Satellite and In-Transit Metastatic Disease in Melanoma Skin Cancer: A Retrospective Review of Disease Presentation, Treatment, and Outcomes.

BACKGROUND: Satellitosis and in-transit metastases (SITM) are uncommon in cutaneous melanoma and are associated with poor prognosis. However, the disease- and treatment-specific variables that predict outcomes among patients with SITM are poorly defined. OBJECTIVE: To identify factors that predict prognosis among patients with SITM. MATERIALS AND METHODS: Retrospective chart review of patients treated for melanoma at a large academic medical center in central Pennsylvania between 2000 and 2012. Patients with pathology reports containing "satellite lesions" or "in-transit metastases" were selected for analysis. Data were collected regarding tumor stage, the timing of SITM discovery, treatment, recurrence-free survival after SITM discovery, and overall survival (OS). RESULTS: We identified SITM in 32 (1.9%) of 1,650 patients with pathology-diagnosed melanoma over the study period. Reduced recurrence-free survival after SITM discovery was associated with higher pathologic stage, metastatic disease, lymph node dissection, and use of adjuvant chemotherapy. Reduced OS was associated with higher T, N, M, and overall prognostic stage; positive surgical margins; disease recurrence; and SITM on initial presentation. CONCLUSION: Our data support previous findings that higher stage disease confers a worse prognosis among patients with SITM. Patients with SITM on initial presentation had worse outcomes, suggesting SITM is indicative of more aggressive disease.

Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia.

In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.

Current practices in venous thromboembolism prophylaxis in otolaryngology-head and neck surgery.

BACKGROUND: There has been recent investigation into the incidence of venous thromboembolism in otolaryngology, but the current utilization of venous thromboembolic (VTE) prophylaxis among practicing otolaryngologists remains largely unknown. METHODS: A survey of 26 questions was emailed to 4376 otolaryngologists. RESULTS: A total of 4376 surveys were sent and 676 were returned for a response rate of 15.4%. Intraoperative prophylaxis was used by 535 respondents (83%), either with intermittent pneumatic compression (91.8%), compression stockings (35.9%), or low-molecular-weight heparin (LMWH; 12.3%). Postoperative prophylaxis was used by 540 respondents (85.4%), either with early ambulation (87.8%), intermittent pneumatic compression (85.4%), compression stockings (43.3%), or LMWH (42.4%). The vast majority (88.3%) stated they would find thromboprophylaxis guidelines released by the American Academy of Otolaryngology - Head and Neck Surgery to be helpful. CONCLUSION: Current practices in venous thromboembolism prophylaxis vary widely among the otolaryngology community. A set of clear specialty-specific guidelines may be helpful. © 2015 Wiley Periodicals, Inc. Head Neck 38: E341-E345, 2016.

A retrospective analysis of the role of adjuvant radiotherapy in the treatment of cutaneous melanoma.

Melanoma is a significant clinical problem, with rising rates of incidence. Surgery is the mainstay of treatment. The role of adjuvant radiotherapy in the control of locoregionally advanced cutaneous melanoma is controversial. A retrospective study of the Surveillance, Epidemiology, and End Results (SEER) database was performed. Patients with locoregionally confined cutaneous melanoma treated surgically between 2004 and 2009 were evaluated, with cancer-specific and all-cause mortality as primary end points. Propensity score matching was used to match 319 radiotherapy patients with 319 non-radiotherapy controls, stratifying by head and neck (HN) and non-head and neck (NHN) primary. Surgery was primarily by wide excision in both the radiotherapy (51.72%) and non-radiotherapy (53.91%) groups. The majority had nodal disease (82.13% vs. 82.44%). White (91.22% vs. 90.59%) males (70.21% vs. 68.96%) predominated. Average ages at diagnosis were 62.27 (SD 15.93) and 63.02 (SD 16.03). Using Cox proportional hazards models, radiation conferred decreased survival in all-cause (HR 1.44, p < 0.0003), and cancer specific mortality (HR 1.57, p < 0.0002) in combined analysis. The NHN group showed significantly decreased 6-year cancer specific survival (HR 2.05, p < 0.0001) for radiated patients. The HN group showed a non-significant hazard with radiotherapy (HR 1.19, p = 0.307). Meaningful differences not captured in the SEER database may exist between cohorts. Based on available SEER data, routine use of adjuvant radiotherapy should be viewed with caution and reserved for high-risk patients. Future trials evaluating patient quality of life may clarify the benefit of adjuvant radiotherapy in high-risk melanoma populations.

HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells.

BACKGROUND: The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance. METHODS: Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. RESULTS: All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib. CONCLUSION: Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.

Incidence of venous thromboembolism in otolaryngology-head and neck surgery.

OBJECTIVE: To examine the incidence of venous thromboembolic disease in the otolaryngology-head and neck surgery (OTO-HNS) patient population. DESIGN, SETTING, AND PATIENTS: Review of medical records for all patients undergoing a surgical procedure during fiscal years 2008 to 2011 (July 1, 2008, through June 30, 2011) at an academic tertiary care medical center. INTERVENTION: A total of 59 884 total surgical procedures among all the surgical services. MAIN OUTCOME MEASURES: The incidence of deep venous thrombosis and pulmonary embolism. RESULTS: There were 5616 otolaryngology procedures performed during the study period. Clinically evident deep venous thrombosis developed in 3 patients; 2 of these patients also developed a pulmonary embolism. The overall incidence of deep venous thrombosis and pulmonary embolism in OTO-HNS was 0.05% and 0.035%, respectively. All patients who developed deep venous thrombosis or a pulmonary embolism in the OTO-HNS population were inpatients being treated for cancer. There were no deep venous thromboses or pulmonary emboli in patients undergoing same-day or overnight surgery or in patients without an active cancer. The OTO-HNS service had significantly lower rates of venous thromboembolism than did most other surgical specialties despite lower rates of adherence to venous thromboembolism prophylaxis guidelines. CONCLUSIONS: The incidence of deep venous thrombosis and pulmonary embolism among the OTO-HNS patient population at our academic center is lower than the incidence reported in previous studies (range, 0.1%-0.3%) and is significantly lower than the incidence observed in other surgical specialties. It is likely that patient- and specialty-specific factors as well as the more aggressive use of venous thromboembolism prophylaxis during recent years are at least partially responsible for the decreased incidence in our population.

Technical refinement of ultrasound-guided transoral resection of parapharyngeal/retropharyngeal thyroid carcinoma metastases.

BACKGROUND: The transoral approach to the parapharyngeal and retropharyngeal space (PPS/RPS) for the management of well-differentiated thyroid carcinoma (WDTC) has been previously described in other articles. However, limited exposure with this approach can be a challenge. METHODS: This is a retrospective review of 6 patients who underwent ultrasound-guided transoral excision of PPS/RPS WDTC metastases from October 2003 to March 2009 in a cancer center setting. Ultrasound-guided methylene blue dye injection of the node was used in 3 patients to facilitate intraoperative identification. The technique, safety, and feasibility of the procedure are described in this study. RESULTS: Successful resection of the metastases was accomplished in all cases without intraoperative complication. The 1 definite recurrence was further treated with transmandibular excision. CONCLUSION: Transoral excision of PPS/RPS WDTC metastases with ultrasound-guided methylene blue dye injection into the metastatic node is safe, feasible, and may further improve intraoperative identification of metastases in poorly accessible locations in the head and neck.

Nonsurgical management of oropharyngeal, laryngeal, and hypopharyngeal cancer: the Fox Chase Cancer Center experience.

BACKGROUND: Oropharyngeal, laryngeal, and hypopharyngeal cancer treatment has changed at our institution, but survival outcomes have not been evaluated. METHODS: We approached the evaluation by a retrospective single-institution cohort study. RESULTS: Review of 180 patient records from 1993 to 2004 revealed that the number of patients with oropharyngeal cancer treated nearly doubled, whereas the number of patients with laryngeal and hypopharyngeal cancers declined (p = .006). Since 2000, concurrent chemotherapeutic regimens rather than radiation alone became the dominant treatment approach, with associated improvements in recurrence-free and overall survival (p = .009 and p = .006, respectively). Stratification by tumor site, however, revealed the survival of patients with oropharyngeal cancer improved markedly, whereas the survival of patients with laryngeal cancer did not change. In the multivariate analysis, T classification (p = .0001) and chemotherapy use (p = .0001) were associated with improved survival. The recurrence-free survival of nonsmokers was better than that for former or current smokers (p = .01), but was accounted for by earlier T classification on presentation in the multivariate analysis (p = .0001). The predominant initial site of failure remained at the primary site for oropharyngeal cancer (14 of 17 relapses or 82%), but not laryngeal cancer (3 of 7 relapses or 42%). As a result, an increasing number of patients with recurrent oropharyngeal cancer, and a decreasing number of recurrent laryngeal cancer patients were evaluated for salvage surgery. Patients with oropharyngeal recurrences, however, were less likely to undergo surgery with curative intent (p = .02) and were less likely to achieve locoregional control after disease recurrence. CONCLUSIONS: The survival of patients with oropharyngeal and hypopharyngeal cancers treated at our institution has improved over the last 15 years, which is likely related to changes in treatment and tumor biology. The improvement was not observed in patients with laryngeal cancer. A subset of patients with oropharyngeal cancer remain subject to local failure and disease-related death.

Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model.

BACKGROUND: We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC). METHODS: The in vitro effects of vandetanib (ZACTIMA) were assessed in 2 HNSCC cell lines on cell growth, apoptosis, receptor and downstream signaling molecule expression, and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival. RESULTS: In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC. CONCLUSION: Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC.

Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis.

BACKGROUND: For patients with head and neck cancer who were treated using primary radiotherapeutic approaches, the pattern of pathologic residual carcinoma in the neck dissection specimen and its effect on clinical outcome remains unknown. METHODS: Medical records of 65 patients who underwent 71 neck dissections a median 7 weeks after radiotherapy were reviewed. Median follow-up was 33 months. RESULTS: Residual cancer, identified in 28 patients (43%), diminished locoregional control (p = .018), recurrence-free (p = .018), and overall survival (p = .02). Thirteen patients (20%) had 2 or more pathologically involved lymph nodes. Nine (13%) involved level V. Four (6%) had pathologic involvement of nodal levels not clinically involved by cancer before treatment. In N2-3 patients with positive pathologic specimens, the presence of these factors diminished recurrence-free survival (p = .01). The outcome of patients with pathologic carcinoma but without such ominous factors approached those with negative pathology. CONCLUSIONS: For patients with residual carcinoma in the neck following radiation, the pattern of residual disease is an effective predictor of recurrence.

Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl-2 expression and increased susceptibility to cisplatin-induced apoptosis.

BACKGROUND: The p53 protein, a well-known tumor suppressor that functions primarily as a transcription factor, initiates cell cycle arrest and apoptosis after genotoxic stress. The antiapoptotic regulator Bcl-2 is a downstream modulator of p53-induced apoptosis. Loss of function of the p53 tumor suppressor through mutation is an important event that contributes to cellular transformation. Mutation of p53 is one of the most common genetic alterations in squamous cell carcinomas of the head and neck (SCCHN). We hypothesized that p53 mutation is associated with Bcl-2 expression and susceptibility to apoptosis in SCCHN. METHODS: Exons 5 to 8 of the p53 gene were sequenced in 22 SCCHN tumor samples and correlated with the Bcl-2 expression and apoptosis rates in these tumors. In addition, a Bcl-2-expressing SCCHN cell line, UMSCC74B, was stably transfected with a temperature-sensitive mutant p53 construct, and Bcl-2 expression levels were examined at the mutant and the wild-type temperatures. RESULTS: Bcl-2 expression was inversely correlated with wild-type p53 status in SCCHN tumors (p = .05). Furthermore, there was a modest increase (1.7-fold) in apoptosis in the wild-type p53 tumors compared with mutant p53 SCCHN. Immunoblotting of UMSCC74B cells stably transfected with the temperature-sensitive mutant p53 construct demonstrated that shifting these cells to the mutant p53 temperature (39.5 degrees C) resulted in decreased expression of Bcl-2 compared with levels in cells grown at the wild-type p53 temperature (32.5 degrees C). Further investigation showed that SCCHN cells expressing predominantly mutant p53 and decreased Bcl-2 were more susceptible to cisplatin-induced apoptosis than vector-transfected controls (p < .0001). CONCLUSIONS: These results suggest that p53 mutation directly modulates Bcl-2 expression and therefore susceptibility to chemotherapy-induced apoptosis in SCCHN cells in vitro.

Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth.

The transcription factor signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers including squamous cell carcinoma of the head and neck (SCCHN). Previous investigations have demonstrated that activated Stat3 contributes to a loss of growth control and transformation. To investigate the therapeutic potential of blocking Stat3 in cancer cells, we developed a transcription factor decoy to selectively abrogate activated Stat3. The Stat3 decoy was composed of a 15-mer double-stranded oligonucleotide, which corresponded closely to the Stat3 response element within the c-fos promoter. The Stat3 decoy bound specifically to activated Stat3 and blocked binding of Stat3 to a radiolabeled Stat3 binding element. By contrast, a mutated version of the decoy that differed by only a single base pair did not bind the activated Stat3 protein. Treatment of head and neck cancer cells with the Stat3 decoy inhibited proliferation and Stat3-mediated gene expression, but did not decrease the proliferation of normal oral keratinocytes. Thus, disruption of activated Stat3 by using a transcription factor decoy approach may serve as a novel therapeutic strategy for cancers characterized by constitutive Stat3 activation.