were performed by three independent assessors. All primary literature, such as retrospective, prospective, and clinical trials as well as basic research studies were considered, and the final search was conducted at the end of February 2023. The level of evidence was rated using the guidelines published by the Oxford Centre for Evidence-based Medicine and quality was assessed using the Newcastle-Ottawa Scale criteria. The literature search resulted in the identification of 1991 articles. A total of 181 full articles were screened, and 66 articles were included in this analysis. Several studies reported that recurrent/metastatic HPV-positive HNSCC had higher rates of TP53 mutation and were genomically similar to HPV-negative HNSCC. The detection of circulating tumour tissue-modified HPV DNA (ctHPVDNA) as a specific biomarker has shown promising results for monitoring treatment response and recurrence in the subset of HPV-positive HNSCC. In addition, evidence for targeted therapy in recurrent/metastatic HPV-positive HNSCC has emerged, including agents that inhibit overexpressed EGFR. Studies of combination immunotherapy are also underway. Our review outlines the latest evidence on the distinct molecular profiles of recurrent/metastatic HPV-positive HNSCC as well as the clinical potential of ctHPVDNA testing in routine practice. More controlled and longitudinal studies are needed to identify additional molecular targets and to assess the performance and benefits of novel molecular biomarkers in clinical practice.

High-dose loco-regional pattern of failure after primary radiotherapy in p16 positive and negative head and neck squamous cell carcinoma – A DAHANCA 19 study

IntroductionPatients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status. Material and methodsPatients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin. ResultsOf 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16− tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures. ConclusionRadioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.

Abstract 4768: Differential expression of triptolide gene targets in human papillomavirus positive and negative head and neck squamous cell carcinomas

Abstract Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the US. HPV represents a more recent risk factor for which treatment may be individualized. HPV expresses viral E6 and E7 oncoproteins which downregulate wild type p53 and Rb respectively. Triptolide, a derivative of a traditional Chinese medicinal herb, has been shown to inhibit viral E6, thereby reactivating wild type p53. Therefore, triptolide may target HPV positive HNSCC as a putative treatment. To explore this, we compared mutation, methylation, and expression of triptolide gene targets between HPV positive and HPV negative samples from The Cancer Genome Atlas (TCGA) program. Patient data was queried from the TCGA PanCancer Atlas for HNSCC using cBioPortal. This included a total of 523 patients with 487 meeting inclusion criteria. 415 patients were HPV (-) and 72 were HPV (+).Differences in direct genomic alterations, DNA methylation, mRNA expression, and protein expression of the 34 known triptolide targets were compared between these two groups using the Benjamini-Hochberg Procedure with a significance level of q < 0.05. Significant differences of the studied genes (q < 0.05) are shown in Table 1. There were no significant differences in protein expression. Of the 34 known triptolide targets, HPV positive and negative samples show variable enrichment. Triptolide targets exhibit greater methylation and mRNA expression in HPV positive samples supporting triptolide’s efficacy in these samples. However, other triptolide targets are the differentially expressed and methylated in HPV negative samples, so the compound may have a beneficial effect in this context as well. Further studies are required to test efficacy of triptolide against HPV positive and HPV negative HNSCC in vitro and in vivo models. Table 1. Significant genomic differences between HPV (+) and HPV (-) samples shown. Enriched in HPV (+) Enriched in HPV (-) Gene Log2 ratio q-value Gene Log2 ratio q-value DNA methylation Direct genomic mutations VEGFA 0 5.85E-03 TP53 3.08 4.53E-29 BCL2 0.07 9.78E-18 DNA methylation JUN 0 4.89E-02 RELA 0.07 5.06E-04 CD80 0.06 2.56E-02 STAT3 0.24 3.19E-20 BIRC3 0.01 1.29E-04 TNF 0.07 4.31E-04 CD274 0.07 4.40E-03 XIAP 0.07 8.02E-06 CCR7 0.11 3.56E-08 CXCR4 0.04 3.58E-03 CD1A 0.10 2.36E-05 CD40 0.06 1.00E-05 C3 0.06 6.91E-03 CD14 0.04 8.12E-03 CD86 0.03 2.45E-02 mRNA expression mRNA expression RELA 0.16 1.90E-03 STAT3 0.25 4.22E-03 CDKN1A 0.28 3.00E-02 BCL2 1.95 1.68E-14 PLAU 1.37 3.24E-12 CASP3 0.45 2.55E-07 CXCL8 1.05 1.51E-04 TP53 1.45 3.16E-25 MCL1 0.23 3.59E-04 IL2 0.52 2.13E-06 TGFB1 0.77 3.27E-11 INFG 1.15 2.08E-05 DEFB4A 1.10 1.77E-02 CXCR4 1.18 8.03E-07 BIRC3 1.20 6.14E-06 IL23A 0.77 3.88E-04 CCR7 1.18 2.10E-06 CD40 0.54 2.27E-04 Citation Format: William E. Kamm, Lindsey J. Mortenson, Frank G. Ondrey. Differential expression of triptolide gene targets in human papillomavirus positive and negative head and neck squamous cell carcinomas [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 4768.

ENID: Phase II Trial of Definitive Chemoradiation with Elective Nodal Irradiation Dose De-Escalation for P16 Positive Squamous Cell Carcinoma of the Oropharynx

ENID: Phase II Trial of Definitive Chemoradiation with Elective Nodal Irradiation Dose De-Escalation for P16 Positive Squamous Cell Carcinoma of the Oropharynx

87 Distinctions in Tumor Microenvironment Between PD-L1 Positive versus Negative Head and Neck Squamous Cell Carcinoma (HNSCC)

87 Distinctions in Tumor Microenvironment Between PD-L1 Positive versus Negative Head and Neck Squamous Cell Carcinoma (HNSCC)

148 Predictors and outcomes of Contralateral Lymph node involvement in node positive oral squamous cell carcinoma: A retrospective analysis of 180 patients.

148 Predictors and outcomes of Contralateral Lymph node involvement in node positive oral squamous cell carcinoma: A retrospective analysis of 180 patients.

256 comparison of clinicopathological and prognostic features of HPV positive and HPV negative head and neck squamous cell carcinoma (HNSCC)

256 comparison of clinicopathological and prognostic features of HPV positive and HPV negative head and neck squamous cell carcinoma (HNSCC)

Tolerability and efficacy of the cancer vaccine UV1 in patients with recurrent or metastatic PD-L1 positive head and neck squamous cell carcinoma planned for first-line treatment with pembrolizumab - the randomized phase 2 FOCUS trial.

Globally, head and neck squamous cell carcinoma (HNSCC) is the seventh most common malignancy. Despite aggressive multimodal treatment approaches, recurrent and/or metastatic (R/M) disease develops in >50% of patients. In this setting, pembrolizumab was approved for patients with PD-L1 expression. However, response rates with checkpoint inhibitor monotherapy remain limited and strategies to strengthen tumor-directed immune responses are needed. The FOCUS trial is designed to estimate the effectiveness of UV1 vaccination in combination with pembrolizumab versus pembrolizumab as a single agent in patients with R/M HNSCC. The FOCUS trial is a two-armed, randomized, multicenter phase II study which was designed to evaluate the efficacy and feasibility of the hTERT-targeted cancer vaccine UV1 as add-on to pembrolizumab in the 1st line treatment of patients with R/M PD-L1 positive (combined positive score ≥1) HNSCC. Secondary objectives are the exploration of patient subgroups most likely deriving benefit from this novel combination and the establishment of liquid biopsy tumor monitoring in HNSCC. This clinical study was designed and will be conducted in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki. It is intended to publish the results of this study in peer-reviewed scientific journals and to present its content at academic conferences. A significant number of patients with R/M HNSCC are frail and may not tolerate chemotherapy, these patients may only be suitable for pembrolizumab monotherapy. However, long term disease stabilizations remain the exception and there is a need for the development of efficacious combination regimens for this patient population. The FOCUS study aims to optimize treatment of R/M HNSCC patients with this promising new treatment approach. https://clinicaltrials.gov/study/NCT05075122, identifier NCT05075122.

Immune microenvironment of human papillomavirus-positive head and neck squamous cell carcinoma.

Research progress of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) based on immune microenvironment. This article preliminarily discusses the composition of immune microenvironment components and immune therapy and elaborates and analyzes the involvement and impact of T cells, B cells, natural killer (NK) cells, tumor-associated fibroblasts, and bone marrow-derived suppressor cells in HPV-positive HNSCC on tumor progression and prognosis. Furthermore, the application of immune-related therapies in HPV-positive HNSCC is explored. It is found that immune microenvironment research plays an important role in the pathogenesis and treatment of HPV-positive HNSCC. Immune microenvironment research as an important means to explore tumors has played an important role in the study of HPV-positive HNSCC. We describe the biological significance of important components of HNSCC immune microenvironment by analyzing the effects of HNSCC immune microenvironment components and immunotherapy on HPV-positive HNSCC. May to provide new strategies for experimental research and clinical prevention and treatment of this disease.

Current Immunotherapy Treatments and Researches Regarding HPV-Positive HNSCC, a Revue of the Literature

Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) represents a distinct and intriguing subset of HNSCCs. This comprehensive review article explores the genetic and clinical aspects of HPV-positive HNSCC, shedding light on its unique characteristics and clinical implications and its difference from HPV-negative HNSCC. We delve into the etiological factors underlying HPV infection in HNSCC, emphasizing the role of high-risk HPV types, especially HPV-16. HPV-driven tumorigenesis through the E6 and E7 oncoproteins and their impact on key tumor suppressor genes, such as p53 and Rb, is discussed, highlighting the relatively lower mutation burden in these tumors compared to HPV-negative HNSCC. This article also explores ongoing research efforts, genomic profiling, and emerging targeted therapies tailored specifically for HPV-positive HNSCC. A deeper understanding of the unique genetic landscape of these tumors offers promising prospects for personalized treatment strategies and improved outcomes. This review provides a comprehensive overview of the genetic mutations, clinical features, and potential therapeutic avenues in the realm of HPVpositive HNSCC, emphasizing the need for continued research to advance our knowledge and treatment options in this distinctive subset of head and neck cancers.

Risk of malignancy in incidental oropharyngeal lesions exhibiting fluorodeoxyglucose uptake which proceed to tissue biopsy.

Utilization of positron emission tomography/computed tomography (PET/CT) with fluorodeoxyglucose is increasing in use for a variety of indications, including surveillance of cancer patients. There is a paucity of evidence pertaining to the significance of incidental PET-avid oropharyngeal lesions. This study aims to examine the clinical and radiological features of these incidental oropharyngeal lesions in patients undergoing PET for indications other than head and neck cancer. Retrospective cohort study of three Australian tertiary hospitals, from 2015 to 2021, on adult patients undergoing biopsy of incidental PET-avid oropharyngeal lesions. Primary outcome of interest was the incidence of malignancy. Patients with a previous history of, or undergoing investigations for, head and neck cancer were excluded. Thirty-one patients were included, wherein 21 patients had tonsillar uptake, and 13 patients had base of tongue uptake. Tonsillar disease was mostly asymmetrical (n = 15/21), bilateral (n = 11/21), and had median SUVmax 9.35 (n = 12, IQR 7.4-11.15). Base of tongue was mostly asymmetrical (n = 7/13, 54%), bilateral (n = 8/13, 62%), and had median SUVmax 8.2 (n = 10, IQR 6.9-12.65). Seven patients had malignancy confirmed on tissue biopsy: five biopsies confirmed the tissue diagnosis of suspected lymphoma, and two incidental findings of unexpected malignancies: one p16 positive tonsillar squamous cell carcinoma, and one metastatic breast cancer. In 31 patients undergoing tissue biopsy for incidental PET-avid oropharyngeal lesions, there were two unexpected malignancies. Our study results indicate that although unexpected malignancies are uncommon, a malignant diagnosis cannot be excluded from clinical features alone.

M1 macrophages induce PD-L1hi cell-led collective invasion in HPV-positive head and neck squamous cell carcinoma via TNF-α/CDK4/UPS14

BackgroundAlthough the roles of PD-L1 in promoting tumor escape from immunosurveillance have been extensively addressed, its non-immune effects on tumor cells remain unclear.MethodsThe spatial heterogeneity of PD-L1 staining in human...

Economic evaluation of serplulimab plus chemotherapy as the first-line treatment of oesophageal squamous cell carcinoma in China

ObjectiveThe ASTRUM-007 study confirmed the significant efficacy and safety of serplulimab plus chemotherapy for patients with locally advanced/metastatic, programmed cell death-ligand 1 positive oesophageal squamous cell carcinoma (OSCC). The economics...

Cost-effectiveness of analysis serplulimab plus chemotherapy as first-line therapy for PD-L1-positive advanced esophageal squamous cell carcinoma.

Our study aimed to evaluate the cost-effectiveness of the addition of serplulimab to chemotherapy (cisplatin and fluorouracil) for programmed death-ligand 1 (PD-L1) positive advanced esophageal squamous cell carcinoma (ESCC) as the first-line treatment in China. A three-state Markov model was established to assess the incremental cost-effectiveness ratio (ICER) for serplulimab plus chemotherapy versus chemotherapy alone. Survival data were extrapolated from the ASTRUM-007 trial, cost data were derived from local sources, and utilities were derived from published literature. Health outcomes were measured as quality-adjusted life-years (QALYs). Sensitivity and probability sensitivity analyses were used to investigate the robustness of the model. In the base-case analysis, compared with chemotherapy alone, serplulimab gained an additional 0.16 QALYs with an incremental cost of $29,547.88, leading to an ICER of $184,674.25/QALY. Additionally, the subgroup analyses presented that the ICERs of serplulimab plus chemotherapy were $157,892.50/QALY and $127,996.45/QALY in advanced ESCC patients with 1≤ CPS< 10 and CPS≥ 10, respectively. These ICERs significantly exceeded the Chinese willingness-to-pay (WTP) threshold. The deterministic sensitivity analysis illustrated that the cost of progression-free survival in serplulimab plus chemotherapy group was the parameter with the strongest influence on the ICERs. In the Chinese health care system, with 3 times China's per capita gross domestic product as the WTP threshold, compared with chemotherapy alone, serplulimab combined chemotherapy is not economical for PD-L1-positive advanced ESCC in the first-line setting.

Radiotherapy combined with docetaxel alters the immune phenotype of HNSCC cells and results in increased surface expression of CD137 and release of HMGB1 of specifically HPV-positive tumor cells

PurposeHuman papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) tumors respond significantly better to anticancer treatments. It is assumed to be due to a better response to radiotherapy (RT), and presumably to an increased immunogenicity. However, little is known how the immune phenotype of HNSCC tumor cells is modulated by standard treatment, namely by radiochemotherapy (RCT). MethodsTherefore, we aimed to examine the impact of the HPV status on the immune phenotype of HNSCC cell lines following RCT with 5 × 3Gy or 1 × 19.3Gy and/or docetaxel, by analyzing cell death, release of damage-associated molecular patterns (DAMPs), surface expression of immune checkpoint molecules (ICMs) and the impact on activation of human monocyte-derived dendritic cells (hmDCs). ResultsCell death induction and Hsp70 release following RCT was independent of the HPV status, and RCT significantly increased the expression of the immune suppressive ICMs PD-L1, PD-L2 and HVEM. An immune stimulatory ICM, CD137, was significantly increased following RCT only on HPV-positive cell lines, as well as the release of HMGB1. Although the treatment increased cell death and modulated ICM expression in HNSCC, the hmDCs were not activated after co-incubation with treated tumor cells. ConclusionOur data with the HPV-dependent release of HMGB1 and increased expression of CD137 following RCT provide a hint for increased immunogenicity underlining the better prognosis for HPV positive tumors following RCT.

Expression of p53 in toluidine blue positive oral squamous cell carcinoma lesions and expression of Ki67 in vinegar positive oral squamous cell carcinoma lesions.

The aims of this study were to investigate the sensitivity and specificity of toluidine blue and/or vinegar in oral cancer screening and to examine the correlation between clinical screening using toluidine blue and vinegar and the expression of the tumor marker p53 and proliferation marker Ki67, respectively. The study consisted of 87 patients with suspected oral squamous cell carcinoma lesions. Toluidine blue and/or vinegar were applied to the lesions, followed by biopsies. The tissues were diagnosed histopathologically and underwent immunohistochemical process for p53 or Ki67. The results revealed that the sensitivity and specificity of oral cancer screening using toluidine blue were 93% and 46%, respectively; whereas the sensitivity and specificity using vinegar were 85% and 81%, respectively. A statistically significant correlation between the use of vinegar and the expression of Ki67 (p = 0.019) was observed. Although there was a difference in the expression of p53 between specimens that were positive and negative to toluidine blue, the correlation did not reach a significant level. Based on the results from this study, vinegar has a lower sensitivity than toluidine blue but a higher specificity for oral cancer screening. The results of the clinical screening using vinegar correlated with the expression of Ki67 at the cellular level.

Primary DEK::AFF2 fusion positive nonkeratinizing squamous cell carcinoma of the middle ear: report of a case

Primary DEK::AFF2 fusion positive nonkeratinizing squamous cell carcinoma of the middle ear: report of a case

Immune Status of Cervical Lymph Nodes in Head and Neck Cancer-A Surgical Oncology Perspective.

Neck dissection for cervical lymph node metastasis is an established procedure for head and neck cancer (HNC). However, with the advent of immunotherapy, head and neck surgical oncologists need to rethink removing all lymph nodes, including those with immune function. We investigated the anti-cancer immune response of the cervical lymph nodes in four patients with human papillomavirus type 16 (HPV16)-positive head and neck squamous cell carcinoma. Using lymphocytes extracted from local, metastatic, and non-metastatic lymph nodes and peripheral blood from these patients, we performed an intracellular flow cytometric cytokine assay using anti-IFNγ and anti-TNF-α monoclonal antibodies to detect HPV16 E6- and E7-specific T cells. HPV status and p16 immunostaining were determined by in situ detection using the HPV RNAscope method and immunohistochemistry. In one case, E6-specific and E7-specific CD8+ T cells were detected in proximal metastatic nodes and distal non-metastatic nodes. This finding suggests that non-metastatic nodes should be preserved for their immune function during neck dissection and that the immune function of non-metastatic lymph nodes is important when administering immunotherapy. In this context, head and neck surgical oncologists treating HNC should consider the place of immunotherapy and neck dissection in the treatment of HNC.

LncRNA SELL/L-selectin promotes HPV-positive HNSCC progression and drives fucoidan-mediated therapeutic strategies

Positive human papillomavirus (HPV+) head and neck squamous cell carcinoma (HNSCC) presents a higher risk of lymph node metastasis and poor prognosis. Here, advanced microarray analysis of clinically collected HNSCC tissues revealed significant upregulation of the lncRNA SELL in HPV+ HNSCC, and its overexpression was obviously associated with lymph node metastasis. The lncRNA SELL could function as a promigratory and proinvasive mediator as well as an inducer of M1-like tumour-associated macrophages (TAM) by increasing the level of L-selectin. Furthermore, fucoidan, as an L-selectin inhibitor, obviously weakened the formation of tongue lesions induced by 4-Nitroquinoline N-oxide (4-NQO) in HPV16 E6/E7 transgenic mice. This result drove us to synchronously develop a nanodelivery platform to verify fucoidan-mediated anti-growth and anti-metastasis effects. This work highlighted the important influence of the lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposed a potential fucoidan-mediated therapeutic strategy. Statement of significanceHead and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV) involvement present a greater risk of lymph node metastasis than HPV negative HNSCC patients. However, treatment protocols, including surgery and platinum-based chemo- and radiotherapy, have not improved the 5-year overall survival due to the high tendency of lymphatic metastasis. Here, microarray of clinical HNSCC samples confirms the oncogenic significance of lncRNA SELL, which acts as an M1-like TAM inducer and promotes tumorigenesis by upregulating L-selectin. Fucoidan, as an L-selectin inhibitor, suppresses tongue lesions in transgenic mice, and a fucoidan-mediated nanodelivery platform inhibits HPV+ HNSCC growth. The present study highlights lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposes a potential fucoidan-mediated therapeutic.