Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy.

Uncontrolled growth is a signature of carcinogenesis, in part mediated by overexpression or overstimulation of growth factor receptors. The epidermal growth factor receptor (EGFR) mediates activation of multiple oncogenic signaling pathways and escape from recognition by the host immune system. We discuss how EGFR signaling downregulates tumor antigen presentation, upregulates suppressive checkpoint receptor ligand programmed death ligand (PD-L1), induces secretion of inhibitory molecules such as transforming growth factor beta (TGFβ) and reprograms the metabolic pathways in cancer cells to upregulate aerobic glycolysis and lactate secretion that ultimately lead to impaired cellular immunity mediated by natural killer (NK) cell and cytotoxic T lymphocytes (CTL).

Effect of transcervical arterial ligation on the severity of postoperative hemorrhage after transoral robotic surgery.

Background: The value of transcervical arterial ligation during transoral robotic surgery (TORS) as a measure to decrease postoperative bleeding incidence or severity is unclear.

Methods: A retrospective single institution study was performed to identify risk factors for hemorrhage after TORS for oropharyngeal squamous cell carcinoma (SCC).

Results: Overall, 13.

Perspectives of Patients, Clinicians, and Health System Leaders on Changes Needed to Improve the Health Care and Outcomes of Older Adults With Multiple Chronic Conditions.

Objective: To ascertain perspectives of multiple stakeholders on contributors to inappropriate care for older adults with multiple chronic conditions.

Method: Perspectives of 36 purposively sampled patients, clinicians, health systems, and payers were elicited. Data analysis followed a constant comparative method.

Interferon-γ Drives T Fragility to Promote Anti-tumor Immunity.

Regulatory T cells (T) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T stability and function but is dispensable for peripheral immune tolerance. T-restricted Nrp1 deletion results in profound tumor resistance due to T functional fragility.

Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Review of Current and Emerging Therapeutic Options.

Unlabelled: Advances in the field of cancer immunotherapy have occurred rapidly over the past decade. Exciting results from clinical trials have led to new treatment options and improved survival for patients with a myriad of solid tumor pathologies. However, questions remain unanswered regarding duration and timing of therapy, combination regimens, appropriate biomarkers of disease, and optimal monitoring of therapeutic response.

A prospective evaluation of short-term dysphagia after transoral robotic surgery for squamous cell carcinoma of the oropharynx.

Background: Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC.

Solid Lymph Nodes as an Imaging Biomarker for Risk Stratification in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

Background And Purpose: Human papillomavirus-related oropharyngeal squamous cell carcinoma is associated with cystic lymph nodes on CT and has a favorable prognosis. A subset of patients with aggressive disease experience treatment failure. Our aim was to determine whether the extent of cystic lymph node burden on staging CT can serve as an imaging biomarker to predict treatment failure in human papillomavirus-related oropharyngeal squamous cell carcinoma.

Increased PD-1 and TIM-3 TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8 tumor-infiltrating lymphocytes (TIL) and compared them with those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8 TILs compared with CD8 PBLs ( = 0.

Concurrent Chemoradiotherapy in the Adjuvant Treatment of High-risk Primary Salivary Gland Malignancies.

Objectives: Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors.

Materials And Methods: Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.

EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial.

Rising incidence of oral tongue cancer among white men and women in the United States, 1973-2012.

Background: Despite significant reductions in tobacco use in the US, oral tongue cancer incidence has reportedly increased in recent years, particularly in young white women. We conducted age-period-cohort analyses to identify birth cohorts that have experienced increased oral tongue cancer incidence, and compared these with trends for oropharyngeal cancer, a cancer caused by human papillomavirus (HPV) that has also recently increased.

Methods: We utilized cancer incidence data (1973-2012) from 18 registries maintained by the NCI SEER Program.

Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high morbidity and mortality. Despite advances in cytotoxic therapies and surgical techniques, overall survival (OS) has not improved over the past few decades. This emphasises the need for intense investigation into novel therapies with good tumour control and minimal toxicity.

TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action.

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity.

Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: Updates on efficacy, surgical technique and margin status.

Importance: Management of cervical unknown primary squamous cell carcinoma (CUP) has evolved with the introduction of transoral robotic surgery (TORS).

Objectives: 1. To describe the efficacy of TORS lingual and palatine tonsillectomy in identifying the primary site of malignancy.

Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. The purpose of this study was to evaluate viral oncogene expression and viral integration sites in HPV16- and HPV18-positive squamous cell carcinoma lines.

Methods: E6/E7 alternate transcripts were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR).

Oncogenic growth factor signaling mediating tumor escape from cellular immunity.

Unrestrained growth factor signals can promote carcinogenesis, as well as other hallmarks of cancer such as immune evasion. Our understanding of the function and complex regulation of HER family of receptors has led to the development of targeted therapeutic agents that suppress tumor growth. However, these receptors also mediate escape from recognition by the host immune system.

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer.

Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL.

Assessment of Surgical Learning Curves in Transoral Robotic Surgery for Squamous Cell Carcinoma of the Oropharynx.

Importance: Transoral robotic surgery (TORS) is increasingly employed as a treatment option for squamous cell carcinoma of the oropharynx (OPSCC). Measures of surgical learning curves are needed particularly as clinical trials using this technology continue to evolve.

Objective: To assess learning curves for the oncologic TORS surgeon and to identify the number of cases needed to identify the learning phase.

fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer.

Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated () gene on chromosome 2 and the gene on chromosome 7 located 12 kb upstream of the gene.

A Model for Perineural Invasion in Head and Neck Squamous Cell Carcinoma.

Perineural invasion (PNI) is found in approximately 40% of head and neck squamous cell carcinomas (HNSCC). Despite multimodal treatment with surgery, radiation, and chemotherapy, locoregional recurrences and distant metastases occur at higher rates, and overall survival is decreased by 40% compared to HNSCC without PNI. In vitro studies of the pathways involved in HNSCC PNI have historically been challenging given the lack of a consistent, reproducible assay.

E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group.

Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae.

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment.

Objectives: To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor β1 (TGF-β1).

Design, Setting, And Participants: A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant.