Search

Data describing features and management of oropharyngeal neuroendocrine carcinomas (NEC) remain sparse. A systematic review was performed. Patients were stratified by treatment modality and examined for disease progression and survival outcomes. Ninety-four patients from 50 publications were included. Average age at diagnosis was 59.7 years (range 14-83). 73.4% were male. Most studies did not document HPV status. Forty patients (85.1%) were p16 positive, and 34 (85.0%) were HPV-ISH positive. Overall survival was 75.4% at 1 year, and 40.0% at 2 years. Of patients with locoregional disease, 33.8% developed distant metastasis. 12.5% of patients developed locoregional recurrence. Patients who developed distant metastases had worse overall survival (p = 0.0004). No significant difference was found between treatment modalities. Human papilloma virus may be associated with oropharyngeal NEC. Current treatments provide locoregional control, but distant metastases are common and confer low overall survival.

Supplementary Figure 1 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Supplementary Figure 3 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

Supplementary Figure 2 from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

PDF file (154KB)

PDF file (1120KB)

Despite our improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinomas (HNSCC) patients remains relatively unchanged at 50% for the past three decades. HNSCCs often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. Among the multiple dysregulated molecular mechanism in HNSCCs, emerging basic, preclinical, and clinical findings support the importance of the mTOR signaling route in HNSCC progression. Indeed, we observed here that the activation of mTOR is a widespread event in clinical specimens of HNSCCs invading locoregional lymph nodes. We developed an orthotopic model of HNSCC consisting of the implantation of HNSCC cells into the tongues of immunocompromised mice. These orthotopic tumors spontaneously metastasize to the cervical lymph nodes, where the presence of HNSCC cells can be revealed by histologic and immunohistochemical evaluation. Both primary and metastatic experimental HNSCC lesions exhibited elevated mTOR activity. The ability to monitor and quantitate lymph node invasion in this model system enabled us to explore whether the blockade of mTOR could impact HNSCC metastasis. We found that inhibition of mTOR with rapamycin and the rapalog RAD001 diminished lymphangiogenesis in the primary tumors and prevented the dissemination of HNSCC cancer cells to the cervical lymph nodes, thereby prolonging animal survival. These findings may provide a rationale for the future clinical evaluation of mTOR inhibitors, including rapamycin and its analogues, as part of a molecular-targeted metastasis preventive strategy for the treatment of patients with HNSCC. Cancer Res; 71(22); 7103–12. ©2011 AACR.

Head and neck squamous cell carcinomas (HNSCCs) arising in the mucosal linings of the upper aerodigestive tract are highly heterogeneous, aggressive, and multifactorial tumors affecting more than half a million patients worldwide each year. Classical etiological factors for HNSCC include alcohol, tobacco, and human papillomavirus (HPV) infection. Current treatment options for HNSCCs encompass surgery, radiotherapy, chemotherapy, or combinatorial remedies. Comprehensive integrative genomic analysis of HNSCC has identified mutations in TP53 gene as the most frequent of all somatic genomic alterations. TP53 mutations are associated with either loss of wild-type p53 function or gain of functions that promote invasion, metastasis, genomic instability, and cancer cell proliferation. Interestingly, disruptive TP53 mutations in tumor DNA are associated with aggressiveness and reduced survival after surgical treatment of HNSCC. This review summarizes the current evidence and impact of TP53 mutations in HNSCC.

Contains fulltext : 290876.pdf (Publisher’s version ) (Open Access) Inadequate resection margins in head and neck squamous cell carcinoma surgery necessitate adjuvant therapies such as re-resection and radiotherapy with or without chemotherapy and imply increasing morbidity and worse prognosis. On the other hand, taking larger margins by extending the resection also leads to avoidable increased morbidity. Oropharyngeal squamous cell carcinomas (OPSCCs) are often difficult to access; resections are limited by anatomy and functionality and thus carry an increased risk for close or positive margins. Therefore, there is a need to improve intraoperative assessment of resection margins. Several intraoperative techniques are available, but these often lead to prolonged operative time and are only suitable for a subgroup of patients. In recent years, new diagnostic tools have been the subject of investigation. This study reviews the available literature on intraoperative techniques to improve resection margins for OPSCCs. A literature search was performed in Embase, PubMed, and Cochrane. Narrow band imaging (NBI), high-resolution microendoscopic imaging, confocal laser endomicroscopy, frozen section analysis (FSA), ultrasound (US), computed tomography scan (CT), (auto) fluorescence imaging (FI), and augmented reality (AR) have all been used for OPSCC. NBI, FSA, and US are most commonly used and increase the rate of negative margins. Other techniques will become available in the future, of which fluorescence imaging has high potential for use with OPSCC.

Low‐income patients have worse head and neck cancer outcomes than those with high‐income. Yet, few targets have been identified to specifically improve outcomes in the low‐income population. Here, we conduct a review on the current literature on head and neck cancer outcomes in the low‐income population and identify targets for intervention. The degree of disparity is in the range of 20%‐90% worse overall survival in the low‐income population. Eliminating smoking would have the greatest effect on head and neck cancer mortality rates in the low‐income population. Additionally, access to oral cancer exams, assistance with transportation, and continued expansion of telemedicine would facilitate early diagnosis and timely treatment in patients who develop head and neck cancer.

There has been a rising trend in HPV-induced head and neck cancers in the last several decades. This subgroup of squamous cell carcinoma is mostly located in the oropharynx and comprises a subset of patients who are typically younger and without the usual risk factors of smoking and alcohol use. As the prognosis of HPV-induced OPC is more favorable, there is a desire to properly select these patients for de-intensification protocols while identifying individuals who may suffer treatment failure. Here, we describe recent developments in circulating tumor HPV DNA as a marker of HPV-positive oropharyngeal cancer that can potentially be used as a diagnostic tool to stratify patients for de-escalation strategies and to survey for recurrence.

Background: New adjuvant therapies for human head and neck (H&N) cancer to improve the quality of life of the patients are in great demand. Our early studies have demonstrated that uncoupling protein 2 (UCP2) is upregulated in the tumor tissues of H&N cancer compared to the adjacent normal tissues; however, the role of UCP2 in H&N cancer has not been studied. Objective: In this manuscript, we aim to examine whether UCP2 contributes to H&N cancer progression in vitro. Methods: We generated UCP2 stable knockdown H&N cancer cells and detected the effects of UCP2 inhibition on cell proliferation, migration, invasion, 3D spheroid formation, and the sensitivity to a chemodrug treatment. Results: Knockdown of UCP2 suppressed the progression of H&N cancer in vitro, which might be mediated via the following mechanism: 1) increased the G1 phase whereas decreased the S phase of the cell cycle, which could be mediated by suppression of the G1/S regulators including CDK4/6 and cyclin D1. 2) Decreased mitochondrial oxygen consumption, ATP production, and lactate formation, which is consistent with the downregulation of c-Myc. 3) FAK may serve as the upstream signaling molecule, and its action was mediated by Akt and ERK. Conclusions: Our studies first demonstrate that targeting UCP2 may suppress H&N cancer progression in vitro.

Introduction: Anaplastic thyroid cancer (ATC) is one of the most lethal diseases known to humans with a median survival of 5 months. The American Thyroid Association (ATA) recently published guidelines for the treatment of this dreadful thyroid malignancy. Areas covered: This review presents the current therapeutic landscape of this challenging disease. We also present the results from trials published over the last five years and summarize currently active clinical trials. Expert opinion: Recent attempts to improve the prognosis of these tumors are moving toward personalized medicine, basing the treatment decision on the specific genetic profile of the individual tumor. The positive results of dabrafenib and trametinib for ATC harboring the BRAF V600E mutation have provided a useful treatment option. For the other genetic profiles, different drugs are available and can be used to individualize the treatment, likely using drug combinations. Combinations of drugs act on different molecular pathways and achieve inhibition at separate areas. With new targeted therapies, average survival has improved considerably and death from local disease progression or airway compromise is less likely with improvement in quality of life. Unfortunately, the results remain poor in terms of survival.

Importance The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists–head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.

There is a lack of well-powered data regarding outcomes in stage IV differentiated thyroid carcinoma (DTC) treated with postsurgical radiation. The objective of this study was to examine survival in patients with stage IV papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) who received radioactive iodine (RAI), external beam radiation therapy (EBRT), or neither following surgery.In this retrospective cohort study, data collected from the National Cancer Data Base (NCDB) yielded 11,832 patients with stage IV DTC who underwent primary surgical treatment between 2002 and 2012. Patients were stratified by histology and sub-stage. Fully parametric, multilevel survival-time models were used to evaluate survival outcomes in three adjuvant treatment groups: RAI, EBRT, or no adjuvant radiation. Hazard ratios (HR) and time ratios (TR) were calculated against patients who did not receive radiation. All models were adjusted for demographic and clinical factors.The mean age of all patients was 61.6 years (SD = 11.6), and 57.5% were female. Patients who received EBRT had significantly higher 5- and 10-year hazards of death in several PTC sub-stages (10-year HRThrough the NCDB, this study sought to describe prognosis and survival for adjuvant radiation in stage IV DTC. RAI was associated with improved survival for stage IV DTC. Despite treatment benefits conferred by adjuvant EBRT, indications to treat with EBRT were associated with poorer survival outcomes in patients with advanced-stage DTC, particularly PTC.

Background: Over the last two decades, there has been a sharp increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) linked to human papillomavirus (HPV). Compared to tobacco-associated, HPV (-) cancers, HPV (+) tumors are generally less aggressive and more likely to respond to new deintensified treatment regimens. However, there is a subset of HPV (+) OPSCC patients with poor oncologic outcomes, and an understanding of underlying molecular characteristics of HPV (+) OPSCC with poor prognosis is lacking. In this study, we sought to determine the impact of HPV-tumor genomic interactions and their impact on prognosis. We define novel, quantifiable, sequencing-based metrics of HPV structure and function with prognostic significance. Methods: We performed targeted DNA sequencing of 770 cancer-associated genes and the full-length HPV genome on 259 HPV (+) OPSCC cases derived from four cohorts. Sequencing data were routed through automated pipelines for DNA, including 1) somatic variant detection, 2) structural variations, and 3) quantitative and qualitative characterization of full-length HPV sequencing. Patients were assigned as either “high” or “low” based on the inherent binomial distribution of E6 and E7 normalized sequenced read counts across the cohort. Patient outcomes were assessed using the hazard ratio from the Cox proportional hazards regression adjusting for known and suspected confounders of outcome including stage, age, and smoking status defined as greater than 10 pack years. Results: We demonstrate that both HPV viral read count and HPV structure significantly impact prognosis in HPV (+) OPSCC. In addition to integrated and episomal structure, we define a novel viral structural subtype in 15% of cases characterized by simple or complex rearrangement composed of single or multiple breakpoints within the viral genome. Furthermore, we demonstrate that patients with the lowest HPV viral loads had a 30% greater hazard of death compared to patients with high viral loads. When we considered the impact of HPV counts and HPV structure taken together, we note that Integrated cases with low viral load were associated with outcomes much lower than expected for HPV-positive oropharyngeal cancer (5-year overall survival: 56.8%). These results were unaffected by smoking status measured by ever/never smoking or pack-year status. Conclusions: In the largest sequenced HPV (+) OPSCC cohort to date, we identify a quantifiable measure of HPV structure and function with prognostic significance. We define a novel rearranged viral structure and define integrated low viral count cases as associated with dismal survival. These findings highlight the molecular heterogeneity of HPV (+) OPSCC and provide a framework for future clinical trials based on molecular viral characterization. Citation Format: Jose P. Zevallos, Angela L. Mazul, Xiaobei Zhao, Heejoon Jo, Cherie-Ann Nathan, Andrew F. Olshan, Bhishamjit S. Chera, D. Neil Hayes. HPV structure and functional alterations impact prognosis in HPV (+) oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR01.

Objectives: Standards of care for total laryngectomy (TL) patients in the postoperative period have not been established. Perioperative care remains highly variable and perhaps primarily anecdotally based. The aim of this study was to survey members of the American Head and Neck Society to capture management practices in the perioperative care of TL patients. Methods: In this survey study, an electronic survey was distributed to the international attending physician body of the American Head and Neck Society. Forty-five-question electronic surveys were distributed. A total of 777 members were invited to respond, of whom 177 (22.8%) fully completed the survey. The survey elicited information on management preferences in the perioperative care of TL patients. Differences in management on the basis of irradiation status and pharyngeal repair (primary closure vs regional or free flap reconstruction) were ascertained. Main outcomes and measures were time to initiate oral feeding, perioperative antibiotic selection and duration, and estimated pharyngocutaneous fistula rates. These measures were stratified by patient type. Results: Most respondents completed head and neck fellowships (77.0%) and practice at academic tertiary centers (72.3%). Ampicillin/sulbactam was the most preferred perioperative antibiotic (43.2%-49.1% depending on patient type), followed by cefazolin and metronidazole in combination (32.0%-33.7%) and then clindamycin (10.8%-12.6%). Compared with nonirradiated patients, irradiated patients were significantly more likely to have longer durations of antibiotics ( P < .05), longer postoperative times to initiate oral feeding ( P < .05), and higher estimated fistula rates ( P < .05). Additionally, in nonirradiated patients, flap-repaired patients (vs primary repair) were significantly more likely to have longer durations of antibiotics (odds ratio, 1.29; 95% confidence interval, 1.13-1.48) and postoperative times to initiate oral feeding (odds ratio, 2.24; 95% confidence interval, 1.76-2.84). Conclusions: Perioperative management of TL patients is highly variable. Management of antibiotics and oral feeding are significantly affected by irradiation status and scope of pharyngeal repair. Further studies are needed to standardize perioperative care for this unique patient population.

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer, affecting more than 300,000 individuals in the United States annually. Although, most cSCC can be treated successfully by surgery and/or radiation, a significant percentage of cSCC are aggressive and often unresectable and/or can metastasize to the lymph nodes. Organ transplant patients are at a significantly higher risk for cSCC due to a compromised immune system. Recently, the PD-1 inhibitor cemiplimab was approved for the treatment of patients with metastatic cSCC or patients with locally advanced cSCC who are not candidates for curative surgery or curative radiation. This suggests a critical role of immune cells in modulation of disease progression in cSCC. Hence, immune profiling of cSCC is important in identifying novel agents that could benefit patients. Our objective was to employ immunohistochemistry (IHC) to characterize the immune cell infiltrate in normal skin and compare it to actinic keratosis (AK), cSCC and metastatic cSCC (cSCC-M), in order to investigate the immune phenotype associated with progressive stages of malignancy. Our results suggest that AK, cSCC and cSCC-M exhibit significantly higher levels of CD3+, CD4+ and CD8+ T-cells compared to normal skin. Although, the number of CD3+ T-cells are comparable in AK, cSCC and cSCC-M, the CD8+ T-cells show higher infiltration in cSCC-M compared with cSCC and AK. The FOXP3+ Regulatory T-cells (T-reg) display higher abundance with progressive stages of carcinogenesis. However, surprisingly no significant alterations were observed in the abundance of CD4+ T-cells among AK, cSCC and cSCC-M. We also found that the CD68+ Tumor-associated macrophages (TAMs) exhibit a trend of increasing abundance with progressive disease stage. Our study suggests that the CD8+ T-cell population in cSCC-M could be potentially exhausted in the immune hostile tumor micro-environment (TME) constituted by T-reg and TAMs. Alternatively, CD8+ T-cells themselves might express FOXP3 and other immune suppressive factors, thereby reaching a state of anergy. Immunotherapy continues to be a burgeoning field and holds exciting therapeutic prospects in the treatment of cSCC. Moreover, transplant patients with aggressive cSCC are a unique patient population that could benefit from immunotherapy. Citation Format: Md Maksudul Alam, Alok Khandelwal, Tara Moore-Medlin, Hillary Savage, Xiaohui Ma, Cherie-Ann Nathan. Immune infiltrate profiling for progressive malignant stages of cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4573.

Medicaid and uninsured patients anecdotally incur higher cost and length of stay because of nonmedical, discharge-related factors. The purpose of this study was to investigate the association between primary payer and length of stay and cost, controlling for comorbidities and complications, in patients undergoing total laryngectomy.The sample included 4128 patients who underwent total laryngectomy in the 2005 to 2010 National Inpatient Sample (NIS). Patients were categorized into 4 subgroups based on payer status: Medicare, Medicaid, uninsured, and private insurance. Using multilevel modeling, we examined differences in length of stay and hospitalization costs.The odds of being in the top quartile of length of stay increased for Medicaid patients by 41% (odds ratio [OR] = 1.41; 95% confidence interval [CI] = 1.03-1.92) compared with privately insured patients.After controlling for medical factors, Medicaid patients had increased lengths of stay. Overall costs were highest for those with public insurance, but no difference was seen for the adjusted cost. © 2016 Wiley Periodicals, Inc. Head Neck 39: 311-319, 2017.

A new method of nanoparticle formulation for low water-soluble materials was demonstrated on the example of curcumin. The drug was dissolved in organic solvent that is miscible with water (ethanol) and drug nucleation was initiated by gradual worsening the solution with addition of aqueous polyelectrolyte assisted by ultrasonication. Curcumin crystals of 60-100 nm size were obtained depending on the component concentrations, sonication power, and an initial solvent. A layer-by-layer shell assembly with biocompatible polyelectrolytes was used to provide particle coating with high surface potential and stabilization of drug nanocolloids. Polyelectrolyte layer-by-layer encapsulation allowed sustained drug release from nanoparticles over the range of 10-20 hours.

Nonoperative management is generally accepted as a treatment strategy for nasopharyngeal cancer characterized by destruction of the skull base. Chemoradiotherapy is considered the standard of care in these cases. We report a case in which imaging studies documented the successful treatment of the patient's locally extensive nasopharyngeal carcinoma with this nonsurgical approach.

Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL). Experimental Design: Patients were randomly assigned to placebo (n = 18), celecoxib 100 mg twice daily (n = 17), or celecoxib 200 mg twice daily (n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL. Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months. Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.