Publications by authors named "Joseph C Sniezek"

21 Publications

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Effect of a second primary thyroid carcinoma on patients with head and neck squamous cell carcinoma.

Head Neck 2016 04 15;38 Suppl 1:E890-4. Epub 2015 Jul 15.

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii.

Background: The purpose of this study was to characterize the timing, histology, and behavior of second primary thyroid carcinoma (SPTC) developing after a diagnosis of head and neck squamous cell carcinoma (HNSCC).

Methods: We conducted a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) 9 database.

Results: Patients with HNSCC who develop SPTC die 1.6 times sooner than those without SPTC. This effect is only seen if SPTC presents >6 months after diagnosis of HNSCC. Models were adjusted for age, sex, year of diagnosis, and location of HNSCC. There was no effect of prior radiation therapy on either mortality rates or time to development of thyroid cancer in patients with SPTC. The type of thyroid carcinoma that developed was similar between cohorts.

Conclusion: The development of SPTC in patients with HNSCC results in decreased overall length of survival. © 2015 Wiley Periodicals, Inc. Head Neck 38: E890-E894, 2016.
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http://dx.doi.org/10.1002/hed.24121DOI Listing
April 2016

Endoscopic management of esophageal discontinuity.

Head Neck 2015 Sep 16;37(9):E103-5. Epub 2015 Jun 16.

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii.

Background: The management of esophageal discontinuity remains challenging and often involves complex reconstructive surgeries.

Methods And Results: We describe a unique and successful treatment of esophageal discontinuity using a modification of the natural orifice translumenal surgery (NOTES) approach in a patient presenting with long-standing esophageal discontinuity resulting from an iatrogenic esophageal injury.

Conclusion: This case provided an opportunity to affirm the efficacy of endoscopy for treating esophageal discontinuities to minimize the degree of morbidity and mortality normally associated with the surgical treatment of this type of injury. Our case reveals a novel and possibly more direct means of evaluating and treating esophageal injuries in which the degree of discontinuity and/or stenosis initially remains unknown.
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http://dx.doi.org/10.1002/hed.23883DOI Listing
September 2015

Otolaryngology and medical malpractice: A review of the past decade, 2001-2011.

Laryngoscope 2014 Apr 7;124(4):896-901. Epub 2013 Oct 7.

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii, U.S.A.

Objectives/hypothesis: To better understand the causes and outcomes of lawsuits involving otolaryngologists in the past decade by analyzing malpractice litigation trends to prevent future litigation and improve physician education.

Study Design: Analysis of a national database for all US civil trials.

Methods: The Westlaw database was reviewed from 2001 to 2011. Data were compiled on the demographics of the plaintiffs, use of expert witnesses, procedures, nature of the injury, legal allegations, verdicts, and indemnities.

Results: One hundred ninety-eight cases met inclusion criteria. Verdicts for the defendant/otolaryngologist predominated (58%), whereas the average award when the verdict favored the plaintiff was $1,782,514. When otolaryngologists were used as expert witnesses by the defense, the verdict outcome statistically favored the defendant. Two of the most commonly cited legal allegations were improper performance and failure to diagnose and treat. Fifty-one cases involved allegations of wrongful death, with the overall outcome favoring the plaintiffs (51%). The average indemnities in these cases were significantly higher for plaintiff verdicts at $2,552,580 versus settlements at $992,896. Forty-two cases involved malignancy, with the two most common allegations being failure to diagnose and treat (79%) and delay in diagnosis (74%).

Conclusions: Our study reveals that in the past decade, in significant malpractice litigations, overall outcomes favored otolaryngologists. The average awards was significantly higher when cases involved malignancy. Our analysis reveals the importance of meticulous surgical techniques and thorough preoperative evaluations. Last, when otolaryngologists are defendants in litigation, our review reiterates the value of the otolaryngologist as the defense's expert witnesses.
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http://dx.doi.org/10.1002/lary.24377DOI Listing
April 2014

Papillary Thyroid Carcinoma in a Branchial Cleft Cyst without a Thyroid Primary: Navigating a Diagnostic Dilemma.

Case Rep Otolaryngol 2013 11;2013:405342. Epub 2013 Jul 11.

Department of Otolaryngology-Head & Neck Surgery, Tripler Army Medical Center (TAMC), MCHK-DSH, 1 Jarrett White Road, honolulu, HI 96859, USA.

We report a rare case of papillary thyroid carcinoma incidentally found within a branchial cleft cyst. Only four other cases have been described in the literature. A total thyroidectomy and selective neck dissection was performed, and no evidence of occult primary disease was found after review of fine sections. Branchial cleft cysts are the most common lateral neck masses. Ectopic thyroid tissue within a branchial cleft cyst is an unusual phenomenon, and papillary thyroid carcinoma arising from this tissue is extremely rare. Clinicians are left with a diagnostic dilemma when presented with thyroid tissue neoplasm within a neck cyst in the absence of a thyroid primary-is this a case of metastatic disease with a missed primary or rather carcinoma arising in ectopic thyroid tissue? A thorough discussion of the etiologies of these lateral neck masses is reviewed including the embryogenesis of thyroid tissue in a branchial cleft cyst. The prognosis of patients with papillary thyroid carcinoma in lateral neck cysts without a primary site identified appears to be good following excision of the cyst and total thyroidectomy. Other management recommendations regarding these unique lateral neck malignancies are also presented.
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http://dx.doi.org/10.1155/2013/405342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728533PMC
August 2013

Microvascular reconstructive surgery in Operations Iraqi and Enduring Freedom: the US military experience performing free flaps in a combat zone.

J Trauma Acute Care Surg 2013 Aug;75(2 Suppl 2):S228-32

Tripler Army Medical Center, Honolulu, Hawaii 96859, USA.

Background: Local nationals with complex wounds resulting from traumatic combat injuries during Operations Iraqi Freedom and Enduring Freedom usually must undergo reconstructive surgery in the combat zone. While the use of microvascular free-tissue transfer (free flaps) for traumatic reconstruction is well documented in the literature, various complicating factors exist when these intricate surgical procedures are performed in a theater of war.

Methods: The microvascular experiences of six military surgeons deployed during a 30-month period between 2006 and 2011 in Iraq and Afghanistan were retrospectively reviewed.

Results: Twenty-nine patients presented with complex traumatic wounds. Thirty-one free flaps were performed for the 29 patients. Location of tissue defects included the lower extremity (15), face/neck (8), upper extremity (6). Limb salvage was successful in all but one patient. Six of eight patients with head and neck wounds were tolerating oral intake at the time of discharge. There were three flap losses in 3 patients; two patients who experienced flap loss underwent a successful second free or regional flap. Minor complications occurred in six patients.

Conclusion: Microvascular free tissue transfer for complex tissue defects in a combat zone is a critically important task and can improve quality of life for host-nation patients. Major US combat hospitals deployed to a war zone should include personnel who are trained and capable of performing these complex reconstructive procedures and who understand the many nuances of optimizing outcomes in this challenging environment.
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http://dx.doi.org/10.1097/TA.0b013e318299da23DOI Listing
August 2013

Salivary gland surgery and medical malpractice.

Otolaryngol Head Neck Surg 2013 Apr 4;148(4):589-94. Epub 2013 Feb 4.

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii 96859, USA.

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 $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.
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http://dx.doi.org/10.1177/0194599813475566DOI Listing
April 2013

Mantle cell lymphoma presenting as a saccular cyst.

Otolaryngol Head Neck Surg 2012 Jan 20;146(1):173-4. Epub 2011 Jun 20.

Department of Otolaryngology-Head & Neck Surgery, Tripler Army Medical Center, Hawaii, USA.

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http://dx.doi.org/10.1177/0194599811412927DOI Listing
January 2012

Head and neck ultrasound: why now?

Authors:
Joseph C Sniezek

Otolaryngol Clin North Am 2010 Dec;43(6):1143-7, v

Otolaryngology/Head & Neck Surgery, Tripler Army Medical Center, MCHK-DSH, Honolulu, HI 96859-5000, USA.

This article provides an overview of ultrasound and the techniques for its use by otolaryngologists in diagnosing and treating neck masses and lesions. Head and neck ultrasound is extremely useful in diagnosing neck masses and lesions and in facilitating many procedures that are commonly performed on the head and neck. Although in the past these studies were generally performed by radiologists, clinicians are now able to perform high-quality ultrasound studies and ultrasound-guided procedures in the head and neck. Given the advanced knowledge of head and neck anatomy and disease processes that otolaryngologists possess, head and neck ultrasound offers a logical and valuable extension of the physical examination. Recent improvements in ultrasound resolution, portability, and affordability have provided an excellent impetus for otolaryngologists to incorporate ultrasound into their office and operative practices.
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http://dx.doi.org/10.1016/j.otc.2010.08.001DOI Listing
December 2010

Preface: Head and neck ultrasound.

Otolaryngol Clin North Am 2010 Dec;43(6):ix-x

Otolaryngology/Head & Neck Surgery, Tripler Army Medical Center, MCHK-DSH, Honolulu, HI 96859-5000, USA.

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http://dx.doi.org/10.1016/j.otc.2010.09.001DOI Listing
December 2010

Oral carcinoma associated with betel nut chewing in the Pacific: an impending crisis?

Pac Health Dialog 2005 Mar;12(1):158-62

University of Arizona, Tuscon, Arizona, USA.

In Western populations, tobacco and alcohol use are the major etiologic factors associated with oral cavity cancers. In developing countries of Asia and the South Pacific, however, oral cancer is increasingly associated with the chewing of betel nut. As the population of Asia and the South Pacific immigrates, Head and Neck surgeons in North America are likely to see more patients with oral carcinoma induced by betel nut chewing. Tumor Registry records from 1977-2003 from a tertiary care, referral medical center were reviewed. All patient charts (27) demonstrating betel quid use of greater than 20 years and carcinoma of the upper aerodigestive tract were entered into the study. Five-year disease-free rates by stage were as follows: Stage 1: 100% (2/2); Stage 11: 50% (2/4); Stage III: 36% (4/9): Stage IV: 25% (3/12). Despite the prevalent misperception in the Pacific region that betel nut chewing is a harmless habit, betel nut-induced oral carcinomas are aggressive malignancies requiring aggressive treatment and long-term follow-up.
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March 2005

Utilization of free tissue transfer in head and neck surgery.

Otolaryngol Head Neck Surg 2007 Aug;137(2):182-91

Department of Otolaryngology--Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

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.
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http://dx.doi.org/10.1016/j.otohns.2007.04.011DOI Listing
August 2007

A Benign, Mature, Parapharyngeal Teratoma Presenting in an Adult.

Radiol Case Rep 2007 7;2(4):46. Epub 2015 Dec 7.

We present a case of an adult female who presented mildly symptomatic and with a history of having a mass removed from her neck as an infant. Radiographic imaging detected the presence of a heterogeneous, encapsulated mass in the parapharyngeal space that was surgically resected, and subsequently pathologically confirmed to be a benign, mature cystic teratoma.
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http://dx.doi.org/10.2484/rcr.v2i4.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896013PMC
June 2016

Osteoradionecrosis of the cervical spine resulting from radiotherapy for primary head and neck malignancies: operative and nonoperative management. Case report.

J Neurosurg Spine 2005 Aug;3(2):159-64

Department of Surgery, Neurosurgery Service, Tripler Army Medical Center Honolulu, Hawaii 96859-5000, USA.

Osteoradionecrosis is a process of dysvascular bone necrosis and fibrous replacement following exposure to high doses of radiation. The poorly vascularized necrotic tissue may cause pain and/or instability, and it cannot resist infection well, which may result in secondary osteomyelitis. When these processes affect the cervical spine, the resulting instability and neurological deficits can be devastating, and immediate reestablishment of spinal stability is paramount. Reconstruction of the cervical spine can be particularly challenging in this subgroup of patients in whom the spine is poorly vascularized after radical surgery, high-dose irradiation, and infection. The authors report three cases of cervical spine osteoradionecrosis following radiotherapy for primary head and neck malignancies. Two patients suffered secondary osteomyelitis, severe spinal deformity, and spinal cord compression. These patients underwent surgery in which a vascularized fibular graft and instrumentation were used to reconstruct the cervical spine; subsequently hyperbaric oxygen (HBO) therapy was instituted. Fusion occurred, spinal stability was restored, and neurological dysfunction resolved at the 2- and 4-year follow-up examinations, respectively. The third patient experienced pain and dysphagia but did not have osteomyelitis, spinal instability, or neurological deficits. He underwent HBO therapy alone, with improved symptoms and imaging findings. Hyperbaric oxygen is an essential part of treatment for osteoradionecrosis and may be sufficient by itself for uncomplicated cases, but surgery is required for patients with spinal instability, spinal cord compression, and/or infection. A vascularized fibular bone graft is a very helpful adjunct in these patients because it adds little morbidity and may increase the rate of spinal fusion.
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http://dx.doi.org/10.3171/spi.2005.3.2.0159DOI Listing
August 2005

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

Laryngoscope 2004 Dec;114(12):2063-72

Department of Otolaryngology-Head and Neck Surgery, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859-5000, USA.

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).

Study Design: Three experiments were performed. In experiment 1, p63 expression was analyzed by immunohistochemical analysis in 36 HNSCC specimens and matched normal tissue control specimens harvested from the same patient. Western blot analysis was also performed on matched specimens to confirm the identity of the p63 isoforms that were found. In experiment 2, reverse transcriptase polymerase chain reaction (RT-PCR) analysis was performed on matched normal and tumor specimens to analyze and quantitatively compare p63 isoform expression at the RNA level. In experiment 3, p63 expression was evaluated by immunohistochemical analysis in oral lichen planus, a benign mucosal lesion marked by hyperdifferentiation and apoptosis.

Methods: Immunohistochemical analysis, RT-PCR, and Western blot analysis of p63 were performed on HNSCC specimens and matched normal tissue control specimens. p63 expression in oral lichen planus specimens was also examined by immunohistochemical analysis.

Results: In experiment 1, analysis of 36 HNSCC specimens from various head and neck subsites showed p63 expression in all tumors and matched normal tissue specimens (36 of 36). Western blot analyses indicated that dominant negative (DeltaN) isoform p63alpha (DeltaNp63alpha) is the major isoform expressed at the protein level in tumors and adjacent normal tissue. In experiment 2, RT-PCR analyses of 10 matched specimens confirmed that, although all three DeltaNp63 isoforms (DeltaNp63alpha, DeltaNp63beta, and DeltaNp63gamma) are expressed in normal and malignant mucosa of the head and neck, DeltaNp63alpha is the predominant transcript expressed. In experiment 3, immunohistochemical analysis of p63 in the pro-apoptotic condition of lichen planus indicated that p63 is underexpressed as compared with normal mucosal specimens.

Conclusion: Although all three DeltaNp63 isoforms are present in HNSCC, DeltaNp63alpha protein is the predominant isoform expressed in these malignancies. DeltaNp63alpha is also overexpressed in tumors compared with matched normal tissue specimens and is underexpressed in the pro-apoptotic condition of lichen planus. These findings suggest that DeltaNp63alpha plays an anti-differentiation and anti-apoptotic role in the mucosal epithelium of the head and neck, possibly playing a pivotal role in the formation of HNSCC. Currently, DeltaNp63alpha is an attractive target for mechanistic study aimed at therapeutic intervention.
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http://dx.doi.org/10.1097/01.mlg.0000149437.35855.4bDOI Listing
December 2004

Use of the vacuum-assisted closure device in enhancing closure of a massive skull defect.

Laryngoscope 2004 Jun;114(6):961-4

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii, USA.

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

Study Design: Case report, literature review, and discussion.

Methods: A 50-year-old woman presented from a remote Pacific Island community with a 12 x 14-cm, necrotic, grossly contaminated eccrine gland carcinoma of the cranial vertex that extended through the calvarium but did not invade the dura. Following tumor extirpation, the resulting bony defect was 10 x 12 cm in size, with a concomitant scalp defect of 14 x 16 cm. Free tissue transfer was impossible because of severe intimal peripheral vascular disease, posing a challenging reconstructive dilemma. After tumor resection, the bony edges were covered with local scalp flaps and the vacuum-assisted closure device was placed over the wound at a constant setting of -50 mm Hg. The vacuum-assisted closure device was changed three times per week for 3 weeks.

Results: A thick, 1-cm bed of granulation tissue developed over the dura, allowing temporary coverage by a split-thickness skin graft, and the scalp defect decreased in size by approximately 25%. The patient did not develop meningitis, headache, or localized infection as a result of placement of the vacuum-assisted closure device and tolerated the vacuum-assisted closure well. After a requisite period of healing, tissue expanders and calvarial reconstruction will be performed.

Conclusion: Use of the vacuum-assisted closure device is a safe, reliable adjunct in the closure of large cranial defects with exposed dura and offers a novel reconstructive option for complex defects of the head and neck.
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http://dx.doi.org/10.1097/00005537-200406000-00001DOI Listing
June 2004

Rare tumors of the thyroid gland.

Otolaryngol Clin North Am 2003 Feb;36(1):107-15

Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859-5000, USA.

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.
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http://dx.doi.org/10.1016/s0030-6665(02)00134-2DOI Listing
February 2003

Inflammatory thyroid disorders.

Otolaryngol Clin North Am 2003 Feb;36(1):55-71

Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, Hawaii 96859-5000, USA.

Inflammatory thyroid disorders encompass a broad spectrum of diseases that are generally self-limited, and relatively easy to diagnose and manage. Autoimmune subtypes are by far the most commonly encountered diagnoses and create the most confusion because of simultaneous overlap and the potential for interconversion among the subtypes. The otolaryngologist will frequently see these disorders and provide valued consultative care and surgical intervention as needed.
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http://dx.doi.org/10.1016/s0030-6665(02)00133-0DOI Listing
February 2003

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

Laryngoscope 2003 Jun;113(6):936-9

Vanderbilt Bill Wilkerson Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

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.

Study Design: In vitro examination of p63 expression after ZD1839 treatment.

Methods: A human HNSCC cell line, SCC-012, was treated with varying doses of ZD1839. p63 protein and messenger RNA levels were analyzed by Western and Northern blot analyses. The effect of ZD1839 on SCC-012 cell cycle was analyzed by flow cytometric analysis.

Results: In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment. Levels of phosphorylated MAPK decreased and p27KIP-1 levels increased after ZD1839 treatment. ZD1839 treatment induced a twofold increase in G1-phase cells and a 3.5-fold decrease in S-phase cells consistent with growth arrest.

Conclusion: ZD1839 downregulates p63 expression at the messenger RNA level, suggesting that p63 is a downstream target of EGFR signaling.
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http://dx.doi.org/10.1097/00005537-200306000-00004DOI Listing
June 2003

The Delta Np63 alpha phosphoprotein binds the p21 and 14-3-3 sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations.

Mol Cell Biol 2003 Apr;23(7):2264-76

Department of Biochemistry, Center in Molecular Toxicology, The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

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 Delta Np63 alpha, and it was present as a phosphorylated protein. During HEK differentiation, Delta Np63 alpha and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3 sigma increased. Delta Np63 alpha had transcriptional repressor activity in vitro, and this activity was reduced in Delta Np63 alpha proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that Delta Np63 alpha and p53 can bind the p21 and 14-3-3 sigma promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that Delta Np63 alpha 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC150720PMC
http://dx.doi.org/10.1128/MCB.23.7.2264-2276.2003DOI Listing
April 2003

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

Otolaryngol Head Neck Surg 2002 Jun;126(6):598-601

Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN 96859-5000, USA.

Objective: Our goal was to analyze p63 and 14-3-3sigma expression in normal and hyperdifferentiated head and neck mucosa.

Study Design: Compare the in vivo expression of p63 and 14-3-3sigma by immunohistochemistry in normal mucosa and oral lichen planus, a benign mucosal lesion marked by hyperdifferentiation and apoptosis.

Results And Conclusion: p63 is underexpressed and 14-3-3sigma is overexpressed in lichen planus on immunohistochemical analysis.

Significance: The findings support the hypothesis that p63 plays an antidifferentiation role, whereas 14-3-3sigma plays a prodifferentiation role in the upper aerodigestive tract epithelium. Lichen planus is a valuable model for the study of p63, 14-3-3sigma, and mucosal differentiation. p63 and 14-3-3sigma may be molecular markers for oral lichen planus.
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http://dx.doi.org/10.1067/mhn.2002.125302DOI Listing
June 2002
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