HEAD & NECK SURGERY - Stanford University School of Medicine

Stanford University Medical Center 

D epartment of 

O TOLARYNGOLOGY– 

H EAD &NECK S URGERY 

PROGRESS REPORT FROM THE CHAIR 

Robert K. Jackler, MD, 

Sewall Professor & Chair 

Three years ago, 

Stanford awarded 

Otolaryngology – 

Head & Neck 

Surgery status as 

an independent 

department and 

provided it a 

generous package 

of resources 

designed to 

enable a period 

of rapid expansion. 

The explicit 

mandate received from Dean Philip Pizzo 

was to create world class clinical and 

translational research programs. 

FACULTY GROWTH 

Over the last few years we have rapidly 

grown from 6 to 16 faculty members (on 

the way to at least 21). These include 6 

new division chiefs: Dr. Peter Koltai (Pediatric 

OHNS), Dr Michael Kaplan (Head & 

Neck Oncology), Dr. Peter Hwang (Rhinology 

and Sinus Surgery), Dr. Samuel Most 

(Facial Plastic Surgery), Dr. Edward Damrose 

(Laryngology), Dr. Gerald Popelka 

(Audiology & Hearing Devices). Dr. Nikolas 

Blevins joined me in the Otology 

& Neurotology division and leads the 

Stanford Cochlear Implant Program. 

World renowned inner ear stem cell biologist 

Stefan Heller, PhD has joined us to 

lead our Research Division along with 

Anthony Ricci, PhD (hair cell biophysicist), 

Sunil Puria, PhD (mechanical engineer 

- middle ear mechanics), and Yuling 

Yan, PhD (electrical engineer – laryngeal 

image analysis). 

EDUCATIONAL PROGRAMS 

Our extraordinarily talented group of 

residents has expanded from 15 in 2003 

(3 in each of 5 years) to 19 in 2006 as we 

gradually expand our training programs 

in proportion to our growing faculty. We 

are proud that our residents obtain a 

splendid experience in the broad spectrum 

of contemporary OHNS procedures 

and have done very well in obtaining 

post-residency fellowship positions in a 

number of subspecialties. 

We now offer seven post-residency fellowship 

programs – more than any other 

OHNS training program. These include: 

facial plastic surgery, head & neck surgery, 

pediatric OHNS, neurotology & skull 

base surgery, sinus surgery, sleep surgery, 

and laryngology (added in 2006). 

These programs not only provide advanced 

training for promising young academicians, 

but as junior faculty members 

the fellows also enhance the residency 

educational experience. 

STANFORD OHNS: 

TRANSLATIONAL RESEARCH 

PROGRAMS 

Regenerative 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 

Fall 2006 

NEW FACILITIES 

The Department is undergoing an 

extraordinary improvement in its physical 

plant with all aspects of the educational, 

research, and administrative 

programs transitioning to newly constructed 

facilities. We are privileged to be 

one of the few OHNS departments to 

have our own home building on a university 

campus – occupied after a $4 million 

renovation in late 2004. This provides 

core facilities for our academic, 

administrative, and educational programs 

and includes state-of-the-art 

library-conference facilities (The Willard 

E. Fee Jr., M.D. Library) and a superb 10 

station educational microdissection laboratory 

(The Rodney Perkins, M.D. Microsurgical 

Laboratory). The building also 

houses some of our adult clinical programs 

(facial plastic surgery, laryngology, 

rhinology-sinus surgery, otology-neurotology, 

the cochlear implant center, and 

the audiology & hearing device program). 

Our Head & Neck Oncology programs are 

housed in the magnificent new Stanford 

Cancer Center, in which OHNS has 3 faculty 

offices, a suite of exam rooms, and a 

conference facility for Head & Neck Tumor 

Board. New clinical facilities for Pediatric 

Otolaryngology and Pediatric Audiology 

opened in October, 2004 (Mary L. Johnson 

Pediatric Ambulatory Care Center) 

close to the main OHNS facility. 

The old outmoded OHNS facility will be 

gutted and rebuilt as a state-of-the-art 

7000 sq ft research laboratory. This project, 

with a budget approaching $5 million, 

will be completed in 2007. It has 

been designed to include both core facilities 

and a flexible layout, facilitating 

ease of adaptation as future research 

interests evolve. 

(continued on page 2)

S TANFORD U NIVERSITY M EDICAL C ENTER D EPARTMENT OF O TOLARYNGOLOGY – HEAD & N ECK S URGERY 

RESEARCH EMPHASIS 

The research division of Stanford OHNS 

is in the midst of rapid expansion. Stanford 

has made a substantial investment 

in new laboratory space, endowment, 

and additional basic science faculty positions. 

The intention is to create a highly 

productive, innovative, and collaborative 

center which takes full advantage of the 

surrounding Stanford bioscience and 

engineering communities. The priority of 

our laboratory programs is to produce 

high quality, innovative research in areas 

of inquiry relevant to human disease. 

Growth in our research programs will 

emphasize two central themes: Regenerative 

Medicine and Bioengineering. 

Stanford OHNS has come a long way in a 

short 3 years since emerging as an independent 

department: more than doubling 

the size of the faculty with recruitment 

of a number of highly talented 

individuals; abandoning antiquated facilities 

for new ones triple their size; sizable 

expansion of both residency and fellowship 

programs; and development of 

dynamic, cutting edge research programs. 

It is a credit to a large team of 

hard working individuals that we have 

made much progress in such a relatively 

short period. We look forward to sharing 

our progress with you in the coming 

years. We plan to keep things hopping 

on “The Farm.” 

BUILDING WORLD CLASS PROGRAMS 

2

I NTRODUCING 

O UR FACULTY (Fall 2006) 

NIKOLAS H. BLEVINS, MD 

Assistant Professor 

Otology & Neurotology 

College: Stanford University 

Medical School: Harvard 

University. 

Residency: University of 

California at San Francisco 

Fellowship: Neurotology/Skull 

Base Surgery – University of 


Former Faculty Position: Tufts 

University (1995-2003) 

Clinical Interests: Otology, 

neurotology, skull base surgery, 

cochlear implants 

Research Interests: Surgical 

simulation and robotics, 

microendoscopy of the inner ear 

KAY W. CHANG, MD 


Pediatric OHNS 

College: Brown University 

Medical School: Brown University 


Washington 

Fellowship: Pediatric 

Otolaryngology at the Children’s 

Hospital of Pittsburgh 

Clinical Interests: Pediatric 

otology, Ear reconstruction 

Research Interests: Pediatric 

hearing loss, cis-platinum 

ototoxicity 

EDWARD J. DAMROSE, MD 


Chief of Laryngology Division 

College: Yale University 

Medical School: UCLA School of 

Medicine 


California at Los Angeles 

Fellowship: Laryngology/ 

Bronchoesophagology – 

University of California at Los 

Angeles 

Clinical Interests: Voice and 

swallowing disorders 

Research Interests: High speed 

laryngeal imaging, spasmodic 

dysphonia, rehabilitation of vocal 

cord palsy 

WILLARD E. FEE, JR., MD 

Edward C. and Amy H. Sewall 

Professor 

Head & Neck Surgery 

College: University of San 

Francisco 

Medical School: University of 

Colorado 


California, Los Angeles 

Clinical Interests: Tumors of the 

head and neck 

Research Interests: Clinical 

outcomes in head & neck cancer 

RICHARD L. GOODE, MD 


Sleep Surgery & Facial Plastic 

Surgery 

Chief VA Service 

College: University of California at 

Santa Barbara, California 


Southern California 

Residency: Stanford University 

Fellowship: NIH Fellow – 

Vestibular Physiology 

Clinical Interests: Facial plastic 

surgery, sleep surgery 

Research Interests: Mechanics of 

middle ear function, innovations 

in sleep surgery 

STEFAN HELLER, PHD 

Associate Professor 

Head of Research 

M.S. Biology: Johannes 

Gutenberg University, Mainz, 

Germany 

PhD Genetics: Johannes 

Gutenberg University, Mainz, 

Germany 

and Max-Planck-Institute for 

Brain Research, Frankfurt/M., 

Germany 

Post-Doctoral Training: The 

Rockefeller University, New York 

Former Faculty Position: Harvard 

University (2000-2005) 

Research Interests: Hair cell 

regeneration to overcome 

deafness, structure and function 

of mechanosensitive ion channel 

proteins. 

Fall 2006 

PETER H. HWANG , MD 


Chief of Rhinology 

College: Stanford University 





Fellowship: Rhinology and Sinus 

Disorders, Hospital of the 

University of Pennsylvania 

Former Faculty Position: Oregon 

Health & Science University 

(1997-2005) 

Clinical Interests: Endoscopic 

sinus surgery, endoscopic tumor 

and skull base surgery 

Research Interests: Mucosal wound 

healing, novel drug delivery 

technologies, clinical outcomes 

ROBERT K. JACKLER, MD 

Sewall Professor and Chair 

Otology & Neurotology 

College: Brandeis University 

Medical School: Boston University 



Fellowship: Neurotology, House 

Ear Clinic, Los Angeles, CA 

Former Faculty Position: UCSF 

(1986 - 2003) 

Clinical Interests: Neurotology 

and skull base surgery 

Research Interests: Innovation in 

skull base surgery, cholesteatoma 

pathogenesis, history of otology 

3

S T ANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY 

MICHAEL J. KAPLAN, MD 


Chief of Head & Neck Surgery 

College: Harvard College 

Medical School: Harvard Medical 

School 

Residency: Massachusetts Eye 

and Ear Infirmary 

Fellowship: University of Virginia 

(Head & Neck Surgery) 

Former Faculty Position: UCSF 

(1984 - 2003) 

Clinical Interests: Tumors of the 

head and neck 

Research Interests: Clinical 

outcomes for head and neck 

malignancy, advanced imaging, 

head & neck cancer stem cells 

PETER J. KOLTAI, MD 


Chief of Pediatric OHNS 

College: Queens College 

Medical School: The Albany 

Medical College 

Residency: University of Texas 

Medical Branch 

Fellowship: Pediatric 

Otolaryngology/Hospital for Sick 

Children at Great Ormond Street 

Former Faculty Position: Albany 

Med. (1982-1998), Cleveland 

Clinic (1998-2004) 

Clinical Interests: Pediatric airway 

obstruction, sleep apnea 

Research Interests: Developing 

new techniques in managing 

sleep apnea 

4 

ANNA H. MESSNER, MD 


Pediatric OHNS 

Vice Chair 

College: Duke University 

Medical School: Wake Forest 

University 

Residency: Wake Forest 


Fellowship: Pediatric OHNS, 

Hospital for Sick Children, 

Toronto, Canada 

Clinical Interests: Pediatric OHNS 

Research Interests: Neonatal 

hearing screening, ankyloglossia 

SAM MOST, MD 


Chief of Facial Plastic Surgery 

College: University of Michigan 

Medical School: Stanford 


Washington 

Fellowship: Facial Plastic Surgery 

(U Washington) 

Former Faculty Position: 

University of Washington (2002 - 

2006), 

Clinical Interests: Aesthetic 

surgery of the face 

Research Interests: Minimally 

invasive improvement of the 

aging face, facial nerve biology 

SUNIL PURIA, PHD 

Consulting Associate Professor 

Research 

College: The City College of NY 

MS: Columbia University 

PhD: City University of NY 

Postdoctoral Fellowships: MIT, 

Harvard 

Former Faculty Position: Harvard 

(1995-1997) 

Research Interests: Biomechanics, 

physiology, and imaging of the 

middle ear and the cochlea. 

GERALD R. POPELKA, PHD 

Consulting Professor 

Research 

Chief of Audiology 

College: Kent State University 

MA: Audiology/Kent State 


PhD: Communication Sciences/ 

University of Wisconsin 

Postdoctoral Fellowship: 

University of California at Los 

Angeles 


Washington University (1980 - 

2004) 

Clinical Interests: Advanced 

hearing devices, advanced 

measures of auditory function 

Research Interests: The 

developing auditory system, 

hyperbilirubinemia 

ANTHONY RICCI, PHD 


Research 

College: Case Western Reserve 


PhD: Neuroscience/Tulane 


Post-doctoral Fellowships: UTMB, 

University of Wisconsin 


Louisiana State University (1999 - 

2006) 

Research Interests: Hair cell 

biophysics 

YULING YAN, PHD 

Consulting Assistant Professor 

Research 

PhD: Mechanical Engineering/ 

Keio University, Yokohama, Japan 

Post-Doctoral Fellowship: McGill 



University of Hawaii, U Wisconsin 

Research Interests: High speed 

laryngeal imaging

STANFORD FACULTY AT SANTA CLARA 

VALLEY MEDICAL CENTER (Fall 2006) 

JOHN B. SHINN, MD 

Clinical Professor 

Santa Clara Valley Medical Center 

College: University of North 

Carolina 


North Carolina, Chapel Hill 

Residency: Stanford 

Clinical Interests: Otology & 

Neurotology 

M. LAUREN LALAKEA, MD 

Clinical Associate Professor 


College: Harvard 

Medical School: Boston University 


Clinical Interests: Pediatric OHNS, 

laryngology 

Research Interests: Ankyloglossia 

KIMBERLY G. SHEPARD, MD 

Clinical Assistant Professor 


College: UC San Diego 

Medical School: Dartmouth 


Clinical Interests: Head & Neck 

Oncology; Sleep apnea 

Research Interests: Non-surgical 

treatment of tonsillar hypertrophy, 

Medical management of postoperative 

pain 

CARRIE ROLLER, MD 

Clinical Assistant Professor 


College: UC Berkeley 

Medical School: Georgetown 


Residency: Baylor 

Clinical Interests: Head & neck 

cancer, trauma 

Research Interests: Functional 

outcomes after Head & Neck 

Surgery 

Fall 2006 

5

S TANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY 

R ESEARCH P ROGRAMS 

CURING HEARING LOSS 

AND UNLOCKING THE SECRETS 

OF HOW THE EAR WORKS 

Stefan Heller, PhD 

All hearing sensation is derived from the 

electrical output of a remarkably small 

number of sensory cells: fewer that 

15,000 per inner ear at birth. These hair 

cells are the mechanoelectrical transducers 

of the inner ear: deflections of the 

sterociliary bundles on their apical surfaces 

lead to transmitter release from 

their basolateral poles, leading, in turn, to 

signal generation in the peripheral axons 

of the auditory nerve fibers. 

Most types of congenital and acquired 

hearing loss arise from damage to, or 

loss of, these sensory cells or their associated 

neurons. The incidence of heritable 

deafness is high: one child in a thousand 

is born deaf; another one in a thousand 

becomes deaf before adulthood. The 

prevalence of acquired hearing loss is rising, 

as the population ages, and as noise 

pollution steadily increases. It is estimated 

that one in three adults over the age 

of 65 has a handicapping hearing loss, 

and this impairment is largely due to the 

irreversible loss of sensory cells. 

Underlying the irreversibility of hearing 

loss in mammals is the incapacity to 

replace lost hair cells by cell division or 

by regeneration from endogenous cells 

6 

The image shows integration and differentiation of inner ear progenitor cells derived 

from mouse embryonic stem cells after injection into the chicken’s developing 

inner ear (otic vesicle). In (A), some of the injected cells, which are expressing 

the ß-Gal marker gene are found to integrate into the epithelium of the otic 

vesicle (arrow). Shown in (B) and (C) are embryonic stem cell-derived cells found 

3 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 chicken 

auditory epithelium where they are surrounded by endogenous chicken hair cells 

(non green cells, labeled red). (D) and (E) show that the mouse cells, here visualized 

with a blue ß-Gal staining with developed hair bundles that are immunopositive 

for the hair bundle marker protein espin. 

in the inner ear epithelia. Hair cell 

replacement, either by stimulation of 

regeneration (as occurs naturally in nonmammalian 

vertebrates) or by transplantation 

of progenitor cells capable of differentiating 

into hair cells, remains 

therefore the ultimate goal in the development 

of treatment applications to 

reconstruct the damaged inner ear. 

Our recent work has focused on creating 

inner ear cell types, in particular hair cells 

and auditory neurons, from a renewable 

source. 

We have shown that embryonic stem 

(ES) cells and adult inner ear stem cells 

can serve as such a 

source, and we are 

currently exploring 

signaling pathways 

that control hair cell 

and neuronal (re-) 

generation in vitro 

and in vivo. 

Our research does 

not only focus on 

generating inner 

ear replacement 

parts. We are also 

exploring novel 

methods to deliver 

such replacement 

parts into the damaged 

cochlea or 

whether it is possible 

to use drugs to coax 

cells of the adult 

damaged cochlea 

into a prenatal status, 

which could result 

in self-repair of the damaged mammalian 

cochlea. 

In an independent line of research, we 

are pursuing the structural basis of hair 

cell mechanoreception. Although the 

individual molecular components of the 

mechanoelectrical transduction apparatus 

are not known, we and other laboratories 

have identified a number of 

potential candidates. Our goal is to solve 

the atomic structure of the different 

components of the transduction machinery 

to study the molecular hinges and 

mechanisms that 

mechanically gate the 

elusive ion channel 

that is central to our 

senses of hearing and 

balance. 

THE THERAPEUTIC RELEVANCE 

OF HAIR CELL BIOPHYSICS 

Anthony Ricci, PhD 

Hair cells are the sensory cells of the 

inner ear. They are responsible for converting 

mechanical signals into one recognized 

by the brain. Hair cells get their 

name from having a tuft of hair-like cilia 

at their apical surface. Deflection of these 

stereocilia opens mechanically-gated ion 

channels that convert the mechanical 

signal into an electrical signal. This 

process, termed mechanotransduction is 

critical to both hearing and balance. Perturbations 

of this system are associated 

with both temporary and permanent 

hearing loss, with age-related and noiseinduced 

hearing loss and may even be 

associated with tinnitus and vertigo. 

Understanding the mechanisms involved 

in regulating mechanotransduction may 

elucidate new and novel sites for intervention. 

Characterizing these pathways 

might also lead to new technological 

breakthroughs in hearing aid and 

cochlear implant development as well as 

in the design of novel noise prevention 

devices. Over the past several years my 

laboratory has identified several important 

attributes of mechanotransduction. 

First, we have discovered a new process, 

called fast adaptation that is critical for 

establishing frequency discrimination, or 

the ability of the ear to separate sound 

into its individual frequency components. 

Second, we demonstrated for the 

first time, biochemical regulation of 

mechanotransduction. This pathway may 

provide a new site for pharmacological 

intervention in preventing noise-induced 

hearing loss. Third, we have recently 

demonstrated the importance of 

mechanotransduction in controlling the 

electrical properties of hair cells. As 

mechanotransduction is very sensitive to 

its ionic environment, particularly the 

concentration of calcium, the importance 

of maintaining low levels of calcium 

bathing the hair bundle has become 

more apparent. Characterizing the regulation 

of extracellular calcium may provide 

a new pathway for intervention and 

may shed light on pathologies related to 

loss of ionic homeostasis within the ear. 

And finally we are involved in identifying 

a mechanism associated with mechanotransduction 

and the hair bundle that

may act to amplify low levels of sound 

and be a major contributor to determining 

how the ear can be sensitive to such 

low energy sound waves. 

Aside from converting a mechanical signal 

into an electrical signal, the hair cell 

must communicate with the brain 

through synaptic transmission. The hair 

cell-afferent nerve synapse is very sensitive 

to overstimulation where the nerve 

ending can swell and retract leading to 

hair cell loss. My laboratory has been 

investigating the functional properties of 

this synapse to identify the properties 

that make it unique in its ability to operate 

with such high fidelity and at such 

high rates. Here too, the goal is to identify 

pathways and mechanisms that might 

offer sites for intervention and modification. 

And finally, my laboratory is trying to 

determine whether hair cells require 

extrinsic factors, like innervation, 

mechanical stimulation or growth factors 

to mature into their final form. This is a 

critical question to answer in order to 

judge feasibility of therapies where hair 

cell regeneration from supporting cells 

or hair cell development from stem cells 

is being investigated as a new therapy to 

replace hair cells in damaged cochlea 

Isolated outer hair cell with sensory hair bundle (left). 

Upper right is patch electrode on hair cell body to 

measure electrical responses elicited by mechanically 

stimulating the sensory hair bundle (lower right). 

INNER EAR FLUORESCENCE 

MICROENDOSCOPY 

Nikolas Blevins, MD, Mark Schnitzer, PhD, 

Eunice Cheung, PhD 

We are developing a method to visualize 

functional hair cells and other cellular 

elements of the inner ear within the 

intact mammalian cochlea using fluorescence 

microendoscopy. Our laboratory 

has begun work on this minimally invasive 

in vivo imaging technique to provide 

high-resolution images of deep tissues 

previously inaccessible in live 

subjects. Using microendoscopes as 

small as 0.3 mm in diameter, we have 

successfully imaged individual red blood 

cells flowing within capillaries inside the 

mammalian cochlea. We are extending 

this work by labeling functional neural 

elements with fluorescent dyes to concurrently 

reveal mechanotransduction as 

well as microanatomy. 

Current work includes microendoscopy 

using a styryl dye (FM-143) in the guinea 

pig. It is anticipated that this will allow us 

View of live cochlear hair cells from a microendoscope 

to accurately map hair cell injury following 

ototoxin exposure, and to observe 

the recovery of hair cells from temporary 

threshold shift noise damage. The use 

of microendoscopes should provide an 

opportunity to observe specific hair cell 

populations over time – information 

previously unavailable through conventional 

techniques. 

An imaging technology to observe functional 

hair cells and dendrites within live 

MIcroendoscope 

Fall 2006 

mammalian subjects will provide considerable 

benefit, and enable progress in a 

broad range of previously intractable 

hearing science questions. The success of 

inner ear microendoscopy will provide a 

basis on which inner ear surgery can be 

established. The inner ear is one of the 

last areas of the human body to remain 

largely inaccessible to direct examina- 

tion and surgical intervention. This is 

because of the combination of its small 

size and its extraordinary fragility to 

mechanical manipulation. The development 

of non-destructive imaging techniques 

will enable diagnostic and therapeutic 

manipulations, including the 

optimal placement of cochlear implant 

arrays, or the specific delivery of stem 

cells or growth factors to enable hearing 

restoration. 

7



THE POSSIBLE ROLE OF STEM 

CELLS IN HEAD & NECK CANCER 

Michael Kaplan, MD, Michael Clarke, MD, 

Laurie Ailles, PHD Willard Fee, MD, Ranjiv 

Sivanidan, MD, Mark Prince, MD 

Head and neck cancer affects 50,000 

Americans annually and remains a devastating 

world-wide killer. In India, for 

example, it is the leading cause of cancer 

deaths. Cisplatin-based concomitant 

chemotherapy and selected monoclonal 

antibodies have improved locoregional 

controls compared to irradiation alone, 

but there has been little to no impact on 

survival because of distant metastasis 

and the therapy-resistant recurrences. 

Why has there been so little progress? Is 

it because we have not adequately 

enough appreciated the underlying 

tumor biology so as to develop more 

effective therapeutic approaches? 

H&E and immunoperodixase staining of CD44 in 

passaged cells growing as explant 

It has been understood for quite some 

time that leukemias and lymphomas 

arise within hematopoietic stem cells, yet 

it has been only recently that a cancer 

stem cell (CSC) hypothesis has been 

extended to solid epithelial cells, including 

head and neck squamous cell carcinomas 

(HNSCC). 

Normal stem cells maintain an organ’s 

stem cell pool by self-renewing, while 

generating large numbers of mature 

daughter differentiated cells that in their 

life cells in time undergo apoptosis (programmed 

cell death). Squamous epithelium 

is comprised of a basal layer of cells 

that contain some stem cells and overlying 

layers that contain daughter cells 

that die as they approach the surface. 

When stem cells divide they asymmetrically 

give rise to both a committed 

daughter cell as well as another stem 

cell. This stem cell must avoid programmed 

cell death (apoptosis) 

throughout the organism’s lifetime. 

Under normal circumstances it also must 

recognize its neighbors in order to know 

8 

when to divide and when not to; in other 

words cell-cell signaling pathways are 

likely important. Stem cells (or their 

immediate daughters) also must be able 

to migrate, both upward in the epithelium 

and in response to trauma. These 

three properties – avoiding apoptosis, 

critical cell-cell signaling, and migration – 

are also key attributes of developmental 

(embryonic, fetal) stem cells. An important 

insight is that avoiding apoptosis 

and migration are also key characteristics 

of cancer cells; and aberrant cell-cell 

signaling pathways are beginning to be 

shown as well. 

A cancer stem cell hypothesis suggests 

that cancer is a result of inadequately 

controlled proliferation of the stem cells 

themselves, and not the heterogeneous 

mix of daughter cells. Such aberrant 

growth would lead to subpopulations 

that contain a small percentage of 

daughter stem cells but many more 

committed differentiated cells that will 

undergo apoptosis in time. In other 

words, one should expect to see functional 

heterogeneity, with only a small 

fraction of cells harboring tumorigenic 

potential. This had been known in hematological 

malignancies for 40 years, but 

was shown in solid tumors (medulloblastoma, 

breast cancer) only in the past 

three years. 

Only CD44+ cells serially maintain clonogenicity. 

Working along similar lines using methods 

employed to identify cancer stem 

cells in breast cancer, collaborating laboratories 

at the University of Michigan 

and at Stanford showed in 2006 (in 

press) that this is also true for HNSCC. 

HNSCC contains a distinct population of 

cancer stem cells with the exclusive ability 

to produce tumors in mice and recreate 

the original tumor heterogeneity. 

They are clonogenic in vitro (Fig 1) and 

initiate tumors in vivo (Fig 2), while the 

remaining cells in the tumor do not 

share these properties. This population is 

distinguished by a cell surface marker 

(CD44) that distinguishes these cells 

from the other epithelial cells within the 

tumor that lack clonogenicity. 

The identification of cancer stem cells in 

HNSCC has important ramifications. Most 

basically, it lends further support to the 

general concept that a CSC model is true 

for all cancers. Second, it suggests one 

possible reason why chemotherapy has 

been disappointing is that the assay 

used clinically (and in some clonogenic 

assays) is overall tumor response, whereas 

it is not overall but rather stem cell 

response that is key. Third, it suggests 

that characterizing selected key molecular 

pathways that are involved in selfrenewal, 

such as cell-cell signaling pathways, 

should provide insights into 

specifically what is abnormally regulated. 

Insights such as these hold promise for 

the development of new treatment 

strategies targeted not against the 

majority of tumor cells (which have limited 

tumorigenicity) but against the critical 

population of cancer stem cells that is 

the key culprit. 

A fourth striking implication of validating 

a CSC model is that one cannot help but 

see the striking similarities between nor- 

mal embryonic development and normal 

stem cells and their dysregulation that is 

cancer. This suggests that understanding 

normal development should lead to 

insight into cancer, and vice versa. The 

cellular genetic control mechanisms 

seen in normal development, stem cell 

regulation, and cancer are likely to be 

the same. 

In the past decade an entirely new layer 

of intranuclear genetic control has been 

identified-small RNAs regulate gene 

expression by suppressing homologous 

or near-homologous DNA sequences.

These microRNAs (miRNA) are normal, 

and derive from pre-miRNA genes within 

us, and the RNA-protein machinery all 

organisms use for this is being increasingly 

identified. MiRNA gene chips are 

available, and abnormal quantities of 

selected miRNAs have begun to be identified 

in a few malignancies. That miRNAs 

are stable in paraffin will allow investigation 

of archived material as well as easier 

investigation of fresh tumor-banked 

material. 

The recognition of cancer stem cells in 

solid tumors, including head and neck 

carcinomas, and the advances in DNA 

control by miRNAs suggest reasons for 

optimism that fundamental insights will 

lead to genetic therapies targeting cancer 

stem cells in the future. Our lab, as 

well as others, will investigate whether 

CD44 (a complex molecule, with multiple 

splice variants, that is involved in cell 

adhesion and mobility) is simply a marker 

for CSCs, or whether it plays an essential 

function. More specific markers are 

likely to be found, which in aggregate 

will better identify the stem cell pool. As 

identification of stem cells becomes 

more precise, investigation of abnormal 

miRNAs will be a goal. As abnormalities 

in cell-cell signaling pathways become 

better understood, it will be of interest to 

look at differences between tumors and 

pre-malignant conditions such as dysplasia 

and inverted papilloma, as well as the 

differences in pathways associated with 

motility between primary tumors and 

both nodal and distant metastases. 

In summary, the initial validation of cancer 

stem cells in head and neck carcinomas 

offers myriad opportunities both to 

understand the fundamental nature of 

cancer and to develop stem cell targets 

for genetic in the future. 

HIGH SPEED LARYNGEAL 

IMAGING & THE VIRTUAL 

LARYNGOSCOPE 

Yuling Yan, PhD & Edward Damrose MD 

The primary objective of our research 

program is to understand the mechanism 

of phonation for normal and for 

pathological voice conditions. We 

employ an interdisciplinary approach to 

these studies that borrows and integrates 

concepts and methodologies 

from bioengineering, biophysics, mathematical 

modeling and physiology. 

Functional Analysis and Modeling of 

Phonation in Normal and Diseased States 

Vibration of the vocal folds is an essential 

yet poorly understood event in human 

voice production. An important aspect of 

our research program is to characterize 

the dynamic behavior of the vocal folds 

during phonation – the ultimate goal for 

these studies is to understand the mech- 

Figure 1 – (Top) A montage of 10 image frames from an HSKI recording of a normal 

subject while producing a sustained vowel phonation; (Bottom) Spatially resolved 

vocal fold vibration representing diplophonic voice, and Nyquist pattern showing the 

bifurcation (transition from a normophonic [red] to a diplophonic phase [black]). 

anism of phonation in terms of the generation 

and interaction of sound waves 

in the vocal system; these studies will 

lead to the development of quantitative 

biomechanical models of vocal fold 

dynamics and acoustic interactions in 

the vocal tract for the detection, diagnosis 

and assessment of treatments for specific 

voice disorders. 

Fall 2006 

Quantitative analysis of vocal fold 

dynamics using High Speed Digital 

Imaging (HSDI) 

HSDI with simultaneously acquired acoustic 

recordings are being used to characterize 

vocal fold dynamics. We have 

developed new methods and software 

platforms to generate comprehensive, 

functional analysis of vocal fold vibrations 

from HSDI and acoustic recordings. 

For example, our analytical platform that 

integrates automatic image segmentation 

of the vocal folds and detection of 

vocal fold edge (Figure 1) with the generation 

of glottal waveforms that include 

the glottal area waveform, glottal width 

function and displacements of the leftright 

vocal fold edges at specific anterior-medial-posterior 

locations. The 

approach also integrates our ‘Nyquist’ 

plot based waveform analysis (Yan et al., 

2005. J. Voice), which provides not only 

an at-a-glance assessment of the vibratory 

properties of 

the vocal fold (Figure 

1, bottom right) 

but a comprehensive 

and quantitative,high-resolution 

description of 

the vibratory 

properties of the 

vocal fold for 

diagnosing specific 

voice disorders 

and assessment of 

therapies. A related 

analysis has 

been described 

for acoustic signals 

(Yan et al, 

2006. J. Voice). 

These studies are 

advancing towards 

a better 

understanding of 

voicing and are 

currently under 

clinical evaluation for the differential 

diagnosis of voice disorders associated 

with neurological disease and the aging 

process. A near-term research goal is to 

develop a large, comprehensive and 

comparative database of dynamic characteristics 

of vocal folds derived from our 

image and acoustic-based analyses that 

will be used to correlate changes in the 

9



vibratory properties of the vocal fold 

with specific voice condition and pathologies. 

The database can be used for online 

clinical diagnoses and for training 

voice researchers, clinicians and medical 

students. 

Virtual Laryngoscopy 

Endoscopy is a routine, minimally invasive 

imaging technique for evaluating 

the three-dimensional (3D) features and 

properties of the inner surface of the 

larynx. We are extending principles and 

methods from Virtual Endoscopy (VE), to 

develop a virtual laryngoscope (VL) for 

non-invasive exploration of the laryngeal 

system for specific applications in medicine, 

medical education and surgery. The 

VL uses software to assemble data from 

diverse imaging techniques (e.g., CT and 

MRI) to reconstruct the internal anatomy 

in 3D. Computer rendering provides a 

continuous luminal view, within which 

one can navigate along inner surfaces, 

just as in conventional laryngoscopy 

(Figure 2). In addition, the VL can display 

a perspective global view in 3D and a 

view of the related CT and MRI slices for 

informative and interactive examination 

for diagnosis and treatment of disease. 

The VL offers several benefits over optical 

endoscopes that include both internal 

unconventional views and external 

anatomical views of the airway and the 

sub-glottal cavity in patients with infection, 

inflammation and neoplasia of the 

lumen. VL maybe especially useful for 

patients with stenosis, congenital defects 

or those unfit for general anesthesia. We 

are exploiting the advantages of the VL 

for applications in surgical examinations 

of sub-glottal cavity and diagnoses of 

laryngeal and airway diseases. 

Figure 2 – Conventional endoscopic view (left) and 

the virtual endoscopic view (right) of the vocal folds in 

a patient with laryngeal tumor. 

10 

RHINOLOGY RESEARCH AT THE 

STANFORD SINUS CENTER 

Peter H. Hwang, MD 

We are evaluating the role of retinoic 

acid in mucosal wound healing and ciliogenesis. 

The process of mucosal wound 

healing in the nose and paranasal sinuses 

is complex yet poorly understood. 

Retinoids have been shown to be important 

co-factors in regulating the differentiation 

and proliferation of ciliated 

epithelial cells of the respiratory tract. 

Using a rabbit model of sinus surgery, we 

are studying reciliation patterns of 

regenerated sinus mucosa after surgical 

demucosalization of the maxillary sinus. 

When evaluated by scanning electron 

microscopy, rabbits receiving topical 

retinoic acid showed greater density and 

uniformity of regenerated cilia compared 

to controls. We are also evaluating functional 

aspects of regenerated mucosa 

through studies of ciliary beat frequency 

and mucociliary transport times. In addition, 

we are pursuing quantitative analysis 

of marker proteins associated with ciliogenesis 

in this model of mucosal 

wound healing. 

5000x scanning electron 

micrographs show 

a) normal rabbit maxillary 

sinus mucosa 

b) regenerated mucosa 

without topical retinoic 

acid 

c) regenerated mucosa 

with topical retinoic 

acid. Retinoic acidtreated 

sinuses showed 

improved ciliary morphology, 

density, and 

orientation compared 

to controls. 

We are also actively engaged in a variety 

of clinical research topics. Among these 

include longitudinal outcomes of endoscopic 

sinus surgery for chronic rhinosinusitis; 

novel drug delivery technologies; 

efficacy of sublingual immunotherapy 

for seasonal allergic rhinitis; and histologic 

correlates of symptomatic improvement 

after endoscopic sinus surgery. 

AUDITORY FUNCTION IN THE 

DEVELOPING HUMAN NEONATE 

Gerald Popelka, PhD, David Stevenson, MD 

The overall research effort centers on 

increasing our understanding of auditory 

function in the developing human 

neonate. This effort is driven by the critical 

role audition plays in the normal 

development of language and speech 

and the need to optimize all interventions 

for pre-lingual hearing loss including 

hearing aids and cochlear implants. 

Human auditory development differs 

significantly from that of most other 

organisms necessitating innovative 

experiments be carried out directly on 

newborns in well baby, special care and 

intensive care nurseries. Measurement 

systems must be non-invasive, integrated, 

very small and insensitive to the 

many forms of ambient acoustic and 

electrical noise found in these environments, 

yet remain precise and repeatable. 

Under a series of carefully controlled 

experiments we recently showed 

that the auditory system undergoes systematic 

and repeatable neural maturation 

during the first two days after birth, 

both across subjects and in individual 

neonates. 

This effect clearly is associated with 

neural development at the level of the 

brainstem because the experimental 

approach allowed control of maturational 

effects associated with other auditory 

structures such as the external ear, 

the middle ear and the cochlea, nonauditory 

developmental factors such as 

birth weight, gestational age, and general 

health of the neonate, and a variety of 

exogenous variables such as exposure to 

maternal anesthetic at delivery. This early 

auditory neural maturation may be associated 

with apoptosis (programmed cell 

death) or dendritic pruning. Current 

research involves understanding the 

relationship between auditory function 

and exposure to bilirubin, a molecule 

that results from the normal catabolism

of maternal senescent red blood cells 

and a potential detriment to normal 

auditory development. Significant bilirubin 

exposure is experienced by 60% of 

well babies and much higher percentages 

in the remaining neonates. This 

molecule is known to permanently affect 

auditory function at extremely high 

exposures. However, its chronic or acute 

effects at lower exposures are largely 

unknown. 

Our experimental approach is to measure 

auditory function simultaneously 

with precise measures of bilirubin exposure 

at several points in time during the 

first few days after birth. A correlation of 

these two measures, after compensating 

for normal neural development, will 

establish the relation between auditory 

neural function and bilirubin exposure. 

Several related projects support these 

experiments. We are developing a lifesized 

neonatal hearing simulator that 

contains computers, electronics and 

transducers that can be programmed to 

simulate normal and impaired neonatal 

cochlear and auditory neural responses. 

This device will help us to understand 

the measurement process by determining 

the effects of known sources of 

acoustic and electrical noise and by 

investigating interactions among the 

various measures. We also are developing 

and incorporating measures of bilirubin 

production derived from measures of 

carbon monoxide concentration in the 

breath and measures of bilirubin accumulation 

derived from transcutaneous 

optical techniques. 

Future efforts will involve the development 

of improved non-invasive measures 

of bilirubin production and accumulation 

and improved auditory neural 

measures. Potentially useful clinical procedures 

resulting from this research 

include improvements in neonatal hearing 

screening achieved from simulatorbased 

training of nursery personnel, 

expansion of neonatal breath analysis to 

include other hemolytic conditions, 

improvements in non-invasive measures 

of bilirubin concentration, and the use of 

non-invasive auditory neural measures 

for early detection of impending toxic 

bilirubin exposure to improve intervention 

for hyperbilirubinemia 

OTOBIOMECHANICS GROUP 

Sunil Puria PhD, Charles Steele PhD, 

Richard L. Goode, MD 

The OtoBiomechanics Group at Stanford 

is developing three-dimensional and 

multiscale bio-computational models of 

the middle ear and the inner ear and 

their applications to understanding disease 

processes and interventions. 

Middle Ear Mechanics – Our goal is to 

understand the relationship between 

anatomical structures and physiological 

responses of the human middle ear. We 

combine dynamical measurements of 

the middle ear with advances in medical 

imaging of anatomical structures, and 

three-dimensional bio-computational 

modeling tailored to the anatomy and 

physiology of individual ears. This 

approach allows us to asses quantitatively 

the effect of the middle ear anatomy 

on sound transmission in the forward 

and reverse directions, from high-resolution 

microCT imaging based morphometry, 

tailored to the individual anatomy. 

Such an approach allows quantification 

of precise causes of conductive hearing 

loss due to damage, based on imaging 

data and computational biomechanics. It 

also allows the possibility to predict the 

outcome of a particular surgical plan to 

repair the damage, or reconstruct it with 

a passive or active prosthetic. 

Inner-ear Mechanics – Our plan is to 

build a three-dimensional and multiscale 

computational model of the human 

organ of Corti with associated vestibular 

canals and ducts on a mm scale, the 

hair cell soma on a um scale and hair cell 

tip links on a nm scale. This will be the 

first biomechanical model valid for both 

air and bone conducted sound, a vital 

distinction, because of its application to 

a broader scope of hearing health issues 

Fall 2006 

than with previous models. The computational 

framework will allow modification 

of structural parameters and provide the 

power to analyze resulting functions in a 

fast and efficient manner on a desktop 

computer. The bio-computational framework 

will be used to systematically understand 

a variety of inner ear pathologies. 

We also plan to integrate the cochlear 

model with the human middle ear 

model. Such a unified model can be used 

to better understand the generation and 

detection of otoacoustic emissions and 

how pathology of the organ of Corti can 

affect their clinical measurements in the 

ear canal. With our model, the mechanical 

etiology of inner ear disease and 

potential strategies for its repair can be 

explored systematically. An important 

future technology is the regeneration of 

cochlear sub structures through the 

introduction and differentiation of stem 

cells. The yet unknown mechanical consequences 

of these regeneration efforts 

on hearing also can be explored in the 

proposed biomechanical framework. 

The research being performed by the 

OtoBiomechanics Group at Stanford and 

funded in part by the NIDCD of NIH, are 

therefore the core foundation for multiple 

projects that are expected to fundamentally 

alter our understanding of middle 

and inner ear function, pathology 

and intervention. 

11



THE EVALUATION, MANAGE- 

MENT, AND PREVENTION 

OF CISPLATIN OTOTOXICITY IN 

PEDIATRIC PATIENTS. 

Kay Chang, MD 

Cisplatin is a commonly administered 

chemotherapeutic agent in multiple 

pediatric neoplasms. The ototoxicity of 

this agent is well-documented, though 

poorly characterized. Reports of ototoxicity 

rates in children vary from 1% to 82%. 

This disparity is due to extreme variability 

between institutions in the audiologic 

assessment of sick pediatric patients, as 

well as the lack of a well established and 

clinically validated classification for 

degrees of ototoxicity. The Common Terminology 

Criteria for Adverse Events 

(CTCAE v3.0) widely used by oncologists, 

fails to classify ototoxicity in a clinically 

consistent, or relevant manner. 

Due to a lack of a robust grading system 

for ototoxicity, it is difficult to design ototoxicity 

studies in patients that can be 

easily compared to other studies. I have 

developed a more clinically useful grading 

system for pediatric ototoxicity and 

have validated it to a large 5-year cohort 

of children treated by the Lucile Packard 

Children’s Hospital (LPCH) at Stanford 

Pediatric Oncology department. By examining 

details such as dose delivery schedule 

and co-administered drugs, a number 

of interesting revelations regarding optimal 

methods of reducing ototoxicity in 

children have been discovered, and will 

be presented at the next ASCO meeting. 

As an active member of the Children’s 

Oncology Group (COG), a national organization 

involved in improving the oncologic 

care of children, I have been intimately 

involved in the ototoxicity 

assessment of multiple large multi-institutional 

studies administered by COG 

12 

20 

15 

10 

5 

0 

dB 

-5 

-10 

-15 

-20 

-25 

Post-Treatment DPOAEs 

2000 2378 2828 3364 4000 4757 5657 6727 8000 9514 11314 13454 16000 

Hz 

(including the Intergroup Hepatoblastoma 

Study P9645 and the ARAR0331 

Nasopharyngeal Carcinoma Study). This 

grading system has been a valuable tool 

and has helped to improve methodologies 

for accurately assessing and characterizing 

ototoxic effects. This is particularly 

important since children seem to be 

much more susceptible to ototoxicity 

than adults. Furthermore, while the effects 

of ototoxicity may be quite limited in 

adults who have mastered speech and 

language, in pre-lingual young children, 

ototoxicity may result in severe speech 

delay and the inability to ever assume a 

normal role in society. So while the children 

may be cured of their cancer, they 

really never fully recover from their treatment 

to live normal unhindered lives. 

While accurately monitoring cisplatin 

ototoxicity may provide some insights 

into improved dosing strategies for 

reducing adverse effects in children, a 

more exciting approach is actual prevention 

of ototoxicity by administering various 

“otoprotective” agents. In the course 

of investigating the protective effect of 

the anti-oxidant N-acetylcysteine in the 

guinea pig cochlea, my laboratory discovered 

a novel otoprotective effect 

induced by the transtympanic administration 

of lactate to the middle ear. In 

this experiment, guinea pigs treated with 

cisplatin that were administered either 

lactated Ringer’s solution or N-acetylcysteine 

had significantly improved cochlear 

function, as measured by DPOAE, compared 

to the normal saline and negative 

control groups (see figure). Currently, 

with the collaboration the LPCH Pediatric 

Oncology department, standardized protocols 

utilizing my grading scale are 

being developed to investigate these as 

well as other otoprotective agents, including 

EPO and several gene therapy 

agents. Our goal is with these 

efforts is to eliminate this most 

devastating late-effect of chemotherapy 

in young children. 

Legend 

IR 

N-AC 

NS 

Control 

Mean post-treatment DPOAE data. Stimulus 

parameters were L2 = 55 dB and F2 ranging 

from 2 to 16 kHz. Error bars represent one 

SEM, and are plotted for the Control and LR 

groups; however they were comparable 

across all 4 groups (average SEM across frequencies 

measured 2.88, 3.27, 2.93, and 2.78 

for the 4 groups). The light dotted line at the 

bottom of the graph represents the average 

noise floor during emission recording. 

CLINICAL RESEARCH IN SLEEP 

SURGERY 

Richard L. Goode, MD, Jose E. Barrera, MD, 

Nelson Powell, MD, Robert Riley, MD 

The Division of sleep surgery aims to 

develop improved diagnostic methods 

in evaluating site of obstruction in sleep 

apnea patients. We are taking two 

approaches to improve our understanding 

of the anatomic reasons for collapse 

of the upper airway in obstructive sleep 

apnea. A protocol which is being coordinated 

with Dr. Gerald Popelka will utilize 

cine real-time MRI scanning of the upper 

airway in patients with sleep disordered 

breathing and normal volunteers, and 

correlate these findings with the endoscopic 

evaluation of patients before and 

after surgery. Electroencephalogram, 

actigraphy, and pulse oximetry data in 

combination with MRI images will be 

collected from patients with upper airway 

resistance syndrome, obstructive 

sleep apnea, and normal controls. We expect 

to be able to significantly improve 

our understanding of the anatomic reasons 

for a given patient’s obstructive 

symptoms, and thus improve clinical 

staging and surgical decision-making. 

Real time MRI scan 

Our second project aims to evaluate 

functional obstruction during sleep as a 

measure of pressure manometry. The use 

of a multi-site pressure probe tube that 

is worn during sleep will be utilized to 

determine the site of obstruction based 

on pressure changes across five transducers 

within the probe tube precisely 

located in the upper airway. We hope to 

characterize what causes multi-site 

obstruction and to what degree patients 

with with obstructive sleep apnea are 

affected.

EVIDENCE-BASED MEDICINE IN 

FACIAL PLASTIC SURGERY 

Sam P. Most, MD 

The primary goal of this research program 

is to develop a higher standard of 

care for facial plastic surgery patients. 

The approach to this goal is two-fold. The 

first involves development of prospective 

studies that examine the efficacy of 

new or existing surgical techniques in 

facial plastic surgery. One clinical problem 

we have already begun to examine 

is nasal obstruction. Functional rhinoplasty 

techniques have been a mainstay 

of otolaryngology, and facial plastic surgery 

in particular, for decades. While 

many have attempted, with mixed success, 

to examine nasal function using 

quantitative measures, few prospective 

studies of quality of life have been performed. 

To this end, we have begun to 

examine prospectively various functional 

rhinoplasty techniques. 

The second approach to development of 

a higher standard of care for our patients 

is the testing of various over-the-counter 

‘cosmeceutical’ products. Generally, products 

that are touted as effective by industry 

have little or no clinical evidence 

to back up said claims. Two of these 

studies have been completed and have 

resulted in remarkable response from 

industry as well as the media. More 

importantly, these types of studies provide 

valuable information about product 

efficacy to physicians and patients alike. 

Facial Nerve Recovery after Injury – 

Facial nerve injury after trauma or extirpative 

surgery can be devastating to 

patients. The Division seeks to develop a 

clinical and basic research program 

studying facial nerve recovery after such 

injuries. The basic research program 

within the Division will use a previously 

developed animal (mouse) model for 

facial nerve injury to examine the agedependence 

of motor neuron survival in 

the facial nucleus and its correlation to 

facial nerve recovery. Furthermore, the 

role of apoptotic cell death in the facial 

nerve nucleus will be studied, with the 

hope that anti-apoptotic processes may 

aid in facial nerve recovery. The clinical 

research program will study quality of 

life issues in facial nerve injury patients. 

Anterior septal reconstruction, a modified extracorporeal 

septoplasty technique. 

A) Murine facial nerve nucleus (outlined with arrowheads); 

B) Facial motor neurons stained with anti-bcl2 

antibody (arrows). 

Fall 2006 

CLINICAL RESEARCH IN 

LARYNGOLOGY 

Edward Damrose, MD and Yuling Yan, PHD 

The Division of Laryngology is currently 

performing research in several fields. 

Since the arrival of Dr. Yuling Yan, PhD, 

we have begun investigations into vocal 

fold vibration using high-speed digital 

imaging. High-speed digital imaging can 

capture motion at a rate of more than 

2000 frames per second, allowing the 

resolution of a single vibration of the 

vocal folds. Because pathological voicing 

represents the generation of an aperiodic 

signal, traditional laryngostroboscopy 

has been somewhat limited in allowing 

extensive analysis of the factors that 

cause abnormal voicing. Coupled with 

algorithms developed by Dr. Yan, highspeed 

imaging techniques can resolve 

the vibratory properties of an individual 

vocal cord through individual cycles, 

affording us insight into the mechanism 

of voice production that has never been 

possible before (Figure 1). 

Figure 1 – A single cycle of vocal fold vibration as seen 

by high-speed digital imaging. 

When multiple vibratory cycles are analyzed 

in regards to symmetry and regularity, 

a visual graphic of periodicity 

can be generated, called a Nyquist plot 

(Figure 2). 

With the incorporation of these new analytical 

tools into the armamentarium of 

the Stanford Voice Center, it is hoped 

that new insight may be provided into 

the causes and treatments of a variety of 

voice disorders. 

Our division is also partnering with the 

Departments of Electrical Engineering 

and Radiology to apply an experimental 

13

S T ANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY – HEAD & N ECK S URGERY 


Figure 2 – Generation of the Nyquist plot, an objective 

representation of normal vocal fold vibration. 

form of high-resolution MRI imaging for 

the detection of early invasive cancer of 

the vocal cords (Figure 3). High-resolution 

MRI scanning may allow images of 

the larynx at 8 to 10 times the resolution 

of standard MRI, and a clinical trial is currently 

underway to determine its role in 

predicting invasion of the cartilage by 

cancer. 

Earlier detection of advanced disease 

may afford higher rates of laryngeal conservation 

in the future. 

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

14 


OTOLOGY-NEUROTOLOGY 

Nikolas H. Blevins and Robert K. Jackler 

Planned Subtotal Resection and 

Stereotactic Radiotherapy for Acoustic 

Neuroma 

The advent of stereotactic radiosurgery 

has provided the clinician with a nonsurgical 

option to control the growth of 

acoustic tumors. With the development 

of the Cyberknife linear accelerator system, 

Stanford has long been a pioneer in 

the non-surgical management of skull 

base disease. Despite considerable experience 

with small acoustic tumors, the 

role of radiosurgery into the treatment 

of large tumors remains to be fully 

defined. The potentially synergistic effect 

of combined microsurgical resection and 

stereotactic radiotherapy could offer 

effective new options to individuals who 

remain at most risk given conventional 

treatment. 

The Stanford Department of Otolaryngology 

in collaboration with the departments 

of Neurosurgery and Radiation 

Oncology, is leading a prospective multicenter 

trial to assess the efficacy of managing 

large acoustic neuromas (over 3 

cm) with a combination of planned 

subtotal resection followed by stereotactic 

radiosurgery. Patients enrolled in the 

protocol will undergo planned subtotal 

resection avoiding potentially injurious 

dissection of the facial nerve from the 

tumor capsule. Patients will be followed 

with serial MRI scans, and will receive 

stereotactic radiation to the tumor remnant 

if growth is detected. 

The prospective nature of this study will 

provide valuable data towards establishing 

optimal treatment of advanced disease, 

while minimizing the risk of postoperative 

facial nerve dysfunction. 

Planned subtotal resection of an acoustic neuroma 

The Stanford Cyberknife. 

The Use of Stacked ABR for the 

Assessment of Hearing Preservation in 

Acoustic Neuroma Resection 

Patients with small acoustic neuromas 

and good hearing are faced with a 

choice of treatment options. Whether 

they choose to undergo microsurgical 

resection or stereotactic radiotherapy 

(such as with Cyberknife) can be largely 

influenced by the likelihood of hearing 

preservation. The short-term rates of 

hearing preservation with stereotactic 

radiation are excellent, but given the persistence 

of tumor and possible long-term 

neurovascular changes, hearing levels 

may deteriorate with time. Microsurgery 

in contrast, often places additional risks 

to hearing in the short term. However, 

the expectation for maintaining hearing 

that is present post-operatively is quite 

favorable. Unfortunately, there is a current 

lack of preoperative predictors of 

which patients are more likely to retain 

hearing through a surgical procedure. 

The Stanford Departments of Otolaryngology 

and Audiology are engaged in a 

prospective clinical trial to assess innovative 

of electrophysiologic testing to predict 

the success of hearing-preservation 

attempts. The study applies highly sensitive 

auditory brainstem response techniques 

(“stacked ABR”) that may be an 

accurate predictor of the potential for an 

involved cochlear nerve to withstand surgical 

manipulation and tumor extraction. 

The development of such non-invasive 

preoperative predictors will substantively 

assist with patient counseling and 

treatment planning in patients with 

acoustic neuromas. Given this additional 

information, patients and their clinicians 

may make better-informed decisions 

about the pursuit of treatment options.

Non-invasive Diagnosis of 

Cholesteatoma using High-Resolution 

Diffusion-Weighted MRI Sequences 

The Department of Otolaryngology, in 

conjunction with the Department of Radiology, 

is engaged in a prospective study 

to establish the efficacy of innovative MRI 

techniques in the diagnosis of cholesteatoma. 

Standard diffusion-weighted MRI is 

capable of detecting intratemporal squamous 

epithelium. However, it is suboptimal 

in its anatomic resolution and is 

subject to significant artifacts, both of 

which limit its clinical utility. 

Our protocol involves the use of new signal 

processing techniques (SENSE-DWI). 

The resulting improved images have the 

potential to make MRI clinically useful in 

treatment planning for patients with 

possible occult cholesteatoma. Patients 

in whom a second-look procedure is 

contemplated may benefit greatly from 

this non-invasive imaging modality. 

Innovations in Cochlear Implant 

Technology 

In 1964, the first human multichannel 

cochlear implant was placed at Stanford. 

The Department of Otolaryngology continues 

this long history of innovation in 

the development 

and 

application 

of inner ear 

prostheses. 

Related 

basic science 

projects 

include the 

application 

of stem-cells for inner ear regeneration, 

computational modeling of inner ear 

function, and inner ear microendoscopy 

for therapeutics and inner ear microrobotics. 

The LPCH/Stanford Cochlear Implant 

Center is actively involved in clinical trials 

for cochlear implants. We are a center 

for the clinical trial of the Nucleus Electrical-Acoustic 

Hybrid implant.These devices 

offer the potential benefits of cochlear 

implantation to the vast number of individuals 

who suffer from high frequency 

hearing loss, since residual acoustic hearing 

in the lower frequencies can be 

maintained. 


AUDIOLOGY 

Gerald Popelka, PhD 

Clinical research in Audiology complements 

the services that are provided and 

consequently covers both diagnostics 

and rehabilitation. All clinical audiology 

research is performed under strict IRB 

protocols with patients providing signed 

consents and receiving compensation in 

most cases and complete protection of 

patient privacy 

Our current auditory diagnostic research 

projects center around the development 

and improvement of clinical information 

derived from auditory evoked potentials. 

A new auditory evoked potential measure 

reported last year has the possibility 

of indicating whether cochlear fluid 

pressure is abnormally high. The measure 

is based on the theory that a prominent 

peak in the waveform of the auditory 

brainstem response will shift in 

latency (about 1 msec) with selective 

stimulation of different portions of the 

basilar membrane. This latency shift is 

due primarily to the normal stiffness gradient 

along the length of the basilar 

membrane. High fluid pressure such as 

that associated with endolymphatic 

hydrops is expected to eliminate this 

gradient stiffness and therefore eliminate 

the latency shift. Currently, several 

parametric variables are being investigated 

including electrode location, automated 

response quantification, methods 

for reducing electromyogenic artifacts, 

and other practical considerations before 

the method can be deemed reliable 

Fall 2006 

enough for routine clinical use. It is 

hoped that the improved procedure will 

provide a repeatable and useful indication 

of cochlear fluid pressure. 

Our current rehabilitative research projects 

center on the development of 

advanced digital signal processing that 

can be implemented with contemporary 

digital hearing aids. These advanced 

hearing aids now constitute over 90% of 

all hearing aids sold nationally and 100% 

of those dispensed in our clinic and continue 

to add new functionality such as 

incorporating cell phone capability. 

Current research projects involve both 

the development of new digital processing 

for improving speech understanding 

in noise and measuring and understanding 

the sources of alterations in other 

auditory tasks caused by the specific digital 

processing such as errors in locating 

sounds in the environment. We wish to 

make sure that an enhancement in one 

type of auditory performance, improved 

understanding in noise, eg, is not 

obtained at the expense of a detriment 

in another type of auditory performance, 

poor speech understanding through the 

internal cell phone function, eg. We also 

wish to determine if the particular digital 

processing interacts with the individual 

hearing status such that a particular processing 

may be beneficial for certain 

types of hearing impairment but detrimental 

for other 

types of hearing 

impairment. 

Patients with well 

documented hearing 

loss are 

recruited to listen 

to speech and 

other sounds 

processed digitally 

under highly-controlled 

conditions 

either in real time 

or with prerecordedrecordings. 

It is hoped 

that this systematic 

approach will result in an understanding 

of the optimal digital processing for 

individual patients allowing us to fulfill 

our goal of providing customized and 

optimized solutions for our hearing 

impaired patients. 

15

S TANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY – HEAD & N ECK S URGERY F ALL 2006 

C ONTINUING 

M EDICAL E DUCATION 

The Departments of Otolaryngology – 

Head & Neck Surgery and Neurosurgery, 

Stanford University School of Medicine 

and Stanford Hospital and Clinics 

present 

STANFORD COURSE IN 

CRANIAL BASE SURGERY: 

Minimally Invasive Approaches 

to Inaccessible Intracranial Lesions 

Friday and Saturday 

March 4th and 5th, 2005 

Clark Center Auditorium 

Stanford Campus 

2005 

To help support our mission to educate our colleagues, Stanford OHNS has developed a series of high quality CME courses. To 

enrich the curriculum, aside from Stanford faculty we invite nationally and internationally renowned guest instructors to teach 

in our programs. 

STANFORD OTOLARYNGOLOGY – HEAD & NECK SURGERY 

801 Welch Road, Palo Alto, CA 94304 

(650) 723-5281 (clinic) • (650) 725-6500 (academic) 

http://med.stanford.edu/ohns 

2006 

The Department of Otolaryngology – 

Head & Neck Surgery 

Stanford University School of Medicine 

presents 

STANFORD 

OTOLOGY 

& NEUROTOLOGY 

UPDATE 2006 

Stanford Court Hotel, San Francisco 

November 2-4, 2006 

S TANFORD O TOLARYNGOLOGY D EPARTMENT 2006

HEAD & NECK SURGERY - Stanford University School of Medicine

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