Clinical Outcomes and Patterns of Failure in Esthesioneuroblatoma: A Single Institutional Experience.

Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy that is typically managed with a combination of surgical resection, radiotherapy and chemotherapy. Data used to guide therapeutic decision making are scant and typically obtained from small retrospective series due to the relative infrequency of the diagnosis. Here, we report our own institutional experience in the management of patients with ENB to help compliment these prior single institutional reports. Records from patients receiving treatment for ENB at the University of Minnesota Medical Center were obtained from 1994 to 2019. A total of 17 patients were identified from our retrospective review. Kadish stage at initial presentation was A in 2 (12%), B in 5 (29%), C in 9 (53%) and D in 1 (6%). All patients underwent surgical resection. Adjuvant radiotherapy was utilized in 12 (71%) patients with concurrent chemotherapy administered in 3 (18%) patients. One patient received neoadjuvant chemoradiotherapy followed by surgical resection. Four patients developed recurrent disease with locoregional failure presenting as the most common site of initial relapse within our study population. Isolated local recurrence occurred in 2 patients, one patient developed combined local and regional failure, while another had combined regional and distant failure with osseous metastases. Recurrent disease was managed by either combined salvage surgery and radiotherapy (RT) or RT alone. Three of the 4 patients who developed recurrence eventually succumbed to their disease. Estimates for 5-year DFS and OS were 65% and 90%, respectively, for the entire cohort.

Estimating Risk of Pituitary Apoplexy after Resection of Giant Pituitary Adenomas.

Background Pituitary apoplexy after resection of giant pituitary adenomas is a rare but often cited morbidity associated with devastating outcomes. It presents as hemorrhage and/or infarction of residual tumor in the postoperative period. Because of its rarity, its incidence and consequences remain ill defined. Objective The aim of this study is to estimate the rate of postoperative pituitary apoplexy after resection of giant pituitary adenomas and assess the morbidity and mortality associated with apoplexy. Methods A systematic review of literature was performed to examine extent of resection in giant pituitary adenomas based on surgical approach, rate of postoperative apoplexy, morbidities, and mortality. Advantages and disadvantages of each approach were compared. Results Seventeen studies were included in quantitative analysis describing 1,031 cases of resection of giant pituitary adenomas. The overall rate of subtotal resection (<90%) for all surgical approaches combined was 35.6% (95% confidence interval: 28.0-43.1). Postoperative pituitary apoplexy developed in 5.65% ( n = 19) of subtotal resections, often within 24 hours and with a mortality of 42.1% ( n = 8). Resulting morbidities included visual deficits, altered consciousness, cranial nerve palsies, and convulsions. Conclusion Postoperative pituitary apoplexy is uncommon but is associated with high rates of morbidity and mortality in subtotal resection cases. These findings highlight the importance in achieving a maximal resection in a time sensitive fashion to mitigate the severe consequences of postoperative apoplexy.

CX-4945 and siRNA-Mediated Knockdown of CK2 Improves Cisplatin Response in HPV(+) and HPV(-) HNSCC Cell Lines.

Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration of HPV(+) and HPV(-) status. Here, we investigated the response of HPV(+) and HPV(-) HNSCC cells to CK2 targeting using CX-4945 or siRNA downregulation combined with cisplatin treatment. HNSCC cell lines were examined for CK2 expression levels and activity and response to CX-4945, with and without cisplatin. CK2 levels and NFκB p65-related activity were high in HPV(+) HNSCC cells relative to HPV(-) HNSCC cells. Treatment with CX-4945 decreased viability and cisplatin IC50 in all cell lines. Targeting of CK2 increased tumor suppressor protein levels for p21 and PDCD4 in most instances. Further study is needed to understand the role of CK2 in HPV(+) and HPV(-) HNSCC and to determine how incorporation of the CK2-targeted inhibitor CX-4945 could improve cisplatin response in HNSCC.

Identification of high protein kinase CK2α in HPV(+) oropharyngeal squamous cell carcinoma and correlation with clinical outcomes.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rising worldwide, especially human papillomavirus (HPV)-associated disease. Historically, high levels of protein kinase CK2 were linked with poor outcomes in head and neck squamous cell carcinoma (HNSCC), without consideration of HPV status. This retrospective study examined tumor CK2α protein expression levels and related clinical outcomes in a cohort of Veteran OPSCC patient tumors which were determined to be predominantly HPV(+). METHODS: Patients at the Minneapolis VA Health Care System with newly diagnosed primary OPSCC from January 2005 to December 2015 were identified. A total of 119 OPSCC patient tumors were stained for CK2α, p16 and Ki-67 proteins and E6/E7 RNA. CK2α protein levels in tumors and correlations with HPV status and Ki-67 index were assessed. Overall survival (OS) analysis was performed stratified by CK2α protein score and separately by HPV status, followed by Cox regression controlling for smoking status. To strengthen the limited HPV(-) data, survival analysis for HPV(-) HNSCC patients in the publicly available The Cancer Genome Atlas (TCGA) PanCancer RNA-seq dataset was determined for CSNK2A1. RESULTS: The patients in the study population were all male and had a predominant history of tobacco and alcohol use. This cohort comprised 84 HPV(+) and 35 HPV(-) tumors. CK2α levels were higher in HPV(+) tumors compared to HPV(-) tumors. Higher CK2α scores positively correlated with higher Ki-67 index. OS improved with increasing CK2α score and separately OS was significantly better for those with HPV(+) as opposed to HPV(-) OPSCC. Both remained significant after controlling for smoking status. High CSNK2A1 mRNA levels from TCGA data associated with worse patient survival in HPV(-) HNSCC. CONCLUSIONS: High CK2α protein levels are detected in HPV(+) OPSCC tumors and demonstrate an unexpected association with improved survival in a strongly HPV(+) OPSCC cohort. Worse survival outcomes for high CSNK2A1 mRNA levels in HPV(-) HNSCC are consistent with historical data. Given these surprising findings and the rising incidence of HPV(+) OPSCC, further study is needed to understand the biological roles of CK2 in HPV(+) and HPV(-) HNSCC and the potential utility for therapeutic targeting of CK2 in these two disease states.

A Rare Case of Recurrent Pituitary Collision Tumors.

Pituitary collision tumors are sporadically reported and rare. We present a case of pituitary collision tumors with nonfunctioning pituitary adenoma (NFPA) and craniopharyngioma. In order to look for any common activated pathway, we examined WNT/ß-CATENIN signaling activation, known to be involved in tumorigenesis in both craniopharyngioma and NFPA. We found nuclear accumulation of ß-CATENIN protein and expression of LEF1 protein, markers of active ß-CATENIN signaling in the craniopharyngioma but not in the pituitary adenomas. In our case, the NFPA is invasive macroadenoma, which is a frequently identified type of pituitary adenoma in collision tumor cases. Recurrence of this tumor was first observed after 8 years of follow-up. Based on this case, we suggest that pituitary collision tumors require long-term follow-up.

Positron emission computed tomography and magnetic resonance imaging features of sinonasal small round blue cell tumors.

AIM: The sinonasal tract hosts numerous types of undifferentiated neoplasms, having small round cell morphology. The aim of this study was to determine whether sinonasal small round blue cell tumors (SRBCT) have distinct imaging features on computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT. METHODS: Seventy-three patients (43 male; Mage = 61.2 years) with histopathologically proven sinonasal SRBCT were retrospectively reviewed. Imaging features of SRBCTs including location, maximum dimension, margin characteristics, presence of calcification, sclerotic bone changes, intratumoral necrosis, tumor extension, bone destruction, bone remodeling, perineural spread, T1- and T2-weighted MRI signal intensity, qualitative features on diffusion-weighted imaging and 18F-FDG PET/CT, and pattern of contrast enhancement were analyzed using Fisher's exact test or the chi-square test. The maximum standardized uptake values (SUVmax) and apparent diffusion coefficient (ADCmean) values of SRBCT were compared by utilizing the Kruskal-Wallis test. RESULTS: There was a significant difference between SRBCT type regarding the tumor location (p = 0.006), 18F-FDG uptake pattern (p = 0.006), involvement of the orbit (p = 0.016) and pterygopalatine fossa (p = 0.043), the presence of perineural spread (p < 0.001), bone destruction (p = 0.034), and intratumoral necrosis (p = 0.022). Bone destruction and necrosis were more common in rhabdomyosarcoma. Perineural spread was common in sinonasal adenoid cystic carcinoma (ACC). Qualitative 18F-FDG uptake features as well as tumor location were significantly different between sinonasal ACC and sinonasal undifferentiated carcinoma. The ADCmean and SUVmax values were not statistically different between SRBCT types. CONCLUSIONS: Sinonasal SRBCTs have numerous distinct imaging features on CT, MRI, and 18F-FDG PET/CT that could be useful in the differentiation between lesions when the histopathologic diagnosis is inconclusive.

Appropriate timing of surveillance intervals with whole-body 18F-FDG PET/CT following treatment for sinonasal malignancies.

PURPOSE: To assess the ideal timing of posttreatment whole-body 18F-FDG PET/CT examination as routine surveillance to determine local recurrence (R), lymph node metastasis (LM), and distant metastasis (DM) of sinonasal malignancies and to investigate the effect of 18F-FDG PET/CT on survival. METHODS: An overall 80 patients who had undergone a total of 197 posttreatment whole-body 18F-FDG PET/CT examinations for sinonasal malignancy were retrospectively examined after institutional review board approval. Patients were grouped regarding the time intervals (<1 month, 1-3 months, 3-6 months, 6-12 months, 12-18 months and >18 months) after the conclusion of treatment. Differences in diagnostic accuracy due to different follow-up intervals were calculated by receiver operator curves (ROC) and a Cox proportional hazards model was used to assess the prognostic value of surveillance 18F-FDG PET/CT. RESULTS: Considering the time intervals of posttreatment 18F-FDG PET/CT scans, the negative predictive value and positive predictive value of the 18F-FDG PET/CT examinations to predict overall recurrence in 1-3 months (100 and 100%, respectively) and >18 months (100 and 95%, respectively) were higher than for recurrence detection in <1 month (50 and 100%, respectively), 3-6 months (81 and 93%, respectively), 6-12 months (79 and 87%, respectively), and 12-18 months (75 and 80%, respectively) (p < 0.05). Positive findings on 18F-FDG PET/CT scans were also independent predictors of poorer overall survival (OS) (p < 0.05). CONCLUSIONS: Whole-body 18F-FDG PET/CT is capable of identifying recurrences following treatment, using an optimal time interval for scanning of 1-3 months and >18 months after therapy.

Analyses of molecular and histopathologic features and expression of PRAME by immunohistochemistry in mucosal melanomas.

Mucosal melanomas are rare, and less is known about the biomarkers of this subtype in comparison to cutaneous or uveal melanomas. Preferentially expressed antigen in melanoma (PRAME) has been studied as a tool for prognostication of uveal melanomas, and immunotherapy against PRAME-expressing tumor cells has already shown promise. Our goal was to retrospectively analyze 29 cases of mucosal melanomas at our institution to determine if any molecular and histopathologic prognosticators could be identified, as well as to study PRAME expression and its association with prognosis. We found that the majority of mucosal melanomas expressed PRAME and a high PRAME expression score predicted a poor prognosis. There was no association between prognosis and the histomorphologic features analyzed, such as presence of spindle cell or epithelioid predominance. BRAF mutations were absent in 16 of 16 cases tested. Pathogenic NRAS mutations were detected in 3 of 11 cases tested and were associated with shorter overall survival compared to those without NRAS alterations, but the presence of NRAS mutations did not correlate with PRAME expression. In conclusion, an increase in PRAME expression and the presence of a pathogenic NRAS were both associated with a worse prognosis in mucosal melanomas.

Prediction of survival with combining quantitative 18 F-FDG PET/CT and DW-MRI parameters in sinonasal malignancies.

BACKGROUND: We aimed to establish the prognostic value of 18 F-fluoro-deoxy-glucose positron emission/CT (18 F-FDG PET/CT) and diffusion-weighted (DW) MRI in determining overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) of sinonasal malignancies. METHODS: Sixty-eight patients with sinonasal cancer who underwent both pretreatment 18 F-FDG PET/CT scan and head-neck MRI from January 2009 through August 2017 were retrospectively reviewed. Kaplan-Meier survival analysis of 18 F-FDG PET/CT and DW-MRI parameters were performed for OS, PFS, and DMFS. RESULTS: Cox regression analysis determined that all the quantitative 18 F-FDG PET/CT and DW-MRI parameters were independently correlated with PFS, DMFS, and OS (P < .05). After controlling for imaging variables, perineural invasion (P = .02) and ill-defined margin (P = .02) were found to be significantly correlated with shorter OS; while the perineural invasion was significantly correlated with shorter PFS (P = .02). CONCLUSIONS: The pretreatment DW-MRI and 18 F-FDG PET/CT parameters could be substantial surrogate markers for sinonasal malignancies.

Role of Whole-Body 18F-FDG PET/CT in Screening for Metastases in Newly Diagnosed Sinonasal Malignancies.

OBJECTIVE. The aim of this study is to assess the utility of pretreatment whole-body 18F-FDG PET/CT in screening for distant metastasis (DM) and regional lymphatic metastasis (LM). MATERIALS AND METHODS. Eighty-nine consecutive patients with untreated sinonasal malignant lesions (32 women and 57 men; mean age, 62 years) underwent whole-body FDG PET/CT between January 2009 and August 2017. A retrospective analysis was performed to determine the presence of DM and LM. Any suspected metastases were confirmed by histopathologic analysis or clinical and imaging follow-up in the subsequent 12 months. The statistics were verified by comparing FDG PET/CT results with a reference standard. RESULTS. Overall, the frequency of DM was 24% (21/89), of which 81% (17/21) were identified by whole-body FDG PET/CT. The sensitivity and specificity of FDG PET/CT in predicting DM were 81% (95% CI, 62-95%) and 99% (95% CI, 82-100%), respectively. The most common DM sites were the lungs (n = 6; 28%) and bones (n = 5; 24%), followed by the liver (n = 2; 10%), brain (n = 1; 5%), and spinal canal (n = 1; 5%), with six patients (28%) having DMs at multiple sites. Overall, the frequency of LM according to the reference standard was 20%, of which 83% (15/18) were confirmed with FDG PET/CT. The sensitivity and specificity of FDG PET/CT in detecting LM were 83% (95% CI, 68-97%) and 96% (95% CI, 77-100%), respectively. CONCLUSION. Our study showed that whole-body FDG PET/CT can be used as a screening tool for the detection of DM and LM in sinonasal neoplasms and could be performed as part of the routine pretreatment evaluation of metastatic workup.

Application of diffusion-weighted MR imaging with ADC measurement for distinguishing between the histopathological types of sinonasal neoplasms.

PURPOSE: To evaluate the potential contribution of quantitative DWI parameters including ADCmean and ADCratio values to help in distinguishing the histopathological types of sinonasal neoplasms. METHODS: This retrospective study included 83 patients (50 males, 33 females; mean age 61 years) with pathologically proven untreated sinonasal neoplasms who have undergone diffusion-weighted MRI imaging from February 2010 to August 2017. Diffusion-weighted MRI was performed on a 3 T unit with b factors of 0 and 1000 s/mm2, and ADC maps were generated. Mean ADC values of sinonasal tumors and ADC ratios (ADCmean of the tumor to ADCmean of pterygoid muscles) were compared with the histopathological diagnosis by utilizing the Kruskal-Wallis non-parametric test. RESULTS: Mean ADCmean and ADCratio were 0.8 (SD, ±0.4) × (10-3 mm2/s) and 1.2 (SD, ±0.5), respectively, and each parameter was significantly different between histopathological types (p < 0.05). Mean ADCmean and ADCratio were higher in adenoid cystic carcinoma (ACC) than in SCC, lymphoma, neuroendocrine carcinoma and sinonasal undifferentiated carcinoma (SNUC) (p < 0.05). Optimized ADCmean thresholds of 0.79, 0.81, 0.74 and 0.78 (10-3 mm2/s) achieved maximal discriminatory accuracies of 100%, 79%, 100% and 89% for ACC/SNUC, ACC/SCC, ACC/neuroendocrine carcinoma, and ACC/lymphoma, respectively. CONCLUSIONS: The optimized ADCmean threshold of 0.80 (10-3 mm2/s) could be used to differentiate ACC from non-ACC sinonasal neoplasms with maximal discriminatory accuracy (82%) and sensitivity of 100%. However, there is considerable overlapping of the ADCmean and ADCratio values among non-ACC sinonasal neoplasms hence surgical biopsy is still needed.

Performance of whole-body 18F-FDG PET/CT as a posttreatment surveillance tool for sinonasal malignancies.

PURPOSE: To determine the diagnostic utility of posttreatment surveillance whole-body 18F-FDG PET/CT in detecting local tumor recurrence (R), regional lymph-node metastasis (LM), and distant metastasis (DM) in asymptomatic sinonasal cancer patients. METHODS: Eighty consecutive patients (53 men, 27 women; mean age, 60 years; range, 28-92 years) who had undergone 197 posttreatment whole-body 18F-FDG PET/CT examinations for sinonasal malignancies between January 2009 and August 2017 were retrospectively reviewed. 18F-FDG PET/CT findings were categorized as positive or negative for R, LM, and DM, separately. Outcomes of 18F-FDG PET/CT scans were compared with the final diagnosis confirmed by histological analysis or follow-up period for a minimum 12 months. The diagnostic accuracy of scans was calculated for each site using contingency tables. Impact on the management of 18F-FDG PET/CT examinations was additionally evaluated. RESULTS: 18F-FDG PET/CT scans identified 37/44 of local recurrences, 21/23 of LMs, and 30/37 of DMs. For local recurrence, sensitivity, specificity, positive predictive value, and negative predictive value were 84% (68-97%), 95% (80-100%), 84% (68-97%), and 95% (80-100%), respectively. For LM, the respective values were 91% (75-100%), 99% (83-100%), 91% (75-100%), and 99% (83-100%). For DM, the values were 81% (64-97%), 99% (85-100%), 97% (81-100%), and 96% (81-100%), respectively. 18F-FDG PET/CT accounted for a change in management of 85% patients with recurrences. CONCLUSIONS: Whole-body 18F-FDG PET/CT is a suitable surveillance tool for sinonasal malignancies in detecting locoregional and distant recurrences in asymptomatic patients without any evidence of recurrence on regular follow-up and endoscopy during the posttreatment period.

Utility of FDG PET/CT in the Characterization of Sinonasal Neoplasms: Analysis of Standardized Uptake Value Parameters.

OBJECTIVE: We aimed to evaluate the contribution of different standardized uptake value (SUV) parameters generated from pretreatment 18F-FDG PET/CT in the characterization of sinonasal neoplasms with histopathologic correlations. MATERIALS AND METHODS: This retrospective study included 97 consecutive patients (58 men, 39 women; age range, 20-93 years; mean age, 62 years) with pathologically proven untreated sinonasal neoplasms who underwent FDG PET/CT from February 2010 to August 2017. Semiquantitative analysis of primary tumors were performed to evaluate the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and the ratio of the SUVmax of the primary tumor to the SUVmean of mediastinal blood pool, which we refer to here as " SUVratio." Various sinonasal tumor histopathologic subgroups (n = 14) were analyzed. The Kruskal-Wallis test was used to compare the SUVmax, SUVmean, and SUVratio with the histopathologic diagnosis. RESULTS: Mean values of SUVmax, SUVmean, and SUVratio for the sinonasal neoplasms were 16.6 ± 9.7 (SD), 8.6 ± 5.1, and 5.9 ± 3.7, respectively, and each parameter was significantly different between histopathologic types (p < 0.05). Mean values of SUVmax, SUVmean, and SUVratio were higher in sinonasal undifferentiated carcinoma (SNUC) than in olfactory neuroblastoma, metastasis, and adenoid cystic carcinoma (p < 0.05). Mean values of SUVmax and SUVmean were higher in squamous cell carcinoma (SCC) than in olfactory neuroblastoma and metastasis (p < 0.05). Also, mean SUVmax was higher in SCC and SNUC than in poorly differentiated carcinoma (p < 0.05). Mean SUVratio was higher in SCC than in small cell carcinoma, olfactory neuroblastoma, and adenoid cystic carcinoma (p < 0.05). CONCLUSION: We conclude that different SUV parameters from FDG PET/CT can be used as so-called "metabolic biopsy" to categorize sinonasal neoplasms into different histopathologic subgroups because it can help in the characterization of some of the more common subgroups of sinonasal neoplasms. However, we found that there is overlap in FDG uptake values among some of the rare histologic subgroups; hence, surgical biopsy is still needed for differentiation of histologic subtypes of aggressive sinonasal masses.

Imaging features of sinonasal tumors on positron emission tomography and magnetic resonance imaging including diffusion weighted imaging: A pictorial review.

INTRODUCTION: Sinonasal inflammatory conditions account for a major component of head and neck pathologies, whereas neoplasms involving the sinonasal region make up only 2-3% of all head and neck lesions. The symptoms of sinonasal tumors are nonspecific; imaging plays a critical role in distinguishing benign and malignant disease and may illustrate characteristic radiological features of specific sinonasal tumors. OBJECTIVE: Aim was to determine the utilization of multimodality imaging, specifically the metabolic information provided by 18-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and diffusivity characteristics seen with diffusion weighted images (DWI) of magnetic resonance imaging (MRI), in a wide range of benign and malignant sinonasal tumors drawn from over 200 sinonasal lesions from our institution and supplemented by the literature. CONCLUSION: In this pictorial essay, we have reviewed common imaging characteristics of frequently encountered in sinonasal tumors and divided them into benign and malignant categories to facilitate creation of focused differential diagnoses.

N-methylnitrosourea­induced carcinoma as a model for laryngeal carcinogenesis.

BACKGROUND: Preclinical animal models to study laryngeal cancer are nonexistent. The purpose of this study was to describe a novel mice laryngeal cancer model. METHODS: A total of 18 six-week-old A/J mice were used. Animals underwent microdirect laryngoscopy, superficial larynx scratching, and instillation of N-methyl-N-nitrosourea (MNU) at 2 different concentrations (15 µL and 30 µL) or dimethyl sulfoxide (DMSO) to the control group directly to the larynx. Mice received a total of 5 instillations of MNU or DMSO at 1-week intervals. Mice were euthanized at 20 and 30 weeks after the last intervention and laryngeal histology was analyzed. RESULTS: Laryngeal instillation of MNU caused a 60% cancer conversion in the study group. CONCLUSION: Our findings demonstrate the feasibility of developing a murine laryngeal carcinogenesis model using direct topical instillation of MNU. This is the first murine model of laryngeal cancer and has great potential for evaluating new agents for chemoprevention and treatment for laryngeal carcinoma.

Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma.

OBJECTIVES: The incidence of high-risk human papillomavirus (HR-HPV) head and neck squamous cell carcinoma (HNSCC) continues to increase, particularly oropharyngeal squamous cell carcinoma (OPSCC) cases. The inactivation of the p53 tumor suppressor gene promotes a chain of molecular events, including cell cycle progression and apoptosis resistance. Reactivation of wild-type p53 function is an intriguing therapeutic strategy. The aim of this study was to investigate whether a novel compound derived from diterpene triepoxide (Minnelide™) can reactivate wild-type p53 function in HPV-positive HNSCC. MATERIALS AND METHODS: For all of our in vitro experiments, we used 2 HPV-positive HNSCC cell lines, University of Michigan squamous cell carcinoma (UM-SCC) 47 and 93-VU-147, and 2 HPV-positive human cervical cancer cell lines, SiHa and CaSki. Cells were treated with different concentrations of triptolide and analyzed for p53 activation. Mice bearing UM-SCC 47 subcutaneous xenografts and HPV-positive patient-derived tumor xenografts were treated with Minnelide and evaluated for tumor growth and p53 activation. RESULTS: In HPV-positive HNSCC, Minnelide reactivated p53 by suppressing E6 oncoprotein. Activation of apoptosis followed, both in vitro and in vivo. In 2 preclinical HNSCC animal models (a subcutaneous xenograft model and a patient-derived tumor xenograft model), Minnelide reactivated p53 function and significantly decreased tumor progression and tumor volume. CONCLUSION: Triptolide and Minnelide caused cell death in vitro and in vivo in HPV-positive HNSCC by reactivating wild-type p53 and thus inducing apoptosis. In addition, in 2 HPV-positive HNSCC animal models, Minnelide decreased tumor progression and induced apoptosis.

Oncologic and functional outcomes of partial laryngeal surgery for intermediate-stage laryngeal cancer.

OBJECTIVE: To evaluate the oncologic and functional outcomes of partial laryngeal surgery (PLS) using transoral laser microsurgery (TLM) and supracricoid laryngectomy (SCL) in patients with intermediate-stage laryngeal squamous cell carcinoma (LSCC). STUDY DESIGN: Historical cohort study. SETTING: Single tertiary care center. SUBJECTS AND METHODS: Retrospective review of oncologic and functional outcomes in intermediate-stage (T2-3/N0-1, stage II and III) LSCC patients who underwent TLM or SCL from 1998 to 2010. RESULTS: Sixty patients were included, of whom 28 (47%) underwent TLM and 32 (53%) underwent SCL. For the entire cohort, 2- and 5-year probabilities were 86.2% (95% confidence interval [CI], 73.0%-93.2%) and 72.9% (95% CI, 52.4%-85.6%), respectively, for overall survival (OS) and 79.3% (95% CI, 65.6%-88.0%) and 62.4% (95% CI, 41.9%-77.4%), respectively, for recurrence-free survival (RFS). There was no difference between the TLM and SCL cohorts in OS (P = .542) or RFS (P = .483). More than 75% of patients avoided adjuvant therapy. Communication Scale and Functional Outcome Swallowing Scale scores at median follow-up of 33 months were 2 or better in 97% and 91% of patients, respectively, reflecting functional voice and swallowing postoperatively. Eighty-eight percent of patients retained a functional larynx. CONCLUSION: PLS provides excellent oncologic and functional outcomes for intermediate-stage LSCC and should be considered an alternative to chemoradiation or total laryngectomy in selected patients.

Minimally invasive surgery for parapharyngeal space tumors.

OBJECTIVES/HYPOTHESIS: Parapharyngeal space (PS) tumors are surrounded by critical anatomical structures. Resection is often challenging due to limited surgical exposure. Herein, we report a novel transcervical, minimally invasive, video-assisted technique that facilitates the resection of PS lesions. STUDY DESIGN: Case series and review of literature. METHODS: Description of surgical technique with analysis of four cases and literature review. RESULTS: The technique combines a transcervical approach to the PS and skull base with video-assisted and image-guided dissection of tumor. Four cases of benign PS tumors resected with this technique are reported. The size of the tumor excised varied between 0.9 cm and 5 cm. Estimated blood losses were minimal. The average length of hospital stay was 1.5 days. No permanent complications were encountered. CONCLUSIONS: Excision of PS tumor abutting the skull base using a novel minimally invasive, video-assisted, image-guided, transcervical approach is feasible and safe. The short hospitalization stay and low morbidity makes it well suited for the resection of benign PS lesions.

Enforced expression of nuclear factor kappa B in p53 deficient keratinocytes induces cell cycle, angiogenic potential and tumorigenesis.

Multiple genetic mutations with subsequent molecular events are required for progression of normal epithelial cells to cancer, with p53 mutations being a very common event in squamous carcinogenesis. Upregulation of nuclear factor kappa B (NF-κB) is an associated feature of malignancy, however studies have not examined purposeful overexpression of the NF-κB p65 subunit in in vitro models of oral carcinogenesis. Our objective is to demonstrate that NF-κB p65 transfection into p53 deficient Rhek keratinocytes produces carcinogenic progression. We constitutively over-expressed NF-κB p65 in Rhek keratinocytes, previously immortalized by SV 40 thus inactivating p53, and studied NF-κB dependent events. NF-κB p65 overexpression provided functional upregulation of NF-κB and produced cyclin D1-mediated proliferation and interleukin 8 transcription and secretion. Consequently, we demonstrated tumorigenesis in athymic mice with NF-κB p65 overexpressing cells. We conclude NF-κB p65 overexpression in p53 inactivated immortalized keratinocytes produces tumorigenesis, and that this single alteration in NF-κB expression on a p53 inactivated background is sufficient for squamous carcinogenesis features, thus providing evidence that p65 may act as a gain of function oncogene in this setting.