Joseph C. Sniezek

The ΔNp63α phosphoprotein binds the p21 and 14-3-3σ promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations

ABSTRACT p63 is a recently identified homolog of p53 that is found in the basal layer of several stratified epithelial tissues such as the epidermis, oral mucosa, prostate, and urogenital tract. Studies with p63−/− mice and analysis of several human autosomal-dominant disorders with germ line p63 mutations suggest p63 involvement in maintaining epidermal stem cell populations. The p63 gene encodes six splice variants with reported transactivating or dominant-negative activities. The goals of the current study were to determine the splice variants that are expressed in primary human epidermal keratinocytes (HEKs) and the biochemical activity p63 has in these epithelial cell populations. We found that the predominant splice variant expressed in HEKs was ΔNp63α, and it was present as a phosphorylated protein. During HEK differentiation, ΔNp63α and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3σ increased. ΔNp63α had transcriptional repressor activity in vitro, and this activity was reduced in ΔNp63α proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that ΔNp63α and p53 can bind the p21 and 14-3-3σ promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that ΔNp63α acts as a transcriptional repressor at select growth regulatory gene promoters in HEKs, and this repression likely plays an important role in the proliferative capacity of basal keratinocytes.

Dominant negative p63 isoform expression in head and neck squamous cell carcinoma.

Objectives/Hypothesis: p63, a member of the p53 family of genes, is vital for normal epithelial development and may play a critical role in epithelial tumor formation. Although p63 has been identified in various head and neck malignancies, a detailed analysis of which of the six isoforms of the p63 gene is present in normal mucosa and head and neck malignancies has not yet been performed. The study analyzed p63 isoform expression on the RNA and protein level in normal, diseased, and malignant mucosa of the head and neck to examine the differential expression of p63 isoforms in head and neck tumors versus adjacent nonmalignant tissue and to identify the predominant p63 isoform expressed in head and neck squamous cell carcinoma (HNSCC).

Utilization of free tissue transfer in head and neck surgery

OBJECTIVE: Free tissue transfer is frequently incorporated into the reconstructive algorithm for a multitude of defects in the head and neck. With the increasing usage of free tissue transfer we undertook to review the most current advances in the field. DATA SOURCES: PubMed search of all pertinent articles as they related to oropharyngeal reconstruction, flap choice, new technologies and techniques, and outcomes. Articles were chosen based on reviewer selection. METHODS: The microvascular committee met and discussed the current important topics in free tissue transfer. A priority list was created and ranked. Topics were assigned to the authors who conducted a narrative review of the literature. RESULTS: Free tissue transfer has evolved to the point where a limited number of specific flaps are now utilized for most defects. Composite tissue is used to reconstruct composite defects. The coupling device and implantable Doppler are demonstrating a positive impact on flap survival and efficiency. Finally, outcomes in terms of quality of life, swallowing, and return to function have been shown to improve with the use of free tissue transfer. CONCLUSION: Free tissue transfer continues to be the reconstructive modality of choice for head and neck defects.

Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells.

Objectives/Hypothesis Both the epidermal growth factor receptor (EGFR) and the p53 homologue p63 are overexpressed in a significant number of cases of head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor and p63 both possess oncogenic properties, including the potential to increase cell proliferation and antagonize apoptosis. ZD1839 (“Iressa”) is an adenosine triphosphate–competitive inhibitor specific to the EGFR tyrosine kinase currently under evaluation as a chemotherapeutic agent in HNSCC. The objective was to investigate whether p63 expression is decreased after treatment of HNSCC cells with ZD1839. Downregulation of p63 by ZD1839 would identify a potential molecular relationship between EGFR signaling and p63 and could provide insight into the mechanism of action of ZD1839.

Diagnostic efficacy of surgeon-performed ultrasound-guided fine needle aspiration: A randomized controlled trial

Objective: To evaluate the clinical efficacy of surgeon-performed, office-based head and neck ultrasound in facilitating diagnostic fine needle aspiration (FNA) of lesions in the head and neck. Study Design: A randomized controlled trial of ultrasound-guided FNA versus traditional palpation-guided technique for palpable masses in the head and neck. Setting: An office-based study performed in a military academic medical center. Subjects and Methods: Eighty-one adults older than 18 years of age with a palpable head and neck mass (less than 3 cm in largest diameter) were randomized to ultrasound-guided or traditional palpation-guided FNA of a head and neck mass. Measured variables and outcomes for the study included tissue adequacy rates, tissue type, and operator variability. Results: Following three passes using either palpation or ultrasound guidance, a comparative tissue adequacy rate of 84 percent for ultrasound guidance versus 58 percent for standard palpation was established (P < 0.014). With regard to tissue type, a statistically significant comparative diagnostic advantage for ultrasound guidance was observed in thyroid tissue while remaining statistically insignificant for lymphatic and salivary tissues. No statistical significance was found when comparing the ability of otolaryngology residents versus attending otolaryngologists to obtain ultrasound-guided diagnostic samples. Conclusion: Office-based surgeon-performed ultrasound-guided FNA of palpable lesions in the head and neck yields a statistically significant higher diagnostic rate compared to standard palpation technique. Our institutional experience supports the utility of surgeon-performed ultrasound as a core competency in clinical practice.

Use of the Vacuum-Assisted Closure Device in Enhancing Closure of a Massive Skull Defect†

Objectives/Hypothesis: The objective was to describe a novel technique for reconstructing the cranial vertex without the use of free tissue transfer.

Salivary Gland Surgery and Medical Malpractice

Objective To better understand the causes and outcomes of lawsuits involving salivary gland surgery by analyzing malpractice litigation trends to prevent future litigation and improve physician education. Study Design Analysis of a national database. Setting All US civil trials. Subjects and Methods The WESTLAW database was reviewed from January 1987 to March 2011. Data were compiled on the demographics of the defendant, anatomic site of injury, initial pathology, nature of injury, legal allegations, verdicts, and indemnities. Results Twenty-six cases met inclusion criteria and were selected for review. Verdicts/settlements for the plaintiffs predominated (58%), and the average sum of the plaintiff’s monetary award was

Paraganglioma surgery : complications and treatment

933,235. Sixteen cases (62%) involved injury to the parotid gland/duct, with 10 cases involving injury to the facial nerve. No cases were filed on the grounds of failure to use facial nerve monitoring. Nine cases (35%) involved injury to the submandibular gland/duct. The most common legal allegations listed were improper performance followed by unnecessary procedures. If failure or inadequate consent was a component of the legal allegations, the verdict outcome significantly favored the defendants. Conclusion Our study reveals that the plaintiffs in litigations involving salivary gland surgery have a slight advantage in outcomes with a fairly substantial award. Our litigation review reiterates the importance of detailed anatomic knowledge of the lingual and facial nerve to avoid the pitfalls of surgical error and consequent litigation. In addition, thorough preoperative evaluation of salivary gland pathology, including radiographic studies and needle biopsy, may help avoid errors in diagnosis and subsequent litigations.

Rare tumors of the thyroid gland

Paragangliomas are vasculature in nature and are surrounded by vital neurovascular structures. The extirpation of these lesions requires careful preoperative evaluation, meticulous surgical technique, and the aid of experienced skull base surgical and rehabilitative teams. When surgery is performed in this way, complications can be minimized, and the function of the upper aerodigestive tract can be protected.

Expression of p63 and 14-3-3σ in normal and hyperdifferentiated mucosa of the upper aerodigestive tract

Although the vast majority of thyroid cancers are well-differentiated and carry an excellent prognosis, several rare tumors occasionally involve the thyroid gland and require unique treatment paradigms. Anaplastic carcinoma of the thyroid is an extremely aggressive neoplasm that is generally best managed with surgery followed by a multimodality regimen of radiotherapy and chemotherapy. Squamous cell carcinoma of the thyroid often mimics the clinical course of anaplastic carcinoma and is best treated with aggressive surgery followed by postoperative radiotherapy. Treatment and prognosis of lymphoma of the thyroid varies depending upon the specific pathological subtype, with combination chemotherapy and radiation therapy used primarily. Sarcomas of the thyroid are primarily managed with surgery, although radiation and chemotherapy are indicated in some cases.