Phase I trials of single-agent new drugs in head and neck cancer: a scoping review.

BACKGROUND: The conventional method of drug development in oncology typically progresses through phase I, phase II and randomized phase III trials. Nevertheless, some recent drug approvals for head and neck cancer (HNC) relied on findings from single-arm phase II trials. This underscores the significance of disease-specific phase I trials as a crucial step in exploring new drugs for HNC patients. The purpose of this review is to present the currently available data of phase I clinical trials conducted in HNC and to provide an overview of ongoing therapeutic trends in HNC. METHODS: We performed a scoping review of phase I trials evaluating single-agent treatments specifically designed for HNC patients. The PubMed database was searched using "(phase I) AND (head and neck)". To ensure exhaustiveness, we also performed a search from the American Society of Clinical Oncology, European Society for Medical Oncology and American Association for Cancer Research websites. RESULTS: We screened 1,134 articles and selected 29 trials that met eligibility criteria, published between 1994 and 2023, for a total of 741 patients. Twenty-one trials comprised patients with different sites of HNSCC and only 8 trials (27%) focused on a specified subsite of head and neck. Most of trials investigated treatments in recurrent/metastatic (R/M) settings (86%). Immunotherapeutic agents were the most examined followed by targeted agents, cytotoxic drugs and "others" including a nanoparticle, a therapeutic gene, a fusion protein and a modulator of gene expression. Among trials reporting activity for R/M head and neck patients (n=23), the global median overall response rate (ORR) was 12% and four trials (17%) did not report any response. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was low (7%). However, in seven trials safety results are not clearly assessable from the published data. CONCLUSIONS: Phase I trials of single agents designed for head and neck patients were generally safe but with a low ORR. Future development of new drugs dedicated for HNC patients that can more accurately reflect the heterogeneity of HNC and provide more detailed subgroup analyses is warranted.

Delay in the Diagnosis of Patients With Head and Neck Cancer: Impact of Different Patient- and Healthcare Provider-Related Factors.

Background In our setup, head and neck cancer (HNC) is the most common, and patients frequently present at an advanced stage, which results in dismal outcomes. Delays on the part of the patient (such as resistance to seeking treatment) or the provider (such as misdiagnosis or an extended wait period for consultation) may be the cause of a late presentation. The presentation stage may vary depending on several factors, including age, gender, smoking status, job status, and education. Objectives The study aims to identify factors that lead to advanced-stage presentations of HNCs and to determine the delays brought on by patient- or healthcare provider-related factors and how these factors affect HNC disease staging among biopsy-proven HNC patients. Materials and methods Participants in the study were those who initially presented with a biopsy-verified HNC at the cancer clinic of the department of otolaryngology-head and neck surgery at Pakistan Institute of Medical Sciences (PIMS), Islamabad. Patients answered questions on their first symptom presentation, past healthcare professional visits, and intervals between visits on a Cancer Symptom Interval Measure (C-SIM) questionnaire. For every patient, clinical and demographic information was gathered. TNM staging was completed. The test of significance was applied where applicable. Results Age, gender, education level, and smoking status had no bearing on the presentation stage. Patients without jobs present at a statistically significant higher stage (p = 0.038). The most prevalent histological form of HNC was squamous cell carcinoma 79 (82.29%), with the oral cavity and larynx being the most common sites of the disease 30 (31.25%) and 29 (30.21%) respectively. Patients took an average of 5.28 ± 9.12 months from the onset of symptoms to their first appointment with a healthcare provider. Prior to diagnosis, the majority of patients saw three or more healthcare providers (range: 1-8). The duration from the initial visit to a healthcare provider to the initiation of treatment was 3.06 ± 5.88 months. Based on the stage at presentation, there were no discernible variations in the times to presentation (p>0.05). Conclusion Significant delays and high stage of presentation are caused by unemployment. The majority of the delay was caused by the patient's tardiness in seeing a medical practitioner, yet the presentation stage was not greatly impacted by this delay.

Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Incidence and risk factors associated with the development of hypothyroidism after postoperative chemoradiotherapy for head and neck cancer patients with high-risk features: Supplementary analysis of JCOG1008.

BACKGROUND AND PURPOSE: Hypothyroidism is a recognized late adverse event following radiotherapy for head and neck cancer (HNC). In the JCOG1008 trial, we treated patients with high-risk HNC with postoperative chemoradiotherapy. We aimed to elucidate factors associated with hypothyroidism by analyzing the JCOG1008 data. MATERIALS AND METHODS: In 2012-2018, 261 patients from 28 institutions were enrolled in JCOG1008. Thyroid function tests were conducted to assess hypothyroidism, including free thyroxine (FT4) and thyroid-stimulating hormone assays. Hypothyroidism was defined as Grade 2 or higher in CTCAE v4.0. Various clinical and dosimetric parameters were analyzed. In radiotherapy, there were no dose constraints for the thyroid. Multivariable analysis was conducted on these variables to identify predictive factors for hypothyroidism. RESULTS: The analysis included 162 patients (57 with 3D-CRT and 105 with IMRT), with a median follow-up of 4.7 years (0.3-9.3 years). Among these, 27 (16.7 %) developed hypothyroidism within 2 years after radiotherapy. In a multivariable analysis, the weekly cisplatin [OR=7.700 (CI: 1.632-36.343, p = 0.010)] and baseline FT4 [OR=0.009 (CI: <0.001-0.313, p = 0.010)] were significantly associated with hypothyroidism in the IMRT group. Regarding dosimetric characteristics, V60Gy [OR=1.069 (CI: 0.999-1.143, p = 0.054)] was potentially associated with the development of hypothyroidism. CONCLUSION: The study revealed that the incidence of hypothyroidism within 2 years after postoperative chemoradiotherapy for high-risk HNC was 16.7 % based on analytical results from prospective clinical trials.

Efficacy of chemoradiotherapy in elderly patients with stage IV inoperable head and neck cancer.

OBJECTIVES: This study aimed to compare the efficacy of chemoradiotherapy (CRT) with radiotherapy (RT) alone for elderly patients (≥ 65 years) with stage IV inoperable head and neck cancer (IV-HNC). METHODS: Elderly patients diagnosed with inoperable IV-HNC from 2010 to 2015 were identified using the SEER database. Then, we performed a 1:1 propensity-score matched (PSM) analysis to reduce treatment selection bias, and the prognostic role of CRT was investigated using Kaplan-Meier analysis, log-rank test, and Cox proportional hazard models. The main outcome was overall survival (OS), and the secondary outcome was cancer-specific survival (CSS). RESULTS: A total of 3318 patients were enrolled, of whom 601 received RT alone and 2717 received CRT. Through PSM, 526 patients were successfully matched, and balances between the two treatment groups were reached. In the matched dataset, multivariable Cox analysis revealed that CRT was associated with better OS (HR = 0.580, P < 0.001) and CSS (HR = 0.586, P < 0.001). Meanwhile, subgroups of patients with IV-HNC (younger age, male sex, being married, black race, grade I-II, oral cavity site, T3-T4 stage, N0-N1 stage, M1 stage) were inclined to benefit more from CRT treatment. Furthermore, the survival benefit of CRT was more pronounced in patients aged 65 to 80 years, but was absent in patients aged 80 years or older. CONCLUSIONS: This study indicated that CRT resulted in better survival than RT alone in elderly patients with inoperable IV-HNC, especially for those subpopulations that benefit more from CRT treatment.

Nodal Yield in Level II-IV Neck Dissections in Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: The main objective of this study is to analyze factors associated with nodal yield in level II-IV selective neck dissections (NDs) and the secondary objective is to assess its impact on overall and disease-free survival. METHODS: Observational retrospective study including adult patients submitted to level II-IV ND from January 2015 to December 2021 in the otorhinolaryngology department of a tertiary hospital center. RESULTS: A total of 44 patients and 78 level II-IV NDs (34 bilateral and 10 unilateral) were included. The median age at diagnosis was 60 (22-74) years, and 93.2% of the patients were male. A lower nodal yield was significantly associated with previous radiotherapy (p = 0.042) and extranodal invasion (p < 0.001) and was non-significantly associated with older age (p = 0.065). Furthermore, on a Cox analysis adjusted to the cN status and age, the nodal yield was not associated with five-year disease-free survival (HR = 0.986; 95% CI = 0.922-1.054; p = 0.681) nor with five-year overall survival (HR = 1.006; 95% CI = 0.925-1.095; p = 0.888). CONCLUSION: A reduced nodal yield in level II-IV NDs was significantly associated with previous radiotherapy and extranodal extension and non-significantly associated with age. There was no association between the nodal yield and five-year overall survival or disease-free survival.

Type I interferon signaling promotes radioresistance in head and neck cancer.

Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.

Impact of Radiation on Dysphagia-Related Structures: A Dosimetric and Clinical Comparative Analysis of Three-Dimensional Conformal Radiotherapy (3D-CRT) and Intensity-Modulated Radiation Therapy (IMRT) Techniques in Patients With Head and Neck Cancer.

Introduction Head and neck squamous cell carcinoma (HNSCC) is a significant health concern in India, with around one million new cases annually. The prevalence of HNSCC is notably high in Asia, especially in India, due to habits like tobacco chewing, betel nut usage, and alcohol consumption. Treatment typically involves a combination of surgery, radiation, chemotherapy, and biological therapy, aiming for tumor control while preserving function and quality of life. However, survivors often face long-term side effects like difficulty swallowing, leading to complications such as aspiration pneumonia. Intensity-modulated radiotherapy (IMRT) has shown promise in improving outcomes by sparing critical swallowing structures. Efforts to minimize radiation-related dysphagia are crucial for enhancing patients' quality of life post-treatment. Our study focuses on examining dosimetric parameters associated with dysphagia aspiration, alongside evaluating dysphagia grades in both treatment groups using the RTOG scale. Material and methods Patients with histologically confirmed non-metastatic head and neck carcinomas were included in our study in November 2018-April 2020. A total of 56 patients were taken into our study with 28 in each arm. They underwent radical radiotherapy (RT) with a total dose of 66-70 Gy, with or without concurrent chemotherapy, meeting specific inclusion criteria and excluding those receiving reirradiation or with distant metastasis. Patients were divided into two groups: Group I received three-dimensional conformal radiotherapy (3D-CRT), and Group II received IMRT. Treatment planning involved immobilization, CT imaging, delineation of target volumes and organs at risk, and contouring of swallowing structures. Dose-volume histogram parameters (mean dose, maximum dose, V30, V70, V80, D50, and D80) were used to assess mean dose to swallowing structures outside the planning target volume (PTV), with a mean dose constraint of 50 Gy. Dysphagia was evaluated using the RTOG criteria at baseline, during treatment, and six months post-treatment. Statistical analysis was performed using SPSS, with significance set at p < 0.05. Results In our study, the mean age at presentation differed slightly between the IMRT and 3D-CRT arms: 58 years versus 55 years, respectively. A higher proportion of patients in both arms experienced symptoms for three to six months, with 53.6% in 3D-CRT and 42.9% in IMRT. Stage distribution varied, with IV being most common in 3D-CRT and stage II in IMRT. Approximately 56% of patients in both groups had a history of smoking. Significant differences were observed in spinal cord dose between 3DCRT and IMRT techniques (p < 0.001). Similarly, a significant difference was found in the mean dose received by dysphagia aspiration-related structures (DARSs) between the 3D-CRT and IMRT arms (p = 0.04). Patients in the IMRT arm exhibited superior dysphagia grades compared to those in the 3D-CRT arm, with statistical significance observed in the third month (p = 0.008) and sixth month (p = 0.048). Conclusion Our study found a notable decrease in the mean DARS dose and reduced dysphagia severity at three and six months in the IMRT group compared to the 3D-CRT group. However, due to the diverse study population, establishing a definitive correlation between the DARS dose and dysphagia severity was challenging. Future large-scale studies are needed to validate these findings for improved preservation of DARS structures.

Deciphering the complex landscape of post-translational modifications on PKM2: Implications in head and neck cancer pathogenesis.

In the vast landscape of human health, head and neck cancer (HNC) poses a significant health burden globally, necessitating the exploration of novel diagnostics and therapeutics. Metabolic alterations occurring within tumor microenvironment are crucial to understand the foundational cause of HNC. Post-translational modifications (PTMs) have recently emerged as a silent foe exerting a significantly heightened influence on various aspects of the biological processes associated with the onset and advancement of cancer, particularly in the context of HNC. There are numerous targets involved in HNC but recently, the enzyme pyruvate kinase M2 (PKM2) has come out as a hot target due to its involvement in glycolysis resulting in metabolic reprogramming of cancer cells. Various PTMs have been reported to affect the structure and function of PKM2 by modulating its activity. This review aims to investigate the impact of PTMs on the interaction between PKM2 and several signaling pathways and transcription factors in the context of HNC. These interactions possess significant ramification for cellular proliferation, apoptosis, angiogenesis and metastasis. This review primarily explores the role of PTMs influencing PKM2 and its involvement in tumor development. While acknowledging the significance of PKM2 interactions with other tumor regulators, the emphasis lies on dissecting PTM-related mechanisms rather than solely scrutinizing individual regulators. It lays the framework for the development of more sophisticated diagnostic tools and uncovers exciting possibilities for precision medicine essential for effectively addressing the complexity of this malignancy in a precise and focused manner.

Risk factors associated with the development of osteoradionecrosis (ORN) in Head and Neck cancer patients in Ireland: A 10-year retrospective review.

BACKGROUND AND PURPOSES: To assess osteoradionecrosis (ORN) incidence in a population of Irish Head and Neck cancer (HNC) patients, and assess precipitating factors that may contribute to ORN development to aid prevention. MATERIALS AND METHODS: Review of 1050 HNC patients attending the Dental Oncology Clinic, CUDSH between 2010 and 2021 identified 47 cases of ORN. Medical, dental and radiotherapy records of these forty-seven patients were retrospectively reviewed. Patient-, tumour-, and treatment-related variables were investigated in association with osteoradionecrosis development. Analysis conducted using SPSS, Pearson's Chi-square test (p < 0.05), and ordinal regression model. RESULTS: ORN incidence was 4.4 %. Median time from radiotherapy (RT) to ORN development was 9.5 months (range 1-98.5 months). ORN development within the mandibular surgical site was significant (p <.001), presenting at a higher Notani grade (p =.002), in mid-mandibular body region (p =.028), at radiation doses ≥ 60 Gy (p =.035), due to induced causes (p =.029), and without resolution (p =.019). CONCLUSION: This is the first retrospective study of ORN in HNC patients in Ireland over 10-year period. ORN incidence was extremely low (4.4%). As patients reported high smoking/alcohol use and poor dental attendance pre-diagnosis, this suggests intensive dental intervention pre/post-diagnosis contributed to low ORN rates. Mandibular surgery pre-RT increased risk of developing ORN at the surgical site. Therefore, we recommend future treatment planning should contour the surgical site, designating it an organ at risk (OAR), assigning a dose constraint, where oncologically possible, with emphasis on reducing the hot-spot to this region; findings reinforce importance of life-long expert dental care to reduce ORN incidence.

A narrative review of oncologic emergencies in patients with head and neck cancers: initial management and the role of radiation therapy.

BACKGROUND AND OBJECTIVE: Head and neck cancers (HNCs) encompass a complex group of malignancies with high morbidity, often leading to critical emergencies such as pain crises, airway obstruction and hemorrhage. This review aims to outline an evidence-based approach to the multidisciplinary management of HNC oncologic emergencies with a focus on the role of emergent radiotherapy (RT). METHODS: A literature search was performed using Medline, Embase and the Cochrane Central Register of Controlled Trials databases with a focus on three common oncological emergencies using the following keywords: "head and neck cancer", "radiation OR radiotherapy", "pain", "bleeding OR haemorrhage", and "airway obstruction". All English language articles published up to April 2022 were screened to identify studies pertaining to the management of oncologic emergencies in HNC. KEY CONTENT AND FINDINGS: The management of oncologic emergencies in HNC present a unique set of challenges that require early recognition and aggressive treatment. In this narrative review, we summarize the evidence supporting the role of RT in the management of HNC patients presenting with pain crisis, malignant airway obstruction and acute haemorrhage. We demonstrate that while RT can be used as a primary or adjunct therapy, optimal management depends on the involvement of a multi-disciplinary team that includes head and neck surgeons, interventional radiology and palliative care. CONCLUSIONS: RT plays a critical role in the multidisciplinary management of HNC oncological emergencies. Further prospective and comparative studies are needed to assess optimal management strategies.

Medical students' knowledge about human papillomavirus (HPV), HPV vaccine and head and neck cancer.

The Human Papillomavirus (HPV) is a sexually transmitted infection that significantly affects the population worldwide. HPV preventive methods include vaccination, prophylactics, and education. Different types of cancers associated with HPV usually take years or decades to develop after infections, such as Head and Neck Cancer(HNC). Therefore, HPV prevention can be considered cancer prevention. A sample of medical students in Puerto Rico was evaluated to assess their knowledge about HPV, HPV vaccine, and HNC through two previously validated online questionnaires composed of 38 dichotomized questions, we measured HPV, HPV vaccination(HPVK), and HNC knowledge (HNCK). Out of 104 students surveyed, the mean HPVK score obtained was 20.07/26, SD = 3.86, while the mean score for HNCK was 6.37/12, SD = 1.78. Bidirectional stepwise regression showed study year and HPV Vaccine name had been the most influential variables on HPVK and HNCK. MS1 participants scored lower than MS2-MS4 participants, with no significant difference between MS2-MS4 scores. The results reveal knowledge gaps in HPV/HPV Vaccine and HNC among surveyed medical students. Our findings also suggest an association between knowledge of personal vaccination status, self-perceived risk, and how uncertainty in these factors may affect the medical students' understanding of HPV, HPV vaccination, and associated cancers.

Phase IV study on the use of benzydamine mouthwash in radiation-induced oral mucositis in patients with head and neck cancer.

Introduction: Oral mucositis (OM) is a main side effect of treatment for head and neck cancer (HNC) and causes severe pain, reduces quality of life, and may interrupt HNC treatment. This study assessed the activity and feasibility of benzydamine mouthwash in the prevention and treatment of radiation-induced OM in patients with HNC during radiation therapy (RT). Methods: This phase IV, international, open-label, single-group study conducted from December 2021 to September 2022. In total, 89 patients were enrolled across seven centers in Hungary and Poland. Patients used benzydamine mouthwash at home two to three times daily. Data were collected during clinical visits at baseline (V0, start of RT) and then weekly for seven visits (V1-V7). The safety population and the modified intention-to-treat (m-ITT) analysis sets contained 89 patients; the per protocol (PP) analysis set contained 67 patients. Results: The m-ITT set was 80.9% male; mean age was 61.4 years. At baseline, 73.0% of patients had stage T3-T4, 23.6% had stage T1-T2, 61.8% had stage N2-N3, and 34.9% had stage N0-N1. Within the m-ITT population, 33.7% (n=30) responded to treatment (NRS < 5) during the study. The PP set responded similarly (29.9%). Most patients were treatment compliant (n=77; 86.5%). OM severity was assessed using the WHO OM grading scale. No patients had severe mucositis at baseline or V1. At V7, 34.1% had mild mucositis, 45.1% had moderate mucositis, 15.9% had severe mucositis, and 1.2% had life-threatening mucositis. In total, 26 patients (29.2%) developed severe mucositis during the study period (V2-V7). From V1 to V4, one patient reported hospitalization due to mucositis or associated complications, two patients at V5, three patients at V6, and four patients at 7. Discussion: This was the first study to assess feasibility of a treatment for radiation-induced OM with benzydamine mouthwash in patients with HNC. Treatment compliance suggested that benzydamine was well tolerated in patients with moderate to severe mucositis. Benzydamine's anesthetic and anti-inflammatory properties might have reduced pain, which potentially influenced patients' compliance with RT. Few patients in the study required hospitalization for OM or an associated complication, suggesting that benzydamine might improve healthcare resource utilization.

Prognostic value of bioelectrical impedance analysis in head and neck cancer patients undergoing radiotherapy: a VALOR® study.

Introduction: Bioelectrical impedance analysis (BIA) serves as a method to estimate body composition. Parameters such as phase angle (PA), standardized phase angle (SPA), body mass cell (BCM), BCM index (BCMI), and fat-free mass (FFM) might significantly impact the prognosis of head and neck cancer (HNC) patients. The present study aimed to investigate whether bioelectrical parameters can be used to predict survival in the HNC population and establish the optimal cutoff points for predictive accuracy. Methods: A multicenter observational study was performed across 12 tertiary hospitals in Andalusia (a region from the south of Spain). A total of 494 patients diagnosed with HNC between 2020 and 2022 at different stages were included in this study, with a minimum follow-up period of 12 months. The BIA assessment was carried out during the first 2 weeks of radical radiotherapy treatment with chemotherapy or other systemic treatments. A multivariate logistic regression analysis of overall survival, complications, hospital admission, and palliative care and its relationship with BIA nutritional assessment was performed. Results: Significant prognostic factors identified in the multivariable analysis encompassed phase angle (PA), standardized phase angle (SPA), body cell mass (BCM), and BCM index (BCMI). Lower PA and BCM values were significantly associated with adverse clinical outcomes. A BCM threshold above 17 kg/m2 was the most significant predictor for predicting survival within the overall HNC population. The PA values of <5.1° in male and <4.8° in female patients showed the best predictive potential for mortality. Increased PA (as a continuous variable) demonstrated a significantly reduced risk for mortality (OR, 0.64; 95% CI, 0.43-0.94; p < 0.05) and a decreased likelihood of hospital admission (OR, 0.75; 95% CI, 0.52-1.07; p < 0.05). Higher BCM correlated with a lower risk of mortality (OR, 0.88; 95% CI, 0.80-0.96; p < 0.01) and a diminished probability of hospital admission (OR, 0.91; 95% CI, 0.83-0.99; p < 0.05). Conclusion: BIA is a crucial tool in the nutritional assessment of HNC patients. BCM and PA are the main bioelectrical parameters used to predict clinical outcomes in this population. Future studies are needed to validate BIA variables in a large cohort to ensure whether early intensification of nutritional treatment would improve survival.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Rethinking treatment paradigms: Neoadjuvant therapy and de-escalation strategies in HPV-positive head and neck cancer.

Head and neck cancer (HNC) is the 6th most common cancer across the world, with a particular increase in HNC associated with human papilloma virus (HPV) among younger populations. Historically, the standard treatment for this disease consisted of combined surgery and radiotherapy or curative platinum-based concurrent chemoradiotherapy, with associated long term and late toxicities. However, HPV-positive HNC is recognized as a unique cancer subtype, typically with improved clinical outcomes. As such, treatment de-escalation strategies have been widely researched to mitigate the adverse effects associated with the current standard of care without compromising efficacy. These strategies include treatment de-escalation, such as novel surgical techniques, alternative radiation technologies, radiation dose and volume reduction, as well as neoadjuvant chemotherapies, immunotherapies, and combined therapies. Although these therapies show great promise, many of them are still under investigation due to hesitation surrounding their widespread implementation. The objective of this review is to summarize the most recent progress in de-escalation strategies and neoadjuvant therapies designed for HPV-positive HNC. While specific treatments may require additional research before being widely adopted, encouraging results from recent studies have highlighted the advantages of neoadjuvant chemotherapy and immunotherapy, as well as radiation and surgical de-escalation approaches in managing HPV-positive HNC.

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

BACKGROUND: Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy. METHODS: Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy. RESULTS: PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period. CONCLUSION: Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Cold atmospheric plasma sensitizes head and neck cancer to chemotherapy and immune checkpoint blockade therapy.

Head and neck cancer (HNC) is the seventh most prevalent cancer globally, often characterized by chemo-resistance and immunosuppression, which significantly hampers treatment efficacy. Cold atmospheric plasma (CAP) has recently emerged as a promising adjuvant oncotherapy with substantial potential and advantages. In this study, Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. We aimed to investigate the effects of CAPPZ2 on various types of HNC cells and elucidate the underlying mechanisms. In addition, we endeavored to examine the efficacy of combining CAPPZ2 with chemotherapy drugs (i.e., cisplatin) or immune checkpoint blockade (ICB, i.e., PD1 antibody) in HNC treatment. Firstly, the results demonstrated that CAPPZ2 exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promoting apoptosis and autophagy. Secondly, using transcriptomic sequencing, Western blotting, and quantitative real-time PCR, the mechanisms underlying CAPPZ2 treatment in vitro was presumed to be a multitargeted blockade of major cancer survival pathways, such as redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling. Lastly, combinatorial thearpy containing CAPPZ2 and cisplatin or PD-1 antibody significantly suppressed tumor growth and prolonged recipient survival in vivo. Collectively, the synergistic effects of CAPPZ2 and cisplatin or PD-1 antibody could serve as a promising solution to enhance head and neck tumor elimination.

MiR-630 Promotes Radioresistance by Induction of Anti-Apoptotic Effect via Nrf2-GPX2 Molecular Axis in Head-Neck Cancer.

Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family's role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2-GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC.

Circulating low density neutrophils are associated with resistance to anti-PD1 immunotherapy in squamous head and neck cancer.

BACKGROUND: Identification of predictive biomarkers to Immune checkpoint inhibitors (ICIs) in head and neck cancer (HNSCC) is an unmet need. METHODS: This was a prospective observational study including 25 patients with HNSCC treated with immunotherapy or chemotherapy after a prior platinum-based regimen. Low density neutrophils (LDNs) and serum markers were analyzed. RESULTS: In the immunotherapy cohort, patients with high LDN levels had a shorter progression free survival (PFS) (1.8 months vs. 10.9 months; *p = 0.034). Also, progressors showed higher percentage of LDNs compared to non-progressors although significance was not reached (mean 20.68% vs. 4.095%, p = 0.0875). These findings were not replicated in patients treated with chemotherapy. High levels of interleukin-7 (IL7) were correlated with a significantly longer overall survival (OS) (13.47 months 3.51 vs. months, *p = 0.013). CONCLUSIONS: High baseline circulating LDNs and low IL7 could identify a subset of patients intrinsically refractory to ICIs as monotherapy in HNSCC.