Adam M. Zanation

Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression.

The prognostication of head and neck squamous cell carcinoma (HNSCC) is largely based upon the tumor size and location and the presence of lymph node metastases. Here we show that gene expression patterns from 60 HNSCC samples assayed on cDNA microarrays allowed categorization of these tumors into four distinct subtypes. These subtypes showed statistically significant differences in recurrence-free survival and included a subtype with a possible EGFR-pathway signature, a mesenchymal-enriched subtype, a normal epithelium-like subtype, and a subtype with high levels of antioxidant enzymes. Supervised analyses to predict lymph node metastasis status were approximately 80% accurate when tumor subsite and pathological node status were considered simultaneously. This work represents an important step toward the identification of clinically significant biomarkers for HNSCC.

Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-κB Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma

Gene expression signatures generated from DNA microarray analyses have shown promise as predictive biomarkers of clinical outcome. In this study, we determined a high-risk signature for disease recurrence using formalin-fixed head and neck squamous cell carcinoma (HNSCC) tumors and compared the results with an independent data set obtained from fresh frozen tumors. We also showed that genes involved in epithelial-to-mesenchymal transition (EMT) and nuclear factor-κB (NF-κB) signaling deregulation are the most prominent molecular characteristics of the high-risk tumors. Gene expression was determined in 40 samples, including 34 formalin-fixed tissues and 6 matched frozen tissues, from 29 HNSCC patients. A 75-gene list predictive of disease recurrence was determined by training on the formalin-fixed tumor data set and tested on data from the independent frozen tumor set from 60 HNSCC patients. The difference in recurrence-free survival (RFS) between the high-risk versus low-risk groups in the training and test sets was statistically significant ( P = 0.002 and 0.03, respectively, log-rank test). In addition, the gene expression data was interrogated using Gene Set Enrichment Analysis to determine biological significance. The most significant sets of genes enriched in the high-risk tumors were genes involving EMT, NF-κB activation, and cell adhesion. In conclusion, global gene expression analysis is feasible using formalin-fixed tissue. The 75-gene list can be used as a prognostic biomarker of recurrence, and our data suggest that the molecular determinants of EMT and NF-κB activation can be targeted as the novel therapy in the identified high-risk patients. (Cancer Res 2006; 66(16): 8210-8)

Nasoseptal flap reconstruction of high flow intraoperative cerebral spinal fluid leaks during endoscopic skull base surgery.

Background Over the past 10 years, significant anatomic, technical, and instrumentation advances have facilitated the exposure and resection of intradural lesions via a fully endoscopic expanded endonasal approach (EEA). The vascularized nasoseptal flap (based on the posterior nasoseptal artery) has become our primary endoscopic reconstructive technique. The goals of this study are to prospectively evaluate the nasoseptal flap and high-risk cerebral spinal fluid (CSF) leak variables. Methods Prospective evaluation was performed of EEA patients with intraoperative high-flow leaks (either a cistern or ventricle open to nasal cavity during tumor dissection) who underwent nasoseptal flap reconstruction. Results Seventy consecutive nasoseptal flaps for high-flow intraoperative leaks were evaluated prospectively by the primary author. Twelve risk factors were then graded at the time of the operations and correlated to CSF leak outcomes. The overall postoperative CSF leak rate was 5.7% (4/70). All four postoperative leaks were successfully managed with endoscopic repair and CSF diversion. A multivariate analysis of all 12 risk factors is detailed. Pediatric patients, large dural defects, and radiation therapy were noted to be factors in reconstructive failure. One flap death occurred in a patient with prior surgery and proton therapy, this leak was managed with a temporoparietal flap and endonasal repair. Conclusion The nasoseptal flap is an excellent anterior skull base reconstructive technique. Patients with high-flow intraoperative CSF leaks had a 94% successful reconstruction rate. Patients with skull base proton radiation therapy are at higher risk for flap failure and preparation for nonradiated tissue reconstruction should be discussed with the patient.

Endoscopic skull base surgery: principles of endonasal oncological surgery.

Endoscopic endonasal surgery can be applied to the management of benign and malignant sinonasal neoplasms with good results. For tumors that involve the skull base, an endoscopic “craniofacial resection” can be performed with en bloc excision of the involved dura. Preliminary experience with completely endoscopic excision of olfactory neuroblastomas indicates good local control and few complications. Advantages of endoscopic endonasal surgery include improved visualization and decreased morbidity compared to traditional approaches. J. Surg. Oncol. 2008;97:658–664.

Minimally invasive endoscopic pericranial flap: a new method for endonasal skull base reconstruction.

One of the major challenges of cranial base surgery is reconstruction of the dural defect. Following a craniofacial resection, the standard reconstructive technique is direct suture repair of the dural defect with a fascial graft and rotation of an anteriorly based pericranial scalp flap to cover the dura. The introduction of endoscopic techniques and an endonasal approach to the ventral skull base has created new challenges for reconstruction. The nasoseptal flap has become the workhorse for vascularized endoscopic skull base reconstruction; however at times, the septal mucosal flap may be unavailable for reconstruction. This can be due to prior surgical resection or involvement of the nasal septum by sinonasal cancer. We have developed a minimally invasive endoscopic pericranial flap for endoscopic skull base reconstruction. The use of a pericranial scalp flap for reconstruction during endonasal skull base surgery using minimally invasive techniques has not been previously reported.

Endoscopic endonasal surgery for petrous apex lesions

Endoscopic endonasal approaches to the ventral skull base are categorized based on their orientation in coronal and sagittal planes. For all of these approaches, the sphenoid sinus is the starting point, and provides orientation to important vascular and neural structures. Surgical approaches to the petrous apex include 1) a medial approach, 2) a medial approach with internal carotid artery (ICA) lateralization, and 3) a transpterygoid infrapetrous approach (inferior to the petrous internal carotid artery). The choice of a surgical approach depends on the relationship of the lesion to the internal carotid artery (medial or inferior), degree of medial expansion, and pathology. The purpose of this paper is to discuss the anatomic and technical features of endoscopic surgical approaches to the petrous apex, provide a new classification for approaches that focuses on the relationship of the lesion to the petrous internal carotid artery, and provide outcomes data on our first 20 endoscopic petrous apex approaches.

Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Endoscopic skull base reconstruction of large dural defects: A Systematic Review of Published Evidence

Systematically review the outcomes of endoscopic endonasal techniques to reconstruct large skull base defects (ESBR). Such surgical innovation is likely to be reported in case series, retrospective cohorts, or case‐control studies rather than higher level evidence.

Endoscopic pedicled nasoseptal flap reconstruction for pediatric skull base defects

A prospective study of endoscopic expanded endonasal approaches (EEA) with nasoseptal flap reconstructions revealed anecdotal evidence of less available relative septal length in pediatric patients. Our goal is to use radioanatomic analysis of computed tomography (CT) scans to determine limitations of the nasoseptal flap in pediatric skull base reconstruction and to describe clinical outcomes after using the nasoseptal flap in six pediatric patients.

CANCER CACHEXIA SYNDROME IN HEAD AND NECK CANCER PATIENTS: PART I. DIAGNOSIS, IMPACT ON QUALITY OF LIFE AND SURVIVAL, AND TREATMENT

Cancer cachexia is a debilitating, wasting condition that affects many cancer patients, including those with head and neck cancer. The overall incidence of cancer cachexia is quite high for some types of cancer, and cachexia will be the main cause of death for more than 20% of all cancer patients. This syndrome uniquely challenges patients with head and neck cancer. This article outlines the diagnosis of cancer cachexia, reviews its impact on patient quality of life (QOL) and survival, and updates the reader on potential therapies that may suppress it.