Role of induction chemotherapy for oral cavity squamous cell carcinoma.

BACKGROUND: Patients with locoregionally advanced oral cavity squamous cell carcinoma (OCSCC) have a poor survival outcome. Treatment involves extensive surgery, adjuvant radiation, or chemoradiation and results in high morbidity. In this study, the authors' objective was to evaluate their experience with induction chemotherapy (IC) in the treatment of locoregionally advanced OCSCC. METHODS: A retrospective review of the medical records of all patients with locoregionally advanced (stage III and IV) OCSCC who received IC followed by definitive local therapy was conducted. Outcomes included response to IC and survival. RESULTS: In total, 120 patients were included in the study. The overall stage was stage IV in 79.2% of patients. After 2 cycles of IC, 76 patients (63.3%) achieved at least a partial response, including 13 who had a complete response. Stable disease was observed in 30 patients (25%), and 14 patients (11.7%) had progressive disease. Among responders, 16 patients received definitive chemoradiation or radiation therapy, and 60 underwent surgical resection, of whom 15 had less extensive surgery than was originally planned. Overall, organ preservation was achieved in 40.8% of patients who had a favorable response to IC. The 5-year overall and disease-specific survival rates were 51.4% and 66.9%, respectively. Patients who had at least a partial response had better 5-year overall survival (60.1%) and disease-specific survival (78.5%) compared with nonresponders (33.8% and 46.4%, respectively). CONCLUSIONS: The results demonstrate a response rate to IC in patients with advanced OCSCC similar to what has been observed in patients with cancer in other head and neck subsites. Patients who achieved at least a partial response to IC had a more favorable outcome, with ensuing organ preservation. Further studies are warranted.

Lower disease control rates and survival outcomes among Blacks with pharyngeal squamous cell carcinomas compared with Whites: a retrospective analysis at the University of Florida.

Disparate clinical outcomes for pharyngeal squamous cell carcinoma (PSCC) of the oropharynx (OPSCC) and hypopharynx (HPSCC) have been observed in Black compared with White patients. Higher tobacco and alcohol use has been associated with decreased survival in Black patients with PSCC. Higher human papilloma virus (HPV) infection rates, associated with specific subsites of the oropharynx, are linked to improved overall survival (OS). Using an institutional cohort of Black and White patients with PSCC, we performed a retrospective analysis using multiple disease endpoints including local control (LC), local-regional control (LRC), freedom from distant metastases (DMFS), OS, cause-specific survival (CSS), and recorded tobacco and alcohol use. 1419 patients [Black (n = 111) and White (n = 1,308)] treated for PSCC from 1973 to 2013 were evaluated. PSCC 5- and 10-year LC, LRC, and DMFS and CSS rates were lower for Blacks. Notably, Black patients with OPSCC had higher stage cancers, higher percentage of soft palate tumors, and lower percentage of base of tongue cancers, were more likely to receive radiotherapy, and had higher tobacco and alcohol use. OS was significantly lower in Black patients at both anatomic sites, with the greatest difference observed for OPSCC. Multivariate analysis showed race and tobacco independently predicted DMFS, OS, and CSS; however, tobacco use had a greater impact on DMFS (HR 2.5, p = 0.021) than race (HR 1.9, p = 0.027). Overall, we propose that the higher burden of tobacco use along with a lower rate of tumors arising from traditional HPV-related subsites were important contributors to disparate disease outcomes seen in our Black patients.

p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

OBJECTIVE: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). STUDY DESIGN: Historical cohort study. SETTING: Tertiary medical center. METHODS: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. RESULTS: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). CONCLUSIONS: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

The Increasing Problem of Syphilis Manifesting as Head and Neck Cancer: A Case Series.

Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Rates have been rising in the US and globally. Known as the "Great Imitator," syphilis can involve head and neck subsites, and often can masquerade as possible carcinoma of the head and neck. Here, we present three distinct cases of syphilis presenting as suspected head and neck malignancy involving the oropharynx, larynx and oral cavity. All cases were diagnosed on surgical pathologic examination of diseased tissues and treated. It is important for practicing otolaryngologists to understand head and neck manifestations of syphilis to facilitate proper diagnosis and treatment. Laryngoscope, 134:236-239, 2024.

Effects of Tongue Strength Training on Quality of Life in Head and Neck Cancer Patients: Results From a Pilot Interventional Clinical Trial.

BACKGROUND: Head and neck cancer (HNC) patients often have dysphagia following surgical and/or chemoradiation treatment, which can lead to reduced quality of life. Some patients suffer from decreased tongue strength and mobility that may cause discomfort and difficulty with swallowing. Our group has developed a patented genioglossus muscle strength trainer (GMST) to increase tongue protrusive force that has been used in patients with sleep apnea. We hypothesized that the GMST device would increase tongue strength in the HNC population. METHODS: We conducted an IRB approved, non-randomized, interventional clinical trial of HNC patients with dysphagia to determine the effect of GMST on tongue strength. Our secondary objective was to assess dysphagia quality of life, as determined by questionnaires. Genioglossus muscle strength measurements (measured in Newtons, N) and dysphagia quality of life scores (SWAL-QoL questionnaire) were obtained from enrolled patients at baseline and following 4 weeks of intervention. Treatment was at-home GMST exercise regimen 3 times daily, 5 days per week. Compliance was assessed via review of training logs. Two-sided paired t-tests at significance level α = .05 were performed to assess difference in mean GG muscle strength pre- and post-treatment. RESULTS: Out of 10 patients initially enrolled, 7 patients completed the trial. Eighty-six percent were male and the average age was 60. About 5 patients had surgery plus adjuvant radiation and 2 patients had primary radiation. All patients had baseline dysphagia as determined by patient complaint and/or objective measurement (prior modified barium swallow). No adverse events were reported. We observed a statistically significant increase in genioglossus muscle strength (mean change: 4.0 N, 95% CI 1.1-6.9, P = .015) after 4 weeks of treatment. Patients reported reduced swallowing burden and feeling of stigma around eating based on SWAL-QoL results. CONCLUSIONS: Our data suggest that protrusive tongue-training exercises utilizing a novel tongue trainer device is well-tolerated and increases genioglossus muscle strength in treated HNC patients complaining of dysphagia. Patient-reported outcomes based on the SWAL-QoL survey indicate improvements in quality-of-life post-treatment, although our results are limited by small sample size. Larger studies are needed to see if this device could have clinically meaningful results for this difficult-to-treat patient population.

Primary fit tracheoesophageal puncture in primary versus salvage laryngectomy: Short-term and long-term complications and functional outcomes.

BACKGROUND: Primary fit tracheoesophageal puncture (TEP) is widely preferred for individuals who have not undergone prior radiation. However, there is no consensus on the relative utility of primary-fit TEP in the setting of salvage laryngectomy. METHODS: A retrospective, single-center review was conducted of individuals undergoing laryngectomy with primary fit TEP between 2012 and 2018. Multivariable analysis was conducted to compare short-term and long-term complications, as well as speech and swallowing outcomes, of those who underwent primary versus salvage laryngectomy. RESULTS: In this study, 134 patients underwent total laryngectomy with primary fit TEP. Aside from a higher rate of peristomal dehiscence (13.1% vs. 1.4%) found in the salvage group, there was no difference in incidence of all other complications, including pharyngocutaneous fistula formation. The groups had comparable speech and swallow outcomes. CONCLUSION: Primary fit TEP is a safe and effective surgical choice for individuals undergoing salvage laryngectomy who desire a voice prosthesis.

Oral Cavity Cancer Surgical and Nodal Management: A Review From the American Head and Neck Society.

Importance: Lymph node metastases from oral cavity cancers are seen frequently, and there is still inconsistency, and occasional controversies, regarding the surgical management of the neck in patients with oral cancer. This review is intended to offer a surgically focused discussion of the current recommendations regarding management of the neck, focusing on the indications and extent of dissection required in patients with oral cavity squamous cell carcinoma while balancing surgical risk and oncologic outcome. Observations: The surgical management of the neck for oral cavity cancer has been robustly studied, as evidenced by substantial existing literature surrounding the topic. Prior published investigations have provided a sound foundation on which data-driven treatment algorithms can generally be recommended. Conclusions: Existing literature suggests that patients with oral cavity cancer should be fully staged preoperatively, and most patients should receive a neck dissection even when clinically N0. Quality standards supported by the literature include separation of each level during specimen handling and lymph node yield of 18 or more nodes. Sentinel lymph node biopsy can be considered in select tumors and within a well-trained multidisciplinary team.

Clinical outcomes of combined cervical and transthoracic surgical approaches in patients with advanced thyroid cancer.

BACKGROUND: Advanced thyroid disease involving the mediastinum may be managed surgically with a combined transcervical and transthoracic approach. Contemporary analysis of this infrequently encountered cohort will aid the multidisciplinary team in personalizing treatment approaches. METHODS: Retrospective review of patients undergoing combined transcervical and transthoracic surgery for thyroid cancer at a single high-volume institution from 1994 to 2015. RESULTS: Thirty-eight patients with median age 59 years (range 28-76) underwent surgery without perioperative mortality. Most patients had primary disease. A majority had distant metastases outside the mediastinum but had locoregionally curable disease. Common complications were temporary (39%) and permanent (18%) hypoparathyroidism, and wound infection (13%). One-year overall survival was 84%; 1-year locoregional disease-free survival was 64%. Median time to locoregional recurrence was 36 months. Only esophageal invasion was associated with worse oncologic outcomes. CONCLUSIONS: Combined transcervical and transthoracic surgery for advanced thyroid cancer can be performed without mortality and with acceptable morbidity.

mRNA challenge predicts brain cancer immunogenicity and response to checkpoint inhibitors.

To prospectively determine whether brain tumors will respond to immune checkpoint inhibitors (ICIs), we developed a novel mRNA vaccine as a viral mimic to elucidate cytokine release from brain cancer cells in vitro. Our results indicate that cytokine signatures following mRNA challenge differ substantially from ICI responsive versus non-responsive murine tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICI or lack thereof in poorly immunogenic settings.

Implementation strategies for integrating tobacco cessation treatment in cancer care: A qualitative study.

Purpose: The objective of this study was to determine how to optimize implementation of tobacco cessation treatment interventions in cancer care by (1) investigating the feasibility and acceptability of a multi-level approach to tobacco cessation treatment intervention, (2) identifying barriers and facilitators to implementation, and (3) eliciting additional strategies to improve implementation of the intervention. Methods: We conducted qualitative interviews with oncologists (n = 15) from one large academic health center in the Southeastern United States. We asked about their knowledge, attitudes, and current practices regarding tobacco use screening and treatment. We also asked about two proposed strategies to support implementation of tobacco cessation treatment: (1) developing a registry of tobacco users in collaboration with the state-run tobacco cessation program, and (2) providing on-site tobacco cessation counseling from trained professionals. Results: Oncologists saw addressing tobacco use as valuable; however, they felt restricted from consistently addressing tobacco use by multi-level barriers such as workload, electronic health record (EHR) design, patient anxiety, and low self-efficacy for treating tobacco dependence. Oncologists responded positively to on-site treatment and felt this strategy would increase treatment accessibility and enhance engagement. Reaction to developing a registry of tobacco users was mixed, with concerns regarding lack of oncologist involvement and patient privacy expressed. Other suggested strategies for supporting implementation of tobacco cessation treatment included reducing referral complexity, establishing financial or quality incentives for oncologists, and leveraging existing EHR tools to facilitate integration of cessation interventions into clinic workflows. Conclusion: We identified several challenges to implementing tobacco use treatment in cancer care; however, we considered strategies to overcome these barriers that were viewed as feasible and acceptable. Our work highlights the importance of engaging stakeholders in implementation efforts. Future work should explore the impact of the implementation strategies identified in this study.

Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234.

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other. Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant. Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.

Human Papillomavirus Vaccination and Human Papillomavirus-Associated Cancer Rates Within Florida Counties.

INTRODUCTION: To direct interventions, the Florida counties with the greatest risk of current and future human papillomavirus‒associated cancers were identified by estimating county-level (1) percentages of adolescents aged 13-17 years who initiated (≥1 dose) and were up to date (2-3 doses) for the human papillomavirus vaccine and (2) human papillomavirus‒associated cancer incidence rates. METHODS: Records were obtained for human papillomavirus vaccinations from the Florida immunization registry (2006-2019), incident cancer cases from the Florida registry (2013-2017), and annual population counts from the Florida Department of Health (2006-2019). In 2020, annual county-level human papillomavirus vaccine initiation, human papillomavirus vaccine up-to-date, and age-adjusted human papillomavirus‒associated cancer incidence rates were estimated. RESULTS: Among adolescents aged 13-17 years, average 2018-2019 county-specific human papillomavirus vaccine initiation ranged from 38% to 100% for females and from 34% to 96% for males. Up-to-date estimates ranged from 20% to 72% for females and from 24% to 77% for males. The majority (78%) of counties with initiation and up-to-date estimates within the lowest tercile were located in Northern Florida. County-specific 2013-2017 annualized, adjusted human papillomavirus‒associated cancer incidence rates ranged from 0 to 29.8 per 100,000 among females and from 5.4 to 24.1 per 100,000 among males. Counties within the highest tercile for human papillomavirus‒associated cancers were primarily (90% for females and 77% for males) located in Northern Florida. CONCLUSIONS: Human papillomavirus‒associated cancer risk varies widely across Florida counties, with particularly high risk within Northern Florida. Targeting interventions toward counties with low vaccination and high cancer rates may reduce human papillomavirus‒associated cancers.

Osteoradionecrosis in osseous free flap reconstruction: Risk factors and treatment.

OBJECTIVE: To determine the rate and risk factors for osteoradionecrosis (ORN) in osseous free flaps after postoperative radiation therapy (PORT). To describe the treatment of free flap ORN. METHODS: Seventy-four patients undergoing osseous free flap reconstruction were analyzed. Thirty-eight completed PORT. Patients were followed for ≥6 months. RESULTS: The rate of ORN was 34% overall; 0% with 50 to 59.9 Gy; 8% with 60 Gy; 40% with 66 Gy; 56% with 70 to 74.4 Gy. Mean time to ORN was 13.1 months. 0/28 patients without PORT developed free flap osteonecrosis. Multivariate analysis found the only factor predicting ORN: PORT >60 Gy, which increased the risk 21-fold. Treatment included PENTACLO, hyperbaric oxygen, and surgical debridement with 75% within 2 years. CONCLUSION: PORT >60 Gy is significantly associated with free flap ORN. As the dose of adjuvant RT increases beyond 60 Gy, the risk of ORN in free flaps rises. Consideration should be given to lower PORT doses or delaying free flap reconstruction when feasible.

An Implementation Trial to Improve Tobacco Treatment for Cancer Patients: Patient Preferences, Treatment Acceptability and Effectiveness.

Continued smoking after a cancer diagnosis increases mortality, risk of recurrence, and negatively impacts treatment effectiveness. However, utilization of tobacco use cessation treatment among cancer patients remains low. We conducted a clinical trial assessing patient preferences, treatment acceptability, and preliminary effectiveness (7-day point prevalence at 12 weeks) of three tobacco treatment options among cancer patients at an academic health center. Implementation strategies included electronic referral and offering the choice of three treatment options: referral to external services, including the quitline (PhoneQuit) and in-person group counseling (GroupQuit), or an internal service consisting of 6-week cognitive behavioral therapy delivered via smartphone video conferencing by a tobacco treatment specialist (SmartQuit). Of 545 eligible patients, 90 (16.5%) agreed to enroll. Of the enrolled patients, 39 (43.3%) chose PhoneQuit, 37 (41.1%) SmartQuit, and 14 (15.6%) GroupQuit. Of patients reached for 12-week follow-up (n = 35), 19 (54.3%) reported receiving tobacco treatment. Of all patients referred, 3 (7.7%) PhoneQuit, 2 (5.4%) SmartQuit, and 2 (14.3%) GroupQuit patients reported 7-day point prevalence abstinence from smoking at 12 weeks. Participants rated the SmartQuit intervention highly in terms of treatment acceptability. Results indicate that more intensive interventions may be needed for this population, and opportunities remain for improving reach and utilization.

Radiotherapy for benign head and neck paragangliomas.

PURPOSE: To update our experience treating benign head-and-neck paragangliomas (PGs) with radiotherapy (RT). METHODS: A total of 149 patients with 176 PGs received curative-intent RT; 126 received RT to 1 PG and 23 to 2 or more PGs. The most common dose fractionation schedule was 45 Gy/25 once-daily fractions/5 weeks which was used to treat 147 PGs (83.5%) in 123 patients (82.6%). Patients were followed with physical examination and CT/MRI. The median follow-up for all patients was 10.6 years (range, 0.2-50.4 years); the median follow-up for surviving patients was 11.1 years (range, 0.2-50.4). RESULTS: The 5-year, 10-year, and 15-year outcomes were: local control, 99%, 96%, and 95%; distant metastasis-free survival, 99%, 99%, and 99%; cause-specific survival, 98%, 98%, and 98%; and overall survival, 90%, 75%, and 64%, respectively. No patient developed a moderate or severe complication, or a radiation-induced second tumor or malignant transformation of the benign PG. CONCLUSION: RT is an effective treatment for head-and-neck PGs with a low risk of complications.

Curative-dose Chemoradiotherapy Versus Total Laryngectomy For Stage T3-T4 Squamous Cell Carcinoma of the Larynx: An "Apples-to-Apples" Analysis of the National Cancer Database.

OBJECTIVE: Chemoradiotherapy (cRT) and total laryngectomy (TL) are acceptable treatments for locally advanced laryngeal squamous cell carcinoma (LSSC). We aimed to compare the outcomes in patients receiving full-dose treatment. METHODS: We identified 11,237 patients in the National Cancer Database treated 2004 to 2015 for T3-4N0-3 LSCC with either TL (with 60 to 80 Gy of adjuvant RT) or cRT (70 to 80 Gy). We evaluated differences in overall survival (OS) using Kaplan-Meier and Cox proportional hazards modeling. RESULTS: For patients with T3 disease, there was no difference in OS regardless of N stage (N0: hazard ratio [HR]=0.94, P=0.38; N+: HR=0.92, P=0.19). TL was associated with improved OS in patients with T4 disease (N0: HR=1.39, P<0.001; N+: HR=1.22, P=0.001). CONCLUSION: In patients who receive optimal therapy, both TL and cRT offer similar outcomes in T3 but not T4a disease.

Discharge Delay in Head and Neck Free Flap Surgery: Risk Factors and Strategies to Minimize Hospital Days.

OBJECTIVE: Length of stay (LOS) includes time medically necessary in the hospital and time waiting for discharge (DC) afterward. This DC delay is determined in head and neck free flap patients. Reasons for and factors leading to DC delay, as well as associated adverse outcomes, are elucidated. METHODS: Retrospective chart review was performed for all head and neck free flap surgeries from 2012 to 2017. Data including demographics, comorbidities, and perioperative factors were collected. Regression analyses were performed to identify factors associated with DC delay. RESULTS: In total, 264 patients were included. Mean total LOS was 13.1 days. DC delay occurred in 65% of patients with a mean of 4.8 days. Factors associated with DC delay on univariate analysis included Medicaid/self-pay insurance, DC to a facility, and not having children ( P < .05). Multivariate analysis showed prolonged medically necessary LOS and surgery on a Monday/Friday ( P < .05) were associated with DC delay. Top reasons for DC delay included case management shortages, rejection by facility, and awaiting supplies. Eleven percent experienced complications during the DC delay. DISCUSSION: DC delay can add days and complications to the LOS. Prevention begins preoperatively with DC planning involving the patient's closest family. Understanding limitations of the patient's insurance may help plan DC destination. Optimizing hospital resources when available should be a focus. IMPLICATIONS FOR PRACTICE: Head and neck free flap patients require a team of teams unified in optimizing quality of care. DC delay is a novel quality metric reflecting the team's overall performance. Through strategic DC planning and capitalizing on available resources, DC delay can be minimized.

MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma.

OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents. MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors. RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models. CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Isolated leptomeningeal progression from sinonasal carcinomas: Implications for staging workup and treatment.

PURPOSE: To evaluate the rate and risk factors of isolated leptomeningeal progression in sinonasal carcinomas. METHODS: We retrospectively reviewed imaging and clinical records to determine progression patterns, and estimated rates using the Kaplan-Meier method. We evaluated risk factors using proportional hazard regression. RESULTS: We analyzed 120 patients who received adjuvant or primary radiotherapy for sinonasal carcinomas. Most patients had T4 disease (68%) and underwent surgery (84%) and chemotherapy (72%). Twenty-seven (23%) patients developed distant metastases (DM), including 20 (17%) with isolated DMs. Leptomeningeal progression was the most common site of isolated DMs (n = 9; 45%) with an average disease-free interval of 1.2 years (0.1-4.3 years). High-grade histology (P = 0.0003), intracranial invasion (P < 0.0001), and neuroendocrine histology (P = 0.06) were associated with increased risk. CONCLUSIONS: Isolated leptomeningeal progression is a common pattern of DM in advanced sinonasal carcinomas. We recommend adding cerebrospinal fluid cytology and contrast-enhanced spine MRI to routine staging evaluations for high-risk patients.

COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms.

PURPOSE: TP53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP53 status.Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine in vitro and in vivo sensitivity of HNSCC cell lines with either wild-type, null, or mutant TP53 to COTI-2 alone, and in combination with cisplatin and/or radiation. Western blotting, cell cycle, live-cell imaging, RNA sequencing, reverse-phase protein array, chromatin immunoprecipitation, and apoptosis analyses were performed to dissect molecular mechanisms. RESULTS: COTI-2 decreased clonogenic survival of HNSCC cells and potentiated response to cisplatin and/or radiation in vitro and in vivo irrespective of TP53 status. Mechanistically, COTI-2 normalized wild-type p53 target gene expression and restored DNA-binding properties to the p53-mutant protein in HNSCC. In addition, COTI-2 induced DNA damage and replication stress responses leading to apoptosis and/or senescence. Furthermore, COTI-2 lead to activation of AMPK and inhibition of the mTOR pathways in vitro in HNSCC cells. CONCLUSIONS: COTI-2 inhibits tumor growth in vitro and in vivo in HNSCC likely through p53-dependent and p53-independent mechanisms. Combination of COTI-2 with cisplatin or radiation may be highly relevant in treating patients with HNSCC harboring TP53 mutations.