PROGRESS REPORT FROM THE CHAIR

Three years ago,Stanford awarded Otolaryngology –Head & NeckSurgery status asan independentdepartment andprovided it a generous pack-age of resourcesdesigned toenable a periodof rapid expan-sion. The explicit

mandate received from Dean Philip Pizzowas to create world class clinical andtranslational research programs.

FACULTY GROWTH

Over the last few years we have rapidlygrown from 6 to 16 faculty members (onthe way to at least 21). These include 6new division chiefs: Dr. Peter Koltai (Pedi-atric OHNS), Dr Michael Kaplan (Head &Neck Oncology), Dr. Peter Hwang (Rhinol-ogy and Sinus Surgery), Dr. Samuel Most(Facial Plastic Surgery), Dr. Edward Dam-rose (Laryngology), Dr. Gerald Popelka(Audiology & Hearing Devices). Dr. Niko-las Blevins joined me in the Otology & Neurotology division and leads theStanford Cochlear Implant Program.

World renowned inner ear stem cell biol-ogist Stefan Heller, PhD has joined us tolead our Research Division along withAnthony Ricci, PhD (hair cell biophysi-cist), Sunil Puria, PhD (mechanical engi-neer - middle ear mechanics), and YulingYan, PhD (electrical engineer – laryngealimage analysis).

EDUCATIONAL PROGRAMS

Our extraordinarily talented group ofresidents has expanded from 15 in 2003(3 in each of 5 years) to 19 in 2006 as wegradually expand our training programs

in proportion to our growing faculty. Weare proud that our residents obtain asplendid experience in the broad spec-trum of contemporary OHNS proceduresand have done very well in obtainingpost-residency fellowship positions in anumber of subspecialties.

We now offer seven post-residency fel-lowship programs – more than any otherOHNS training program. These include:facial plastic surgery, head & neck sur-gery, pediatric OHNS, neurotology & skullbase surgery, sinus surgery, sleep sur-gery, and laryngology (added in 2006).These programs not only provide advanc-ed training for promising young acade-micians, but as junior faculty membersthe fellows also enhance the residencyeducational experience.

NEW FACILITIES

The Department is undergoing anextraordinary improvement in its physi-cal plant with all aspects of the educa-tional, research, and administrative programs transitioning to newly con-structed facilities. We are privileged to beone of the few OHNS departments tohave our own home building on a uni-versity campus – occupied after a $4 mil-lion renovation in late 2004. This pro-vides core facilities for our academic,administrative, and educational pro-grams and includes state-of-the-artlibrary-conference facilities (The WillardE. Fee Jr., M.D. Library) and a superb 10station educational microdissection lab-oratory (The Rodney Perkins, M.D. Micro-surgical Laboratory). The building alsohouses some of our adult clinical pro-grams (facial plastic surgery, laryngology,rhinology-sinus surgery, otology-neuro-tology, the cochlear implant center, andthe audiology & hearing device program).Our Head & Neck Oncology programs arehoused in the magnificent new StanfordCancer Center, in which OHNS has 3 fac-ulty offices, a suite of exam rooms, and aconference facility for Head & Neck TumorBoard. New clinical facilities for PediatricOtolaryngology and Pediatric Audiologyopened in October, 2004 (Mary L. John-son Pediatric Ambulatory Care Center)close to the main OHNS facility.

The old outmoded OHNS facility will begutted and rebuilt as a state-of-the-art7000 sq ft research laboratory. This proj-ect, with a budget approaching $5 mil-lion, will be completed in 2007. It hasbeen designed to include both core facil-ities and a flexible layout, facilitatingease of adaptation as future researchinterests evolve.

S t a n f o r d U n i v e r s i t y M e d i c a l C e n t e rD e p a r t m e n t o f

O T O L A R Y N G O L O G Y –H E A D & N E C K S U R G E R Y

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(continued on page 2)

Robert K. Jackler, MD,Sewall Professor & Chair

STANFORD OHNS:TRANSLATIONAL RESEARCHPROGRAMSRegenerative Medicine• Developing stem cell therapy to

overcome deafness• Elucidating the role of of stem cells

in head & neck cancer• Regenerating ciliated mucosa in the

nose and paranasal sinuses• Tissue engineering

Bioengineering• Integration of the human ear and

voice with digital devices• Biophysical properties of hair cells• Surgical simulation using 3D -

haptic enhanced simulators• Robotic microsurgery• High speed laryngeal imaging• Virtual laryngoscopy• Mechanics of sound transmission

through the tympano-ossicular chain• Mathematical modeling of cochlear

function• Microendoscopy of the inner ear

RESEARCH EMPHASIS

The research division of Stanford OHNSis in the midst of rapid expansion. Stan-ford has made a substantial investmentin new laboratory space, endowment,and additional basic science faculty posi-tions. The intention is to create a highlyproductive, innovative, and collaborativecenter which takes full advantage of thesurrounding Stanford bioscience andengineering communities. The priority ofour laboratory programs is to producehigh quality, innovative research in areasof inquiry relevant to human disease.Growth in our research programs willemphasize two central themes: Regener-ative Medicine and Bioengineering.

Stanford OHNS has come a long way in ashort 3 years since emerging as an inde-pendent department: more than dou-bling the size of the faculty with recruit-ment of a number of highly talentedindividuals; abandoning antiquated facil-ities for new ones triple their size; sizableexpansion of both residency and fellow-ship programs; and development ofdynamic, cutting edge research pro-grams. It is a credit to a large team ofhard working individuals that we havemade much progress in such a relativelyshort period. We look forward to sharingour progress with you in the comingyears. We plan to keep things hoppingon “The Farm.”

BUILDING WORLD CLASS PROGRAMS

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S TA N F O R D U N I V E R S I T Y M E D I C A L C E N T E R D E PA R T M E N T O F O T O L A R Y N G O L O G Y – H E A D & N E C K S U R G E R Y

NIKOLAS H. BLEVINS, MDAssistant ProfessorOtology & Neurotology

College: Stanford University Medical School: HarvardUniversity.Residency: University ofCalifornia at San FranciscoFellowship: Neurotology/SkullBase Surgery – University ofCalifornia at San FranciscoFormer Faculty Position: TuftsUniversity (1995-2003)Clinical Interests: Otology,neurotology, skull base surgery,cochlear implantsResearch Interests: Surgicalsimulation and robotics,microendoscopy of the inner ear

KAY W. CHANG, MDAssistant Professor Pediatric OHNS

College: Brown UniversityMedical School: Brown UniversityResidency: University ofWashington Fellowship: PediatricOtolaryngology at the Children’sHospital of PittsburghClinical Interests: Pediatricotology, Ear reconstructionResearch Interests: Pediatrichearing loss, cis-platinumototoxicity

EDWARD J. DAMROSE, MDAssistant ProfessorChief of Laryngology Division

College: Yale University Medical School: UCLA School ofMedicineResidency: University ofCalifornia at Los AngelesFellowship: Laryngology/Bronchoesophagology –University of California at LosAngelesClinical Interests: Voice andswallowing disordersResearch Interests: High speedlaryngeal imaging, spasmodicdysphonia, rehabilitation of vocalcord palsy

WILLARD E. FEE, JR., MDEdward C. and Amy H. SewallProfessorHead & Neck Surgery

College: University of SanFranciscoMedical School: University ofColorado Residency: University ofCalifornia, Los Angeles Clinical Interests: Tumors of thehead and neckResearch Interests: Clinicaloutcomes in head & neck cancer

RICHARD L. GOODE, MDProfessor Sleep Surgery & Facial PlasticSurgeryChief VA Service

College: University of California atSanta Barbara, CaliforniaMedical School: University ofSouthern CaliforniaResidency: Stanford University Fellowship: NIH Fellow –Vestibular PhysiologyClinical Interests: Facial plasticsurgery, sleep surgeryResearch Interests: Mechanics ofmiddle ear function, innovationsin sleep surgery

STEFAN HELLER, PHD Associate Professor Head of Research

M.S. Biology: JohannesGutenberg University, Mainz,GermanyPhD Genetics: JohannesGutenberg University, Mainz,Germany and Max-Planck-Institute forBrain Research, Frankfurt/M.,GermanyPost-Doctoral Training: TheRockefeller University, New YorkFormer Faculty Position: HarvardUniversity (2000-2005)Research Interests: Hair cellregeneration to overcomedeafness, structure and functionof mechanosensitive ion channelproteins.

PETER H. HWANG , MDAssociate Professor Chief of Rhinology

College: Stanford UniversityMedical School: University ofCalifornia at San Francisco Residency: University ofCalifornia at San Francisco Fellowship: Rhinology and SinusDisorders, Hospital of theUniversity of Pennsylvania Former Faculty Position: OregonHealth & Science University(1997-2005)Clinical Interests: Endoscopicsinus surgery, endoscopic tumorand skull base surgeryResearch Interests: Mucosal woundhealing, novel drug deliverytechnologies, clinical outcomes

ROBERT K. JACKLER, MDSewall Professor and Chair Otology & Neurotology

College: Brandeis UniversityMedical School: Boston UniversityResidency: University ofCalifornia at San Francisco Fellowship: Neurotology, HouseEar Clinic, Los Angeles, CAFormer Faculty Position: UCSF(1986 - 2003)Clinical Interests: Neurotologyand skull base surgeryResearch Interests: Innovation inskull base surgery, cholesteatomapathogenesis, history of otology

INTRODUCINGOUR FACULTY ( Fa l l 2006)

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MICHAEL J. KAPLAN, MDProfessor Chief of Head & Neck Surgery

College: Harvard CollegeMedical School: Harvard MedicalSchoolResidency: Massachusetts Eyeand Ear InfirmaryFellowship: University of Virginia(Head & Neck Surgery)Former Faculty Position: UCSF(1984 - 2003)Clinical Interests: Tumors of thehead and neckResearch Interests: Clinicaloutcomes for head and neckmalignancy, advanced imaging,head & neck cancer stem cells

PETER J. KOLTAI, MD ProfessorChief of Pediatric OHNS College: Queens College Medical School: The AlbanyMedical CollegeResidency: University of TexasMedical BranchFellowship: PediatricOtolaryngology/Hospital for SickChildren at Great Ormond StreetFormer Faculty Position: AlbanyMed. (1982-1998), ClevelandClinic (1998-2004)Clinical Interests: Pediatric airwayobstruction, sleep apneaResearch Interests: Developingnew techniques in managingsleep apnea

ANNA H. MESSNER, MDAssociate Professor Pediatric OHNSVice Chair

College: Duke UniversityMedical School: Wake ForestUniversityResidency: Wake ForestUniversityFellowship: Pediatric OHNS,Hospital for Sick Children,Toronto, CanadaClinical Interests: Pediatric OHNSResearch Interests: Neonatalhearing screening, ankyloglossia

SAM MOST, MDAssociate Professor Chief of Facial Plastic Surgery

College: University of MichiganMedical School: StanfordResidency: University ofWashingtonFellowship: Facial Plastic Surgery(U Washington)Former Faculty Position:University of Washington (2002 -2006),Clinical Interests: Aestheticsurgery of the faceResearch Interests: Minimallyinvasive improvement of theaging face, facial nerve biology

SUNIL PURIA, PHDConsulting Associate ProfessorResearch

College: The City College of NYMS: Columbia UniversityPhD: City University of NYPostdoctoral Fellowships: MIT,HarvardFormer Faculty Position: Harvard(1995-1997)Research Interests: Biomechanics,physiology, and imaging of themiddle ear and the cochlea.

GERALD R. POPELKA, PHD Consulting Professor Research Chief of Audiology

College: Kent State UniversityMA: Audiology/Kent StateUniversityPhD: Communication Sciences/University of WisconsinPostdoctoral Fellowship:University of California at LosAngelesFormer Faculty Position:Washington University (1980 -2004)Clinical Interests: Advancedhearing devices, advancedmeasures of auditory function Research Interests: Thedeveloping auditory system,hyperbilirubinemia

ANTHONY RICCI, PHD Associate Professor Research

College: Case Western ReserveUniversityPhD: Neuroscience/TulaneUniversityPost-doctoral Fellowships: UTMB,University of WisconsinFormer Faculty Position:Louisiana State University (1999 -2006)Research Interests: Hair cellbiophysics

YULING YAN, PHD Consulting Assistant ProfessorResearch

PhD: Mechanical Engineering/Keio University, Yokohama, Japan Post-Doctoral Fellowship: McGillUniversityFormer Faculty Position:University of Hawaii, U WisconsinResearch Interests: High speedlaryngeal imaging

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S TA N F O R D U N I V E R S I T Y D E PA R T M E N T O F O T O L A R Y N G O L O G Y – H E A D & N E C K S U R G E R Y

JOHN B. SHINN, MDClinical Professor Santa Clara Valley Medical Center

College: University of NorthCarolinaMedical School: University ofNorth Carolina, Chapel HillResidency: StanfordClinical Interests: Otology &Neurotology

M. LAUREN LALAKEA, MDClinical Associate Professor Santa Clara Valley Medical Center

College: HarvardMedical School: Boston UniversityResidency: StanfordClinical Interests: Pediatric OHNS,laryngologyResearch Interests: Ankyloglossia

KIMBERLY G. SHEPARD, MDClinical Assistant Professor Santa Clara Valley Medical Center

College: UC San DiegoMedical School: DartmouthResidency: StanfordClinical Interests: Head & NeckOncology; Sleep apneaResearch Interests: Non-surgicaltreatment of tonsillar hypertrophy,Medical management of post-operative pain

CARRIE ROLLER, MDClinical Assistant Professor Santa Clara Valley Medical Center

College: UC BerkeleyMedical School: GeorgetownUniversityResidency: BaylorClinical Interests: Head & neckcancer, traumaResearch Interests: Functionaloutcomes after Head & NeckSurgery

STANFORD FACULTY AT SANTA CLARAVALLEY MEDICAL CENTER (Fall 2006)

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CURING HEARING LOSS AND UNLOCKING THE SECRETS OF HOW THE EAR WORKS

Stefan Heller, PhD

All hearing sensation is derived from theelectrical output of a remarkably smallnumber of sensory cells: fewer that15,000 per inner ear at birth. These haircells are the mechanoelectrical transduc-ers of the inner ear: deflections of thesterociliary bundles on their apical sur-faces lead to transmitter release fromtheir basolateral poles, leading, in turn, tosignal generation in the peripheral axonsof the auditory nerve fibers.

Most types of congenital and acquiredhearing loss arise from damage to, orloss of, these sensory cells or their associ-ated neurons. The incidence of heritabledeafness is high: one child in a thousandis born deaf; another one in a thousandbecomes deaf before adulthood. Theprevalence of acquired hearing loss is ris-ing, as the population ages, and as noisepollution steadily increases. It is estimat-ed that one in three adults over the ageof 65 has a handicapping hearing loss,and this impairment is largely due to theirreversible loss of sensory cells.

Underlying the irreversibility of hearingloss in mammals is the incapacity toreplace lost hair cells by cell division orby regeneration from endogenous cells

in the inner ear epithelia. Hair cellreplacement, either by stimulation ofregeneration (as occurs naturally in non-mammalian vertebrates) or by transplan-tation of progenitor cells capable of dif-ferentiating into hair cells, remainstherefore the ultimate goal in the devel-opment of treatment applications toreconstruct the damaged inner ear.

Our recent work has focused on creatinginner ear cell types, in particular hair cellsand auditory neurons, from a renewablesource.

We have shown that embryonic stem(ES) cells and adult inner ear stem cells

can serve as such asource, and we arecurrently exploringsignaling pathwaysthat control hair celland neuronal (re-)generation in vitroand in vivo.

Our research doesnot only focus ongenerating inner ear replacementparts. We are alsoexploring novelmethods to deliversuch replacementparts into the dam-aged cochlea orwhether it is possibleto use drugs to coaxcells of the adultdamaged cochleainto a prenatal status,which could result

in self-repair of the damaged mammal-ian cochlea.

In an independent line of research, weare pursuing the structural basis of haircell mechanoreception. Although theindividual molecular components of themechanoelectrical transduction appara-tus are not known, we and other labora-tories have identified a number ofpotential candidates. Our goal is to solvethe atomic structure of the differentcomponents of the transduction machin-ery to study the molecular hinges and

mechanisms thatmechanically gate theelusive ion channelthat is central to oursenses of hearing andbalance.

THE THERAPEUTIC RELEVANCE OF HAIR CELL BIOPHYSICS

Anthony Ricci, PhD

Hair cells are the sensory cells of theinner ear. They are responsible for con-verting mechanical signals into one rec-ognized by the brain. Hair cells get theirname from having a tuft of hair-like ciliaat their apical surface. Deflection of thesestereocilia opens mechanically-gated ionchannels that convert the mechanicalsignal into an electrical signal. Thisprocess, termed mechanotransduction iscritical to both hearing and balance. Per-turbations of this system are associatedwith both temporary and permanenthearing loss, with age-related and noise-induced hearing loss and may even beassociated with tinnitus and vertigo.Understanding the mechanisms involvedin regulating mechanotransduction mayelucidate new and novel sites for inter-vention. Characterizing these pathwaysmight also lead to new technologicalbreakthroughs in hearing aid andcochlear implant development as well asin the design of novel noise preventiondevices. Over the past several years mylaboratory has identified several impor-tant attributes of mechanotransduction.First, we have discovered a new process,called fast adaptation that is critical forestablishing frequency discrimination, orthe ability of the ear to separate soundinto its individual frequency compo-nents. Second, we demonstrated for thefirst time, biochemical regulation ofmechanotransduction. This pathway mayprovide a new site for pharmacologicalintervention in preventing noise-inducedhearing loss. Third, we have recentlydemonstrated the importance ofmechanotransduction in controlling theelectrical properties of hair cells. Asmechanotransduction is very sensitive toits ionic environment, particularly theconcentration of calcium, the impor-tance of maintaining low levels of calci-um bathing the hair bundle has becomemore apparent. Characterizing the regu-lation of extracellular calcium may pro-vide a new pathway for intervention andmay shed light on pathologies related toloss of ionic homeostasis within the ear.And finally we are involved in identifyinga mechanism associated with mechan-otransduction and the hair bundle that

RESEARCH PROGRAMS

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The image shows integration and differentiation of inner ear progenitor cells de-rived from mouse embryonic stem cells after injection into the chicken’s develop-ing inner ear (otic vesicle). In (A), some of the injected cells, which are expressingthe ß-Gal marker gene are found to integrate into the epithelium of the oticvesicle (arrow). Shown in (B) and (C) are embryonic stem cell-derived cells found3 days after injection (in green). These cells start expressing markers of hair cells,such as myosin VIIA (red) and appear to have integrated well into the chickenauditory epithelium where they are surrounded by endogenous chicken hair cells(non green cells, labeled red). (D) and (E) show that the mouse cells, here visual-ized with a blue ß-Gal staining with developed hair bundles that are immuno-positive for the hair bundle marker protein espin.

may act to amplify low levels of soundand be a major contributor to determin-ing how the ear can be sensitive to suchlow energy sound waves.

Aside from converting a mechanical sig-nal into an electrical signal, the hair cellmust communicate with the brainthrough synaptic transmission. The haircell-afferent nerve synapse is very sensi-tive to overstimulation where the nerveending can swell and retract leading tohair cell loss. My laboratory has beeninvestigating the functional properties ofthis synapse to identify the propertiesthat make it unique in its ability to oper-ate with such high fidelity and at suchhigh rates. Here too, the goal is to identi-fy pathways and mechanisms that mightoffer sites for intervention and modifica-tion.

And finally, my laboratory is trying todetermine whether hair cells requireextrinsic factors, like innervation,mechanical stimulation or growth factorsto mature into their final form. This is acritical question to answer in order tojudge feasibility of therapies where haircell regeneration from supporting cellsor hair cell development from stem cellsis being investigated as a new therapy toreplace hair cells in damaged cochlea

Isolated outer hair cell with sensory hair bundle (left).Upper right is patch electrode on hair cell body tomeasure electrical responses elicited by mechanicallystimulating the sensory hair bundle (lower right).

INNER EAR FLUORESCENCEMICROENDOSCOPY

Nikolas Blevins, MD, Mark Schnitzer, PhD,Eunice Cheung, PhD

We are developing a method to visualizefunctional hair cells and other cellularelements of the inner ear within theintact mammalian cochlea using fluores-cence microendoscopy. Our laboratoryhas begun work on this minimally inva-sive in vivo imaging technique to pro-vide high-resolution images of deep tis-sues previously inaccessible in livesubjects. Using microendoscopes assmall as 0.3 mm in diameter, we havesuccessfully imaged individual red bloodcells flowing within capillaries inside themammalian cochlea. We are extendingthis work by labeling functional neuralelements with fluorescent dyes to con-currently reveal mechanotransduction aswell as microanatomy.

Current work includes microendoscopyusing a styryl dye (FM-143) in the guineapig. It is anticipated that this will allow us

to accurately map hair cell injury follow-ing ototoxin exposure, and to observethe recovery of hair cells from temporarythreshold shift noise damage. The use of microendoscopes should provide anopportunity to observe specific hair cellpopulations over time – information previously unavailable through conven-tional techniques.

An imaging technology to observe func-tional hair cells and dendrites within live

mammalian subjects will provide consid-erable benefit, and enable progress in abroad range of previously intractablehearing science questions. The success ofinner ear microendoscopy will provide abasis on which inner ear surgery can be established. The inner ear is one of thelast areas of the human body to remainlargely inaccessible to direct examina-

tion and surgical intervention. This isbecause of the combination of its smallsize and its extraordinary fragility tomechanical manipulation. The develop-ment of non-destructive imaging tech-niques will enable diagnostic and thera-peutic manipulations, including theoptimal placement of cochlear implantarrays, or the specific delivery of stemcells or growth factors to enable hearingrestoration.

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MIcroendoscope

View of live cochlear hair cells from a microendoscope

THE POSSIBLE ROLE OF STEMCELLS IN HEAD & NECK CANCER

Michael Kaplan, MD, Michael Clarke, MD,Laurie Ailles, PHD Willard Fee, MD, RanjivSivanidan, MD, Mark Prince, MD

Head and neck cancer affects 50,000Americans annually and remains a dev-astating world-wide killer. In India, forexample, it is the leading cause of cancerdeaths. Cisplatin-based concomitantchemotherapy and selected monoclonalantibodies have improved locoregionalcontrols compared to irradiation alone,but there has been little to no impact onsurvival because of distant metastasisand the therapy-resistant recurrences.Why has there been so little progress? Isit because we have not adequatelyenough appreciated the underlyingtumor biology so as to develop moreeffective therapeutic approaches?

It has been understood for quite sometime that leukemias and lymphomasarise within hematopoietic stem cells, yetit has been only recently that a cancerstem cell (CSC) hypothesis has beenextended to solid epithelial cells, includ-ing head and neck squamous cell carci-nomas (HNSCC).

Normal stem cells maintain an organ’sstem cell pool by self-renewing, whilegenerating large numbers of maturedaughter differentiated cells that in theirlife cells in time undergo apoptosis (pro-grammed cell death). Squamous epitheli-um is comprised of a basal layer of cellsthat contain some stem cells and overly-ing layers that contain daughter cellsthat die as they approach the surface.When stem cells divide they asymmetri-cally give rise to both a committeddaughter cell as well as another stemcell. This stem cell must avoid pro-grammed cell death (apoptosis)throughout the organism’s lifetime.Under normal circumstances it also mustrecognize its neighbors in order to know

when to divide and when not to; in otherwords cell-cell signaling pathways arelikely important. Stem cells (or theirimmediate daughters) also must be ableto migrate, both upward in the epitheli-um and in response to trauma. Thesethree properties – avoiding apoptosis,critical cell-cell signaling, and migration –are also key attributes of developmental(embryonic, fetal) stem cells. An impor-tant insight is that avoiding apoptosisand migration are also key characteris-tics of cancer cells; and aberrant cell-cellsignaling pathways are beginning to beshown as well.

A cancer stem cell hypothesis suggeststhat cancer is a result of inadequatelycontrolled proliferation of the stem cellsthemselves, and not the heterogeneousmix of daughter cells. Such aberrantgrowth would lead to subpopulationsthat contain a small percentage ofdaughter stem cells but many morecommitted differentiated cells that willundergo apoptosis in time. In otherwords, one should expect to see func-tional heterogeneity, with only a smallfraction of cells harboring tumorigenicpotential. This had been known in hema-tological malignancies for 40 years, butwas shown in solid tumors (medulloblas-toma, breast cancer) only in the pastthree years.

Working along similar lines using meth-ods employed to identify cancer stemcells in breast cancer, collaborating labo-ratories at the University of Michiganand at Stanford showed in 2006 (inpress) that this is also true for HNSCC.

HNSCC contains a distinct population ofcancer stem cells with the exclusive abili-ty to produce tumors in mice and recre-ate the original tumor heterogeneity.They are clonogenic in vitro (Fig 1) andinitiate tumors in vivo (Fig 2), while the

remaining cells in the tumor do notshare these properties. This population isdistinguished by a cell surface marker(CD44) that distinguishes these cellsfrom the other epithelial cells within thetumor that lack clonogenicity.

The identification of cancer stem cells inHNSCC has important ramifications. Mostbasically, it lends further support to thegeneral concept that a CSC model is truefor all cancers. Second, it suggests onepossible reason why chemotherapy hasbeen disappointing is that the assayused clinically (and in some clonogenicassays) is overall tumor response, where-as it is not overall but rather stem cellresponse that is key. Third, it suggeststhat characterizing selected key molecu-lar pathways that are involved in self-renewal, such as cell-cell signaling path-ways, should provide insights intospecifically what is abnormally regulated.Insights such as these hold promise forthe development of new treatmentstrategies targeted not against themajority of tumor cells (which have limit-ed tumorigenicity) but against the criti-cal population of cancer stem cells that isthe key culprit.

A fourth striking implication of validatinga CSC model is that one cannot help butsee the striking similarities between nor-

mal embryonic development and normalstem cells and their dysregulation that iscancer. This suggests that understandingnormal development should lead toinsight into cancer, and vice versa. Thecellular genetic control mechanismsseen in normal development, stem cellregulation, and cancer are likely to bethe same.

In the past decade an entirely new layerof intranuclear genetic control has beenidentified-small RNAs regulate geneexpression by suppressing homologousor near-homologous DNA sequences.

RESEARCH PROGRAMS

S TA N F O R D U N I V E R S I T Y D E PA R T M E N T O F O T O L A R Y N G O L O G Y – H E A D & N E C K S U R G E R Y

H&E and immunoperodixase staining of CD44 in passaged cells growing as explant

Only CD44+ cells serially maintain clonogenicity.

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These microRNAs (miRNA) are normal,and derive from pre-miRNA genes withinus, and the RNA-protein machinery allorganisms use for this is being increas-ingly identified. MiRNA gene chips areavailable, and abnormal quantities ofselected miRNAs have begun to be iden-tified in a few malignancies. That miRNAsare stable in paraffin will allow investiga-tion of archived material as well as easierinvestigation of fresh tumor-bankedmaterial.

The recognition of cancer stem cells insolid tumors, including head and neckcarcinomas, and the advances in DNAcontrol by miRNAs suggest reasons foroptimism that fundamental insights willlead to genetic therapies targeting can-cer stem cells in the future. Our lab, aswell as others, will investigate whetherCD44 (a complex molecule, with multiplesplice variants, that is involved in celladhesion and mobility) is simply a mark-er for CSCs, or whether it plays an essen-tial function. More specific markers arelikely to be found, which in aggregatewill better identify the stem cell pool. Asidentification of stem cells becomesmore precise, investigation of abnormalmiRNAs will be a goal. As abnormalitiesin cell-cell signaling pathways becomebetter understood, it will be of interest tolook at differences between tumors andpre-malignant conditions such as dyspla-sia and inverted papilloma, as well as thedifferences in pathways associated withmotility between primary tumors andboth nodal and distant metastases.

In summary, the initial validation of can-cer stem cells in head and neck carcino-mas offers myriad opportunities both tounderstand the fundamental nature ofcancer and to develop stem cell targetsfor genetic in the future.

HIGH SPEED LARYNGEAL IMAGING & THE VIRTUAL LARYNGOSCOPE

Yuling Yan, PhD & Edward Damrose MD

The primary objective of our researchprogram is to understand the mecha-nism of phonation for normal and forpathological voice conditions. Weemploy an interdisciplinary approach tothese studies that borrows and inte-grates concepts and methodologiesfrom bioengineering, biophysics, mathe-matical modeling and physiology.

Functional Analysis and Modeling ofPhonation in Normal and Diseased States

Vibration of the vocal folds is an essentialyet poorly understood event in humanvoice production. An important aspect ofour research program is to characterizethe dynamic behavior of the vocal foldsduring phonation – the ultimate goal forthese studies is to understand the mech-

anism of phonation in terms of the gen-eration and interaction of sound wavesin the vocal system; these studies willlead to the development of quantitativebiomechanical models of vocal folddynamics and acoustic interactions inthe vocal tract for the detection, diagno-sis and assessment of treatments for spe-cific voice disorders.

Quantitative analysis of vocal folddynamics using High Speed DigitalImaging (HSDI)

HSDI with simultaneously acquired acous-tic recordings are being used to charac-terize vocal fold dynamics. We havedeveloped new methods and softwareplatforms to generate comprehensive,functional analysis of vocal fold vibra-tions from HSDI and acoustic recordings.

For example, our analytical platform thatintegrates automatic image segmenta-tion of the vocal folds and detection ofvocal fold edge (Figure 1) with the gen-eration of glottal waveforms that includethe glottal area waveform, glottal widthfunction and displacements of the left-right vocal fold edges at specific anteri-or-medial-posterior locations. Theapproach also integrates our ‘Nyquist’plot based waveform analysis (Yan et al.,2005. J. Voice), which provides not onlyan at-a-glance assessment of the vibrato-

ry properties ofthe vocal fold (Fig-ure 1, bottom right)but a comprehen-sive and quantita-tive, high-resolu-tion description ofthe vibratoryproperties of thevocal fold fordiagnosing specif-ic voice disordersand assessment oftherapies. A relat-ed analysis hasbeen describedfor acoustic sig-nals (Yan et al,2006. J. Voice).These studies areadvancing to-wards a betterunderstanding ofvoicing and arecurrently under

clinical evaluation for the differentialdiagnosis of voice disorders associatedwith neurological disease and the agingprocess. A near-term research goal is todevelop a large, comprehensive andcomparative database of dynamic char-acteristics of vocal folds derived from ourimage and acoustic-based analyses thatwill be used to correlate changes in the

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Figure 1 – (Top) A montage of 10 image frames from an HSKI recording of a normalsubject while producing a sustained vowel phonation; (Bottom) Spatially resolvedvocal fold vibration representing diplophonic voice, and Nyquist pattern showing the bifurcation (transition from a normophonic [red] to a diplophonic phase [black]).

vibratory properties of the vocal foldwith specific voice condition and pathol-ogies. The database can be used for on-line clinical diagnoses and for trainingvoice researchers, clinicians and medicalstudents.

Virtual Laryngoscopy

Endoscopy is a routine, minimally inva-sive imaging technique for evaluatingthe three-dimensional (3D) features andproperties of the inner surface of the larynx. We are extending principles andmethods from Virtual Endoscopy (VE), todevelop a virtual laryngoscope (VL) fornon-invasive exploration of the laryngealsystem for specific applications in medi-cine, medical education and surgery. TheVL uses software to assemble data fromdiverse imaging techniques (e.g., CT andMRI) to reconstruct the internal anatomyin 3D. Computer rendering provides acontinuous luminal view, within whichone can navigate along inner surfaces,just as in conventional laryngoscopy(Figure 2). In addition, the VL can displaya perspective global view in 3D and aview of the related CT and MRI slices forinformative and interactive examinationfor diagnosis and treatment of disease.The VL offers several benefits over opti-cal endoscopes that include both inter-nal unconventional views and externalanatomical views of the airway and thesub-glottal cavity in patients with infec-tion, inflammation and neoplasia of thelumen. VL maybe especially useful forpatients with stenosis, congenital defectsor those unfit for general anesthesia. Weare exploiting the advantages of the VLfor applications in surgical examinationsof sub-glottal cavity and diagnoses oflaryngeal and airway diseases.

Figure 2 – Conventional endoscopic view (left) andthe virtual endoscopic view (right) of the vocal folds ina patient with laryngeal tumor.

RHINOLOGY RESEARCH AT THESTANFORD SINUS CENTER

Peter H. Hwang, MD

We are evaluating the role of retinoicacid in mucosal wound healing and cilio-genesis. The process of mucosal woundhealing in the nose and paranasal sinus-es is complex yet poorly understood.Retinoids have been shown to be impor-tant co-factors in regulating the differen-tiation and proliferation of ciliatedepithelial cells of the respiratory tract.Using a rabbit model of sinus surgery, weare studying reciliation patterns ofregenerated sinus mucosa after surgicaldemucosalization of the maxillary sinus.When evaluated by scanning electronmicroscopy, rabbits receiving topicalretinoic acid showed greater density anduniformity of regenerated cilia comparedto controls. We are also evaluating func-tional aspects of regenerated mucosathrough studies of ciliary beat frequencyand mucociliary transport times. In addi-tion, we are pursuing quantitative analy-sis of marker proteins associated with cil-iogenesis in this model of mucosalwound healing.

5000x scanning elec-tron micrographs showa) normal rabbit maxil-lary sinus mucosa

b) regenerated mucosawithout topical retinoicacid

c) regenerated mucosawith topical retinoicacid. Retinoic acid-treated sinuses showedimproved ciliary mor-phology, density, andorientation comparedto controls.

We are also actively engaged in a varietyof clinical research topics. Among theseinclude longitudinal outcomes of endo-scopic sinus surgery for chronic rhinosi-nusitis; novel drug delivery technologies;efficacy of sublingual immunotherapyfor seasonal allergic rhinitis; and histo-logic correlates of symptomatic improve-ment after endoscopic sinus surgery.

AUDITORY FUNCTION IN THEDEVELOPING HUMAN NEONATE

Gerald Popelka, PhD, David Stevenson, MD

The overall research effort centers onincreasing our understanding of auditoryfunction in the developing humanneonate. This effort is driven by the criti-cal role audition plays in the normaldevelopment of language and speechand the need to optimize all interven-tions for pre-lingual hearing loss includ-ing hearing aids and cochlear implants.

Human auditory development differssignificantly from that of most otherorganisms necessitating innovativeexperiments be carried out directly onnewborns in well baby, special care andintensive care nurseries. Measurementsystems must be non-invasive, integrat-ed, very small and insensitive to themany forms of ambient acoustic andelectrical noise found in these environ-ments, yet remain precise and repeat-able. Under a series of carefully con-trolled experiments we recently showedthat the auditory system undergoes sys-tematic and repeatable neural matura-tion during the first two days after birth,both across subjects and in individualneonates.

This effect clearly is associated with neural development at the level of thebrainstem because the experimentalapproach allowed control of matura-tional effects associated with other audi-tory structures such as the external ear,the middle ear and the cochlea, non-auditory developmental factors such asbirth weight, gestational age, and gener-al health of the neonate, and a variety ofexogenous variables such as exposure tomaternal anesthetic at delivery. This earlyauditory neural maturation may be asso-ciated with apoptosis (programmed celldeath) or dendritic pruning. Currentresearch involves understanding therelationship between auditory functionand exposure to bilirubin, a moleculethat results from the normal catabolism

RESEARCH PROGRAMS

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of maternal senescent red blood cellsand a potential detriment to normalauditory development. Significant biliru-bin exposure is experienced by 60% ofwell babies and much higher percent-ages in the remaining neonates. Thismolecule is known to permanently affectauditory function at extremely highexposures. However, its chronic or acuteeffects at lower exposures are largelyunknown.

Our experimental approach is to meas-ure auditory function simultaneouslywith precise measures of bilirubin expo-sure at several points in time during thefirst few days after birth. A correlation ofthese two measures, after compensatingfor normal neural development, willestablish the relation between auditoryneural function and bilirubin exposure.Several related projects support theseexperiments. We are developing a life-sized neonatal hearing simulator thatcontains computers, electronics andtransducers that can be programmed tosimulate normal and impaired neonatalcochlear and auditory neural responses.This device will help us to understandthe measurement process by determin-ing the effects of known sources ofacoustic and electrical noise and byinvestigating interactions among thevarious measures. We also are develop-ing and incorporating measures of biliru-bin production derived from measures ofcarbon monoxide concentration in thebreath and measures of bilirubin accu-mulation derived from transcutaneousoptical techniques.

Future efforts will involve the develop-ment of improved non-invasive meas-ures of bilirubin production and accumu-lation and improved auditory neuralmeasures. Potentially useful clinical pro-cedures resulting from this researchinclude improvements in neonatal hear-ing screening achieved from simulator-based training of nursery personnel,expansion of neonatal breath analysis toinclude other hemolytic conditions,improvements in non-invasive measuresof bilirubin concentration, and the use ofnon-invasive auditory neural measuresfor early detection of impending toxicbilirubin exposure to improve interven-tion for hyperbilirubinemia

OTOBIOMECHANICS GROUP

Sunil Puria PhD, Charles Steele PhD,Richard L. Goode, MD

The OtoBiomechanics Group at Stanfordis developing three-dimensional andmultiscale bio-computational models ofthe middle ear and the inner ear andtheir applications to understanding dis-ease processes and interventions.

Middle Ear Mechanics – Our goal is tounderstand the relationship betweenanatomical structures and physiologicalresponses of the human middle ear. Wecombine dynamical measurements ofthe middle ear with advances in medicalimaging of anatomical structures, andthree-dimensional bio-computationalmodeling tailored to the anatomy andphysiology of individual ears. Thisapproach allows us to asses quantitative-ly the effect of the middle ear anatomyon sound transmission in the forwardand reverse directions, from high-resolu-tion microCT imaging based morphome-try, tailored to the individual anatomy.Such an approach allows quantificationof precise causes of conductive hearingloss due to damage, based on imagingdata and computational biomechanics. Italso allows the possibility to predict theoutcome of a particular surgical plan torepair the damage, or reconstruct it witha passive or active prosthetic.

Inner-ear Mechanics – Our plan is tobuild a three-dimensional and multiscalecomputational model of the humanorgan of Corti with associated vestibularcanals and ducts on a mm scale, the hair cell soma on a um scale and hair celltip links on a nm scale. This will be thefirst biomechanical model valid for bothair and bone conducted sound, a vitaldistinction, because of its application toa broader scope of hearing health issues

than with previous models. The computa-tional framework will allow modificationof structural parameters and provide thepower to analyze resulting functions in afast and efficient manner on a desktopcomputer. The bio-computational frame-work will be used to systematically under-stand a variety of inner ear pathologies.

We also plan to integrate the cochlearmodel with the human middle earmodel. Such a unified model can be usedto better understand the generation anddetection of otoacoustic emissions andhow pathology of the organ of Corti canaffect their clinical measurements in theear canal. With our model, the mechani-cal etiology of inner ear disease andpotential strategies for its repair can beexplored systematically. An importantfuture technology is the regeneration ofcochlear sub structures through theintroduction and differentiation of stemcells. The yet unknown mechanical con-sequences of these regeneration effortson hearing also can be explored in theproposed biomechanical framework.

The research being performed by theOtoBiomechanics Group at Stanford andfunded in part by the NIDCD of NIH, aretherefore the core foundation for multi-ple projects that are expected to funda-mentally alter our understanding of mid-dle and inner ear function, pathologyand intervention.

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THE EVALUATION, MANAGE-MENT, AND PREVENTION OF CISPLATIN OTOTOXICITY INPEDIATRIC PATIENTS.Kay Chang, MD

Cisplatin is a commonly administeredchemotherapeutic agent in multiplepediatric neoplasms. The ototoxicity ofthis agent is well-documented, thoughpoorly characterized. Reports of ototoxic-ity rates in children vary from 1% to 82%.This disparity is due to extreme variabili-ty between institutions in the audiologicassessment of sick pediatric patients, aswell as the lack of a well established andclinically validated classification fordegrees of ototoxicity. The Common Ter-minology Criteria for Adverse Events(CTCAE v3.0) widely used by oncologists,fails to classify ototoxicity in a clinicallyconsistent, or relevant manner.

Due to a lack of a robust grading systemfor ototoxicity, it is difficult to design oto-toxicity studies in patients that can beeasily compared to other studies. I havedeveloped a more clinically useful grad-ing system for pediatric ototoxicity andhave validated it to a large 5-year cohortof children treated by the Lucile PackardChildren’s Hospital (LPCH) at StanfordPediatric Oncology department. By exam-ining details such as dose delivery sched-ule and co-administered drugs, a numberof interesting revelations regarding opti-mal methods of reducing ototoxicity inchildren have been discovered, and willbe presented at the next ASCO meeting.

As an active member of the Children’sOncology Group (COG), a national organ-ization involved in improving the onco-logic care of children, I have been inti-mately involved in the ototoxicityassessment of multiple large multi-insti-tutional studies administered by COG

(including the Intergroup Hepatoblas-toma Study P9645 and the ARAR0331Nasopharyngeal Carcinoma Study). Thisgrading system has been a valuable tooland has helped to improve methodolo-gies for accurately assessing and charac-terizing ototoxic effects. This is particu-larly important since children seem to bemuch more susceptible to ototoxicitythan adults. Furthermore, while the effectsof ototoxicity may be quite limited inadults who have mastered speech andlanguage, in pre-lingual young children,ototoxicity may result in severe speechdelay and the inability to ever assume anormal role in society. So while the chil-dren may be cured of their cancer, theyreally never fully recover from their treat-ment to live normal unhindered lives.

While accurately monitoring cisplatinototoxicity may provide some insightsinto improved dosing strategies forreducing adverse effects in children, amore exciting approach is actual preven-tion of ototoxicity by administering vari-ous “otoprotective” agents. In the courseof investigating the protective effect ofthe anti-oxidant N-acetylcysteine in theguinea pig cochlea, my laboratory dis-covered a novel otoprotective effectinduced by the transtympanic adminis-tration of lactate to the middle ear. Inthis experiment, guinea pigs treated withcisplatin that were administered eitherlactated Ringer’s solution or N-acetylcys-teine had significantly improved cochlearfunction, as measured by DPOAE, com-pared to the normal saline and negativecontrol groups (see figure). Currently,with the collaboration the LPCH PediatricOncology department, standardized pro-tocols utilizing my grading scale arebeing developed to investigate these aswell as other otoprotective agents, in-cluding EPO and several gene therapy

agents. Our goal is with theseefforts is to eliminate this mostdevastating late-effect of chemo-therapy in young children.

Mean post-treatment DPOAE data. Stimulusparameters were L2 = 55 dB and F2 rangingfrom 2 to 16 kHz. Error bars represent oneSEM, and are plotted for the Control and LRgroups; however they were comparableacross all 4 groups (average SEM across fre-quencies measured 2.88, 3.27, 2.93, and 2.78for the 4 groups). The light dotted line at thebottom of the graph represents the averagenoise floor during emission recording.

CLINICAL RESEARCH IN SLEEPSURGERYRichard L. Goode, MD, Jose E. Barrera, MD,Nelson Powell, MD, Robert Riley, MD

The Division of sleep surgery aims todevelop improved diagnostic methodsin evaluating site of obstruction in sleepapnea patients. We are taking twoapproaches to improve our understand-ing of the anatomic reasons for collapseof the upper airway in obstructive sleepapnea. A protocol which is being coordi-nated with Dr. Gerald Popelka will utilizecine real-time MRI scanning of the upperairway in patients with sleep disorderedbreathing and normal volunteers, andcorrelate these findings with the endo-scopic evaluation of patients before andafter surgery. Electroencephalogram,actigraphy, and pulse oximetry data incombination with MRI images will becollected from patients with upper air-way resistance syndrome, obstructivesleep apnea, and normal controls. We ex-pect to be able to significantly improveour understanding of the anatomic rea-sons for a given patient’s obstructivesymptoms, and thus improve clinicalstaging and surgical decision-making.

Our second project aims to evaluatefunctional obstruction during sleep as ameasure of pressure manometry. The useof a multi-site pressure probe tube thatis worn during sleep will be utilized todetermine the site of obstruction basedon pressure changes across five trans-ducers within the probe tube preciselylocated in the upper airway. We hope tocharacterize what causes multi-siteobstruction and to what degree patientswith with obstructive sleep apnea areaffected.

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EVIDENCE-BASED MEDICINE INFACIAL PLASTIC SURGERY

Sam P. Most, MD

The primary goal of this research pro-gram is to develop a higher standard ofcare for facial plastic surgery patients.The approach to this goal is two-fold. Thefirst involves development of prospec-tive studies that examine the efficacy ofnew or existing surgical techniques infacial plastic surgery. One clinical prob-lem we have already begun to examineis nasal obstruction. Functional rhino-plasty techniques have been a mainstayof otolaryngology, and facial plastic sur-gery in particular, for decades. Whilemany have attempted, with mixed suc-cess, to examine nasal function usingquantitative measures, few prospectivestudies of quality of life have been per-formed. To this end, we have begun toexamine prospectively various functionalrhinoplasty techniques.

The second approach to development ofa higher standard of care for our patientsis the testing of various over-the-counter‘cosmeceutical’ products. Generally, pro-ducts that are touted as effective by in-dustry have little or no clinical evidenceto back up said claims. Two of thesestudies have been completed and haveresulted in remarkable response fromindustry as well as the media. Moreimportantly, these types of studies pro-vide valuable information about productefficacy to physicians and patients alike.

Facial Nerve Recovery after Injury –Facial nerve injury after trauma or extir-pative surgery can be devastating topatients. The Division seeks to develop aclinical and basic research programstudying facial nerve recovery after suchinjuries. The basic research programwithin the Division will use a previouslydeveloped animal (mouse) model forfacial nerve injury to examine the age-dependence of motor neuron survival inthe facial nucleus and its correlation tofacial nerve recovery. Furthermore, therole of apoptotic cell death in the facialnerve nucleus will be studied, with thehope that anti-apoptotic processes mayaid in facial nerve recovery. The clinicalresearch program will study quality oflife issues in facial nerve injury patients.

Anterior septal reconstruction, a modified extracorpo-real septoplasty technique.

A) Murine facial nerve nucleus (outlined with arrow-heads); B) Facial motor neurons stained with anti-bcl2antibody (arrows).

CLINICAL RESEARCH IN LARYNGOLOGY

Edward Damrose, MD and Yuling Yan, PHD

The Division of Laryngology is currentlyperforming research in several fields.Since the arrival of Dr. Yuling Yan, PhD,we have begun investigations into vocalfold vibration using high-speed digitalimaging. High-speed digital imaging cancapture motion at a rate of more than2000 frames per second, allowing theresolution of a single vibration of thevocal folds. Because pathological voicingrepresents the generation of an aperiod-ic signal, traditional laryngostroboscopyhas been somewhat limited in allowingextensive analysis of the factors thatcause abnormal voicing. Coupled withalgorithms developed by Dr. Yan, high-speed imaging techniques can resolvethe vibratory properties of an individualvocal cord through individual cycles,affording us insight into the mechanismof voice production that has never beenpossible before (Figure 1).

Figure 1 – A single cycle of vocal fold vibration as seenby high-speed digital imaging.

When multiple vibratory cycles are ana-lyzed in regards to symmetry and regu-larity, a visual graphic of periodicity can be generated, called a Nyquist plot(Figure 2).

With the incorporation of these new ana-lytical tools into the armamentarium ofthe Stanford Voice Center, it is hopedthat new insight may be provided intothe causes and treatments of a variety ofvoice disorders.

Our division is also partnering with theDepartments of Electrical Engineeringand Radiology to apply an experimental

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form of high-resolution MRI imaging forthe detection of early invasive cancer ofthe vocal cords (Figure 3). High-resolu-tion MRI scanning may allow images ofthe larynx at 8 to 10 times the resolutionof standard MRI, and a clinical trial is cur-rently underway to determine its role inpredicting invasion of the cartilage bycancer.

Earlier detection of advanced diseasemay afford higher rates of laryngeal con-servation in the future.

CLINICAL RESEARCH IN OTOLOGY-NEUROTOLOGY

Nikolas H. Blevins and Robert K. Jackler

Planned Subtotal Resection and Stereotactic Radiotherapy for AcousticNeuroma

The advent of stereotactic radiosurgeryhas provided the clinician with a non-surgical option to control the growth ofacoustic tumors. With the developmentof the Cyberknife linear accelerator sys-tem, Stanford has long been a pioneer inthe non-surgical management of skullbase disease. Despite considerable expe-rience with small acoustic tumors, therole of radiosurgery into the treatmentof large tumors remains to be fullydefined. The potentially synergistic effectof combined microsurgical resection andstereotactic radiotherapy could offereffective new options to individuals whoremain at most risk given conventionaltreatment.

The Stanford Department of Otolaryn-gology in collaboration with the depart-ments of Neurosurgery and RadiationOncology, is leading a prospective multi-center trial to assess the efficacy of man-aging large acoustic neuromas (over 3cm) with a combination of plannedsubtotal resection followed by stereotac-tic radiosurgery. Patients enrolled in theprotocol will undergo planned subtotalresection avoiding potentially injuriousdissection of the facial nerve from thetumor capsule. Patients will be followedwith serial MRI scans, and will receivestereotactic radiation to the tumor rem-nant if growth is detected.

The prospective nature of this study willprovide valuable data towards establish-ing optimal treatment of advanced dis-ease, while minimizing the risk of post-operative facial nerve dysfunction.

Planned subtotal resection of an acoustic neuroma

The Stanford Cyberknife.

The Use of Stacked ABR for the Assessment of Hearing Preservation inAcoustic Neuroma Resection

Patients with small acoustic neuromasand good hearing are faced with achoice of treatment options. Whetherthey choose to undergo microsurgicalresection or stereotactic radiotherapy(such as with Cyberknife) can be largelyinfluenced by the likelihood of hearingpreservation. The short-term rates ofhearing preservation with stereotacticradiation are excellent, but given the per-sistence of tumor and possible long-termneurovascular changes, hearing levelsmay deteriorate with time. Microsurgeryin contrast, often places additional risksto hearing in the short term. However,the expectation for maintaining hearingthat is present post-operatively is quitefavorable. Unfortunately, there is a cur-rent lack of preoperative predictors ofwhich patients are more likely to retainhearing through a surgical procedure.

The Stanford Departments of Otolaryn-gology and Audiology are engaged in aprospective clinical trial to assess innova-tive of electrophysiologic testing to pre-dict the success of hearing-preservationattempts. The study applies highly sensi-tive auditory brainstem response tech-niques (“stacked ABR”) that may be anaccurate predictor of the potential for aninvolved cochlear nerve to withstand sur-gical manipulation and tumor extraction.

The development of such non-invasivepreoperative predictors will substantive-ly assist with patient counseling andtreatment planning in patients withacoustic neuromas. Given this additionalinformation, patients and their cliniciansmay make better-informed decisionsabout the pursuit of treatment options.

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Figure 2 – Generation of the Nyquist plot, an objectiverepresentation of normal vocal fold vibration.

Figure 3 – High-resolution MRI of the human larynx.

Non-invasive Diagnosis ofCholesteatoma using High-ResolutionDiffusion-Weighted MRI Sequences

The Department of Otolaryngology, inconjunction with the Department of Radi-ology, is engaged in a prospective studyto establish the efficacy of innovative MRItechniques in the diagnosis of cholestea-toma. Standard diffusion-weighted MRI iscapable of detecting intratemporal squa-mous epithelium. However, it is subopti-mal in its anatomic resolution and is subject to significant artifacts, both ofwhich limit its clinical utility.

Our protocol involves the use of new sig-nal processing techniques (SENSE-DWI).The resulting improved images have thepotential to make MRI clinically useful intreatment planning for patients withpossible occult cholesteatoma. Patientsin whom a second-look procedure iscontemplated may benefit greatly fromthis non-invasive imaging modality.

Innovations in Cochlear Implant Technology

In 1964, the first human multichannelcochlear implant was placed at Stanford.The Department of Otolaryngology con-tinues this long history of innovation in

the develop-ment andapplicationof inner earprostheses.Relatedbasic scienceprojectsinclude theapplication

of stem-cells for inner ear regeneration,computational modeling of inner earfunction, and inner ear microendoscopyfor therapeutics and inner ear microro-botics.

The LPCH/Stanford Cochlear ImplantCenter is actively involved in clinical tri-als for cochlear implants. We are a centerfor the clinical trial of the Nucleus Electri-cal-Acoustic Hybrid implant.These devicesoffer the potential benefits of cochlearimplantation to the vast number of indi-viduals who suffer from high frequencyhearing loss, since residual acoustic hear-ing in the lower frequencies can bemaintained.

CLINICAL RESEARCH IN AUDIOLOGY

Gerald Popelka, PhD

Clinical research in Audiology comple-ments the services that are provided andconsequently covers both diagnosticsand rehabilitation. All clinical audiologyresearch is performed under strict IRBprotocols with patients providing signedconsents and receiving compensation inmost cases and complete protection ofpatient privacy

Our current auditory diagnostic researchprojects center around the developmentand improvement of clinical informationderived from auditory evoked potentials.A new auditory evoked potential meas-ure reported last year has the possibilityof indicating whether cochlear fluidpressure is abnormally high. The meas-ure is based on the theory that a promi-nent peak in the waveform of the audito-ry brainstem response will shift inlatency (about 1 msec) with selectivestimulation of different portions of thebasilar membrane. This latency shift isdue primarily to the normal stiffness gra-dient along the length of the basilarmembrane. High fluid pressure such asthat associated with endolymphatichydrops is expected to eliminate thisgradient stiffness and therefore elimi-nate the latency shift. Currently, severalparametric variables are being investi-gated including electrode location, auto-mated response quantification, methodsfor reducing electromyogenic artifacts,and other practical considerations beforethe method can be deemed reliable

enough for routine clinical use. It ishoped that the improved procedure willprovide a repeatable and useful indica-tion of cochlear fluid pressure.

Our current rehabilitative research proj-ects center on the development ofadvanced digital signal processing thatcan be implemented with contemporarydigital hearing aids. These advancedhearing aids now constitute over 90% ofall hearing aids sold nationally and 100%of those dispensed in our clinic and con-tinue to add new functionality such asincorporating cell phone capability.

Current research projects involve boththe development of new digital process-ing for improving speech understandingin noise and measuring and understand-ing the sources of alterations in otherauditory tasks caused by the specific dig-ital processing such as errors in locatingsounds in the environment. We wish tomake sure that an enhancement in onetype of auditory performance, improvedunderstanding in noise, eg, is notobtained at the expense of a detrimentin another type of auditory performance,poor speech understanding through theinternal cell phone function, eg. We alsowish to determine if the particular digitalprocessing interacts with the individualhearing status such that a particular pro-cessing may be beneficial for certaintypes of hearing impairment but detri-

mental for othertypes of hearingimpairment.Patients with welldocumented hear-ing loss arerecruited to listento speech andother soundsprocessed digitallyunder highly-con-trolled conditionseither in real timeor with pre-recorded record-ings. It is hopedthat this systemat-

ic approach will result in an understand-ing of the optimal digital processing forindividual patients allowing us to fulfillour goal of providing customized andoptimized solutions for our hearingimpaired patients.

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To help support our mission to educate our colleagues, Stanford OHNS has developed a series of high quality CME courses. Toenrich the curriculum, aside from Stanford faculty we invite nationally and internationally renowned guest instructors to teachin our programs.

CONTINUINGMEDICAL EDUCAT ION

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STANFORD OTOLARYNGOLOGY – HEAD & NECK SURGERY801 Welch Road, Palo Alto, CA 94304(650) 723-5281 (clinic) • (650) 725-6500 (academic)http://med.stanford.edu/ohns

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6The Department of Otolaryngology –Head & Neck SurgeryStanford University School of Medicine

presents

STANFORDOTOLOGY& NEUROTOLOGYUPDATE 2006Stanford Court Hotel, San FranciscoNovember 2-4, 20062

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5The Departments of Otolaryngology –Head & Neck Surgery and Neurosurgery,Stanford University School of Medicineand Stanford Hospital and Clinics

present

STANFORD COURSE INCRANIAL BASE SURGERY:Minimally Invasive Approaches to Inaccessible Intracranial Lesions

Friday and Saturday March 4th and 5th, 2005

Clark Center Auditorium Stanford Campus

STANFORD OTOLARYNGOLOGY DEPARTMENT 2006