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									Stanford University Medical Center
Department of

                                                                                     Fall 2006

PROGRESS REPORT FROM THE CHAIR                 in proportion to our growing faculty. We    NEW FACILITIES
                                               are proud that our residents obtain a
                         Three years ago,                                                  The Department is undergoing an
                                               splendid experience in the broad spec-
                         Stanford awarded                                                  extraordinary improvement in its physi-
                                               trum of contemporary OHNS procedures
                         Otolaryngology –                                                  cal plant with all aspects of the educa-
                                               and have done very well in obtaining
                         Head & Neck                                                       tional, research, and administrative
                                               post-residency fellowship positions in a
                         Surgery status as                                                 programs transitioning to newly con-
                                               number of subspecialties.
                         an independent                                                    structed facilities. We are privileged to be
                         department and        We now offer seven post-residency fel-      one of the few OHNS departments to
                         provided it a         lowship programs – more than any other      have our own home building on a uni-
                         generous pack-        OHNS training program. These include:       versity campus – occupied after a $4 mil-
                         age of resources      facial plastic surgery, head & neck sur-    lion renovation in late 2004. This pro-
                         designed to           gery, pediatric OHNS, neurotology & skull   vides core facilities for our academic,
                         enable a period       base surgery, sinus surgery, sleep sur-     administrative, and educational pro-
Robert K. Jackler, MD,
Sewall Professor & Chair
                         of rapid expan-       gery, and laryngology (added in 2006).      grams and includes state-of-the-art
                         sion. The explicit    These programs not only provide advanc-     library-conference facilities (The Willard
mandate received from Dean Philip Pizzo        ed training for promising young acade-      E. Fee Jr., M.D. Library) and a superb 10
was to create world class clinical and         micians, but as junior faculty members      station educational microdissection lab-
translational research programs.               the fellows also enhance the residency      oratory (The Rodney Perkins, M.D. Micro-
                                               educational experience.                     surgical Laboratory). The building also
FACULTY GROWTH                                                                             houses some of our adult clinical pro-
Over the last few years we have rapidly                                                    grams (facial plastic surgery, laryngology,
grown from 6 to 16 faculty members (on           STANFORD OHNS:                            rhinology-sinus surgery, otology-neuro-
the way to at least 21). These include 6                                                   tology, the cochlear implant center, and
                                                 TRANSLATIONAL RESEARCH                    the audiology & hearing device program).
new division chiefs: Dr. Peter Koltai (Pedi-     PROGRAMS
atric OHNS), Dr Michael Kaplan (Head &                                                     Our Head & Neck Oncology programs are
Neck Oncology), Dr. Peter Hwang (Rhinol-         Regenerative Medicine                     housed in the magnificent new Stanford
ogy and Sinus Surgery), Dr. Samuel Most          • Developing stem cell therapy to         Cancer Center, in which OHNS has 3 fac-
(Facial Plastic Surgery), Dr. Edward Dam-          overcome deafness                       ulty offices, a suite of exam rooms, and a
rose (Laryngology), Dr. Gerald Popelka           • Elucidating the role of of stem cells   conference facility for Head & Neck Tumor
(Audiology & Hearing Devices). Dr. Niko-           in head & neck cancer                   Board. New clinical facilities for Pediatric
las Blevins joined me in the Otology                                                       Otolaryngology and Pediatric Audiology
                                                 • Regenerating ciliated mucosa in the     opened in October, 2004 (Mary L. John-
& Neurotology division and leads the               nose and paranasal sinuses
Stanford Cochlear Implant Program.                                                         son Pediatric Ambulatory Care Center)
                                                 • Tissue engineering                      close to the main OHNS facility.
World renowned inner ear stem cell biol-         Bioengineering
ogist Stefan Heller, PhD has joined us to                                                  The old outmoded OHNS facility will be
                                                 • Integration of the human ear and        gutted and rebuilt as a state-of-the-art
lead our Research Division along with              voice with digital devices
Anthony Ricci, PhD (hair cell biophysi-                                                    7000 sq ft research laboratory. This proj-
cist), Sunil Puria, PhD (mechanical engi-        • Biophysical properties of hair cells    ect, with a budget approaching $5 mil-
neer - middle ear mechanics), and Yuling         • Surgical simulation using 3D -          lion, will be completed in 2007. It has
Yan, PhD (electrical engineer – laryngeal          haptic enhanced simulators              been designed to include both core facil-
image analysis).                                 • Robotic microsurgery                    ities and a flexible layout, facilitating
                                                 • High speed laryngeal imaging            ease of adaptation as future research
EDUCATIONAL PROGRAMS                                                                       interests evolve.
                                                 • Virtual laryngoscopy                                           (continued on page 2)
Our extraordinarily talented group of            • Mechanics of sound transmission
residents has expanded from 15 in 2003             through the tympano-ossicular chain
(3 in each of 5 years) to 19 in 2006 as we       • Mathematical modeling of cochlear
gradually expand our training programs             function
                                                 • Microendoscopy of the inner ear
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

The research division of Stanford OHNS
is in the midst of rapid expansion. Stan-
ford has made a substantial investment
in new laboratory space, endowment,
and additional basic science faculty posi-
tions. 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: Regener-
ative Medicine and Bioengineering.
Stanford OHNS has come a long way in a
short 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 talented
individuals; abandoning antiquated facil-
ities for new ones triple their size; sizable
expansion of both residency and fellow-
ship programs; and development of
dynamic, cutting edge research pro-
grams. 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.”


                                                                                                                                    Fall 2006

O U R F A C U LT Y           (Fall 2006)

NIKOLAS H. BLEVINS, MD             EDWARD J. DAMROSE, MD                RICHARD L. GOODE, MD                   PETER H. HWANG , MD
Assistant Professor                Assistant Professor                  Professor                              Associate Professor
Otology & Neurotology              Chief of Laryngology Division        Sleep Surgery & Facial Plastic         Chief of Rhinology
College: Stanford University       College: Yale University             Surgery                                College: Stanford University
                                                                        Chief VA Service
Medical School: Harvard            Medical School: UCLA School of                                              Medical School: University of
University.                        Medicine                             College: University of California at   California at San Francisco
                                   Residency: University of             Santa Barbara, California              Residency: University of
Residency: University of
California at San Francisco        California at Los Angeles            Medical School: University of          California at San Francisco
                                   Fellowship: Laryngology/             Southern California                    Fellowship: Rhinology and Sinus
Fellowship: Neurotology/Skull
Base Surgery – University of       Bronchoesophagology –                Residency: Stanford University         Disorders, Hospital of the
California at San Francisco        University of California at Los      Fellowship: NIH Fellow –               University of Pennsylvania
Former Faculty Position: Tufts     Angeles                              Vestibular Physiology                  Former Faculty Position: Oregon
University (1995-2003)             Clinical Interests: Voice and        Clinical Interests: Facial plastic     Health & Science University
Clinical Interests: Otology,       swallowing disorders                 surgery, sleep surgery                 (1997-2005)
neurotology, skull base surgery,   Research Interests: High speed       Research Interests: Mechanics of       Clinical Interests: Endoscopic
cochlear implants                  laryngeal imaging, spasmodic         middle ear function, innovations       sinus surgery, endoscopic tumor
Research Interests: Surgical       dysphonia, rehabilitation of vocal   in sleep surgery                       and skull base surgery
simulation and robotics,           cord palsy                                                                  Research Interests: Mucosal wound
microendoscopy of the inner ear                                                                                healing, novel drug delivery
                                                                                                               technologies, clinical outcomes

KAY W. CHANG, MD                   WILLARD E. FEE, JR., MD              STEFAN HELLER, PHD                     ROBERT K. JACKLER, MD
Assistant Professor                Edward C. and Amy H. Sewall          Associate Professor                    Sewall Professor and Chair
Pediatric OHNS                     Professor                            Head of Research                       Otology & Neurotology
College: Brown University          Head & Neck Surgery                  M.S. Biology: Johannes                 College: Brandeis University
Medical School: Brown University   College: University of San           Gutenberg University, Mainz,           Medical School: Boston University
Residency: University of           Francisco                            Germany
                                                                                                               Residency: University of
Washington                         Medical School: University of        PhD Genetics: Johannes                 California at San Francisco
Fellowship: Pediatric              Colorado                             Gutenberg University, Mainz,
                                                                                                               Fellowship: Neurotology, House
Otolaryngology at the Children’s   Residency: University of             Germany
                                                                                                               Ear Clinic, Los Angeles, CA
Hospital of Pittsburgh             California, Los Angeles              and Max-Planck-Institute for
                                                                        Brain Research, Frankfurt/M.,          Former Faculty Position: UCSF
Clinical Interests: Pediatric      Clinical Interests: Tumors of the                                           (1986 - 2003)
                                   head and neck                        Germany
otology, Ear reconstruction                                                                                    Clinical Interests: Neurotology
                                   Research Interests: Clinical         Post-Doctoral Training: The
Research Interests: Pediatric                                           Rockefeller University, New York       and skull base surgery
hearing loss, cis-platinum         outcomes in head & neck cancer
                                                                        Former Faculty Position: Harvard       Research Interests: Innovation in
ototoxicity                                                                                                    skull base surgery, cholesteatoma
                                                                        University (2000-2005)
                                                                                                               pathogenesis, history of otology
                                                                        Research Interests: Hair cell
                                                                        regeneration to overcome
                                                                        deafness, structure and function
                                                                        of mechanosensitive ion channel

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

MICHAEL J. KAPLAN, MD                      ANNA H. MESSNER, MD                        SUNIL PURIA, PHD                    ANTHONY RICCI, PHD
Professor                                  Associate Professor                        Consulting Associate Professor      Associate Professor
Chief of Head & Neck Surgery               Pediatric OHNS                             Research                            Research
College: Harvard College                   Vice Chair                                 College: The City College of NY     College: Case Western Reserve
Medical School: Harvard Medical            College: Duke University                   MS: Columbia University             University
School                                     Medical School: Wake Forest                PhD: City University of NY          PhD: Neuroscience / Tulane
Residency: Massachusetts Eye               University                                 Postdoctoral Fellowships: MIT,      University
and Ear Infirmary                          Residency: Wake Forest                     Harvard                             Post-doctoral Fellowships: UTMB,
Fellowship: University of Virginia         University                                 Former Faculty Position: Harvard    University of Wisconsin
(Head & Neck Surgery)                      Fellowship: Pediatric OHNS,                (1995-1997)                         Former Faculty Position:
Former Faculty Position: UCSF              Hospital for Sick Children,                Research Interests: Biomechanics,   Louisiana State University (1999 -
(1984 - 2003)                              Toronto, Canada                            physiology, and imaging of the      2006)
Clinical Interests: Tumors of the          Clinical Interests: Pediatric OHNS         middle ear and the cochlea.         Research Interests: Hair cell
head and neck                              Research Interests: Neonatal                                                   biophysics
Research Interests: Clinical               hearing screening, ankyloglossia
outcomes for head and neck
malignancy, advanced imaging,
head & neck cancer stem cells

PETER J. KOLTAI, MD                        SAM MOST, MD                               GERALD R. POPELKA, PHD              YULING YAN, PHD
Professor                                  Associate Professor                        Consulting Professor                Consulting Assistant Professor
Chief of Pediatric OHNS                    Chief of Facial Plastic Surgery            Research                            Research
College: Queens College                    College: University of Michigan            Chief of Audiology
                                                                                                                          PhD: Mechanical Engineering/
Medical School: The Albany                 Medical School: Stanford                   College: Kent State University      Keio University, Yokohama, Japan
Medical College                            Residency: University of                   MA: Audiology/Kent State            Post-Doctoral Fellowship: McGill
Residency: University of Texas             Washington                                 University                          University
Medical Branch                             Fellowship: Facial Plastic Surgery         PhD: Communication Sciences/        Former Faculty Position:
Fellowship: Pediatric                      (U Washington)                             University of Wisconsin             University of Hawaii, U Wisconsin
Otolaryngology/Hospital for Sick           Former Faculty Position:                   Postdoctoral Fellowship:            Research Interests: High speed
Children at Great Ormond Street            University of Washington (2002 -           University of California at Los     laryngeal imaging
Former Faculty Position: Albany            2006),                                     Angeles
Med. (1982-1998), Cleveland                                                           Former Faculty Position:
                                           Clinical Interests: Aesthetic              Washington University (1980 -
Clinic (1998-2004)                         surgery of the face
Clinical Interests: Pediatric airway                                                  2004)
                                           Research Interests: Minimally              Clinical Interests: Advanced
obstruction, sleep apnea                   invasive improvement of the
Research Interests: Developing                                                        hearing devices, advanced
                                           aging face, facial nerve biology           measures of auditory function
new techniques in managing
sleep apnea                                                                           Research Interests: The
                                                                                      developing auditory system,

                                                                            Fall 2006


JOHN B. SHINN, MD                     KIMBERLY G. SHEPARD, MD
Clinical Professor                    Clinical Assistant Professor
Santa Clara Valley Medical Center     Santa Clara Valley Medical Center
College: University of North          College: UC San Diego
Carolina                              Medical School: Dartmouth
Medical School: University of         Residency: Stanford
North Carolina, Chapel Hill           Clinical Interests: Head & Neck
Residency: Stanford                   Oncology; Sleep apnea
Clinical Interests: Otology &         Research Interests: Non-surgical
Neurotology                           treatment of tonsillar hypertrophy,
                                      Medical management of post-
                                      operative pain

Clinical Associate Professor          Clinical Assistant Professor
Santa Clara Valley Medical Center     Santa Clara Valley Medical Center
College: Harvard                      College: UC Berkeley
Medical School: Boston University     Medical School: Georgetown
Residency: Stanford                   University
Clinical Interests: Pediatric OHNS,   Residency: Baylor
laryngology                           Clinical Interests: Head & neck
Research Interests: Ankyloglossia     cancer, trauma
                                      Research Interests: Functional
                                      outcomes after Head & Neck

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


CURING HEARING LOSS                                       in the inner ear epithelia. Hair cell                     THE THERAPEUTIC RELEVANCE
AND UNLOCKING THE SECRETS                                 replacement, either by stimulation of                     OF HAIR CELL BIOPHYSICS
OF HOW THE EAR WORKS                                      regeneration (as occurs naturally in non-
                                                                                                                    Anthony Ricci, PhD
                                                          mammalian vertebrates) or by transplan-
Stefan Heller, PhD
                                                          tation of progenitor cells capable of dif-                Hair cells are the sensory cells of the
All hearing sensation is derived from the                 ferentiating into hair cells, remains                     inner ear. They are responsible for con-
electrical output of a remarkably small                   therefore the ultimate goal in the devel-                 verting mechanical signals into one rec-
number of sensory cells: fewer that                       opment of treatment applications to                       ognized by the brain. Hair cells get their
15,000 per inner ear at birth. These hair                 reconstruct the damaged inner ear.                        name from having a tuft of hair-like cilia
cells are the mechanoelectrical transduc-                 Our recent work has focused on creating                   at their apical surface. Deflection of these
ers of the inner ear: deflections of the                  inner ear cell types, in particular hair cells            stereocilia opens mechanically-gated ion
sterociliary bundles on their apical sur-                 and auditory neurons, from a renewable                    channels that convert the mechanical
faces lead to transmitter release from                    source.                                                   signal into an electrical signal. This
their basolateral poles, leading, in turn, to                                                                       process, termed mechanotransduction is
signal generation in the peripheral axons                 We have shown that embryonic stem                         critical to both hearing and balance. Per-
of the auditory nerve fibers.                             (ES) cells and adult inner ear stem cells                 turbations of this system are associated
                                                                                can serve as such a                 with both temporary and permanent
                                                                                source, and we are                  hearing loss, with age-related and noise-
                                                                                currently exploring                 induced hearing loss and may even be
                                                                                signaling pathways                  associated with tinnitus and vertigo.
                                                                                that control hair cell              Understanding the mechanisms involved
                                                                                and neuronal (re-)                  in regulating mechanotransduction may
                                                                                generation in vitro                 elucidate new and novel sites for inter-
                                                                                and in vivo.                        vention. Characterizing these pathways
                                                                                          Our research does         might also lead to new technological
                                                                                          not only focus on         breakthroughs in hearing aid and
                                                                                          generating inner          cochlear implant development as well as
                                                                                          ear replacement           in the design of novel noise prevention
                                                                                          parts. We are also        devices. Over the past several years my
                                                                                          exploring novel           laboratory has identified several impor-
  The image shows integration and differentiation of inner ear progenitor cells de-       methods to deliver        tant attributes of mechanotransduction.
  rived from mouse embryonic stem cells after injection into the chicken’s develop- such replacement
  ing inner ear (otic vesicle). In (A), some of the injected cells, which are expressing
                                                                                                                    First, we have discovered a new process,
  the ß-Gal marker gene are found to integrate into the epithelium of the otic            parts into the dam-       called fast adaptation that is critical for
  vesicle (arrow). Shown in (B) and (C) are embryonic stem cell-derived cells found       aged cochlea or           establishing frequency discrimination, or
  3 days after injection (in green). These cells start expressing markers of hair cells,  whether it is possible    the ability of the ear to separate sound
  such as myosin VIIA (red) and appear to have integrated well into the chicken           to use drugs to coax      into its individual frequency compo-
  auditory epithelium where they are surrounded by endogenous chicken hair cells          cells of the adult
  (non green cells, labeled red). (D) and (E) show that the mouse cells, here visual-                               nents. Second, we demonstrated for the
  ized with a blue ß-Gal staining with developed hair bundles that are immuno-            damaged cochlea           first time, biochemical regulation of
  positive for the hair bundle marker protein espin.                                      into a prenatal status,   mechanotransduction. This pathway may
                                                                                          which could result        provide a new site for pharmacological
Most types of congenital and acquired                             in self-repair of the damaged mammal-             intervention in preventing noise-induced
hearing loss arise from damage to, or                             ian cochlea.                                      hearing loss. Third, we have recently
loss of, these sensory cells or their associ-                                                                       demonstrated the importance of
                                                                  In an independent line of research, we
ated neurons. The incidence of heritable                                                                            mechanotransduction in controlling the
                                                                  are pursuing the structural basis of hair
deafness is high: one child in a thousand                                                                           electrical properties of hair cells. As
                                                                  cell mechanoreception. Although the
is born deaf; another one in a thousand                                                                             mechanotransduction is very sensitive to
                                                                  individual molecular components of the
becomes deaf before adulthood. The                                                                                  its ionic environment, particularly the
                                                                  mechanoelectrical transduction appara-
prevalence of acquired hearing loss is ris-                                                                         concentration of calcium, the impor-
                                                                  tus are not known, we and other labora-
ing, as the population ages, and as noise
                                                                  tories have identified a number of                tance of maintaining low levels of calci-
pollution steadily increases. It is estimat-
                                                                  potential candidates. Our goal is to solve        um bathing the hair bundle has become
ed that one in three adults over the age
                                                                  the atomic structure of the different             more apparent. Characterizing the regu-
of 65 has a handicapping hearing loss,
                                                                  components of the transduction machin-            lation of extracellular calcium may pro-
and this impairment is largely due to the
                                                                  ery to study the molecular hinges and             vide a new pathway for intervention and
irreversible loss of sensory cells.
                                                                                         mechanisms that            may shed light on pathologies related to
Underlying the irreversibility of hearing                                                mechanically gate the      loss of ionic homeostasis within the ear.
loss in mammals is the incapacity to                                                     elusive ion channel        And finally we are involved in identifying
replace lost hair cells by cell division or                                              that is central to our     a mechanism associated with mechan-
by regeneration from endogenous cells                                                    senses of hearing and      otransduction and the hair bundle that

                                                                                                                                                    Fall 2006

may act to amplify low levels of sound                      INNER EAR FLUORESCENCE
and be a major contributor to determin-                     MICROENDOSCOPY
ing how the ear can be sensitive to such
                                                            Nikolas Blevins, MD, Mark Schnitzer, PhD,
low energy sound waves.
                                                            Eunice Cheung, PhD
Aside from converting a mechanical sig-
                                                            We are developing a method to visualize
nal into an electrical signal, the hair cell
                                                            functional hair cells and other cellular
must communicate with the brain
                                                            elements of the inner ear within the
through synaptic transmission. The hair
                                                            intact mammalian cochlea using fluores-
cell-afferent nerve synapse is very sensi-
                                                            cence microendoscopy. Our laboratory
tive to overstimulation where the nerve
                                                            has begun work on this minimally inva-
ending can swell and retract leading to
                                                            sive in vivo imaging technique to pro-
hair cell loss. My laboratory has been
                                                            vide high-resolution images of deep tis-
investigating the functional properties of
                                                            sues previously inaccessible in live
this synapse to identify the properties
                                                            subjects. Using microendoscopes as
that make it unique in its ability to oper-
                                                            small as 0.3 mm in diameter, we have
ate with such high fidelity and at such
                                                            successfully imaged individual red blood                 MIcroendoscope
high rates. Here too, the goal is to identi-
                                                            cells flowing within capillaries inside the              mammalian subjects will provide consid-
fy pathways and mechanisms that might
                                                            mammalian cochlea. We are extending                      erable benefit, and enable progress in a
offer sites for intervention and modifica-
                                                            this work by labeling functional neural                  broad range of previously intractable
                                                            elements with fluorescent dyes to con-                   hearing science questions. The success of
And finally, my laboratory is trying to                     currently reveal mechanotransduction as                  inner ear microendoscopy will provide a
determine whether hair cells require                        well as microanatomy.                                    basis on which inner ear surgery can be
extrinsic factors, like innervation,                                                                                 established. The inner ear is one of the
                                                            Current work includes microendoscopy
mechanical stimulation or growth factors                                                                             last areas of the human body to remain
                                                            using a styryl dye (FM-143) in the guinea
to mature into their final form. This is a                                                                           largely inaccessible to direct examina-
                                                            pig. It is anticipated that this will allow us
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

                                                            View of live cochlear hair cells from a microendoscope
                                                            to accurately map hair cell injury follow-               tion and surgical intervention. This is
                                                            ing ototoxin exposure, and to observe                    because of the combination of its small
                                                            the recovery of hair cells from temporary                size and its extraordinary fragility to
Isolated outer hair cell with sensory hair bundle (left).   threshold shift noise damage. The use                    mechanical manipulation. The develop-
Upper right is patch electrode on hair cell body to         of microendoscopes should provide an                     ment of non-destructive imaging tech-
measure electrical responses elicited by mechanically       opportunity to observe specific hair cell                niques will enable diagnostic and thera-
stimulating the sensory hair bundle (lower right).
                                                            populations over time – information                      peutic manipulations, including the
                                                            previously unavailable through conven-                   optimal placement of cochlear implant
                                                            tional techniques.                                       arrays, or the specific delivery of stem
                                                                                                                     cells or growth factors to enable hearing
                                                            An imaging technology to observe func-
                                                            tional hair cells and dendrites within live              restoration.

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


THE POSSIBLE ROLE OF STEM                                when to divide and when not to; in other                  remaining cells in the tumor do not
CELLS IN HEAD & NECK CANCER                              words cell-cell signaling pathways are                    share these properties. This population is
                                                         likely important. Stem cells (or their                    distinguished by a cell surface marker
Michael Kaplan, MD, Michael Clarke, MD,
                                                         immediate daughters) also must be able                    (CD44) that distinguishes these cells
Laurie Ailles, PHD Willard Fee, MD, Ranjiv
                                                         to migrate, both upward in the epitheli-                  from the other epithelial cells within the
Sivanidan, MD, Mark Prince, MD
                                                         um and in response to trauma. These                       tumor that lack clonogenicity.
Head and neck cancer affects 50,000                      three properties – avoiding apoptosis,
Americans annually and remains a dev-                    critical cell-cell signaling, and migration –             The identification of cancer stem cells in
astating world-wide killer. In India, for                are also key attributes of developmental                  HNSCC has important ramifications. Most
example, it is the leading cause of cancer               (embryonic, fetal) stem cells. An impor-                  basically, it lends further support to the
deaths. Cisplatin-based concomitant                      tant insight is that avoiding apoptosis                   general concept that a CSC model is true
chemotherapy and selected monoclonal                     and migration are also key characteris-                   for all cancers. Second, it suggests one
antibodies have improved locoregional                    tics of cancer cells; and aberrant cell-cell              possible reason why chemotherapy has
controls compared to irradiation alone,                  signaling pathways are beginning to be                    been disappointing is that the assay
but there has been little to no impact on                shown as well.                                            used clinically (and in some clonogenic
survival because of distant metastasis                                                                             assays) is overall tumor response, where-
                                                         A cancer stem cell hypothesis suggests                    as it is not overall but rather stem cell
and the therapy-resistant recurrences.
                                                         that cancer is a result of inadequately                   response that is key. Third, it suggests
Why has there been so little progress? Is
                                                         controlled proliferation of the stem cells                that characterizing selected key molecu-
it because we have not adequately
                                                         themselves, and not the heterogeneous                     lar pathways that are involved in self-
enough appreciated the underlying
                                                         mix of daughter cells. Such aberrant                      renewal, such as cell-cell signaling path-
tumor biology so as to develop more
                                                         growth would lead to subpopulations                       ways, should provide insights into
effective therapeutic approaches?
                                                         that contain a small percentage of                        specifically what is abnormally regulated.
                                                         daughter stem cells but many more                         Insights such as these hold promise for
                                                         committed differentiated cells that will                  the development of new treatment
                                                         undergo apoptosis in time. In other                       strategies targeted not against the
                                                         words, one should expect to see func-                     majority of tumor cells (which have limit-
                                                         tional heterogeneity, with only a small                   ed tumorigenicity) but against the criti-
                                                         fraction of cells harboring tumorigenic                   cal population of cancer stem cells that is
H&E and immunoperodixase staining of CD44 in             potential. This had been known in hema-                   the key culprit.
passaged cells growing as explant                        tological malignancies for 40 years, but
                                                         was shown in solid tumors (medulloblas-                   A fourth striking implication of validating
It has been understood for quite some                    toma, breast cancer) only in the past                     a CSC model is that one cannot help but
time that leukemias and lymphomas                        three years.                                              see the striking similarities between nor-
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, includ-
ing head and neck squamous cell carci-
nomas (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              Only CD44+ cells serially maintain clonogenicity.
                                                                                                                   mal embryonic development and normal
life cells in time undergo apoptosis (pro-               Working along similar lines using meth-                   stem cells and their dysregulation that is
grammed cell death). Squamous epitheli-                  ods employed to identify cancer stem                      cancer. This suggests that understanding
um is comprised of a basal layer of cells                cells in breast cancer, collaborating labo-               normal development should lead to
that contain some stem cells and overly-                 ratories at the University of Michigan                    insight into cancer, and vice versa. The
ing layers that contain daughter cells                   and at Stanford showed in 2006 (in                        cellular genetic control mechanisms
that die as they approach the surface.                   press) that this is also true for HNSCC.                  seen in normal development, stem cell
When stem cells divide they asymmetri-                                                                             regulation, and cancer are likely to be
                                                         HNSCC contains a distinct population of
cally give rise to both a committed                                                                                the same.
                                                         cancer stem cells with the exclusive abili-
daughter cell as well as another stem
                                                         ty to produce tumors in mice and recre-                   In the past decade an entirely new layer
cell. This stem cell must avoid pro-
                                                         ate the original tumor heterogeneity.                     of intranuclear genetic control has been
grammed cell death (apoptosis)
                                                         They are clonogenic in vitro (Fig 1) and                  identified-small RNAs regulate gene
throughout the organism’s lifetime.
                                                         initiate tumors in vivo (Fig 2), while the                expression by suppressing homologous
Under normal circumstances it also must
recognize its neighbors in order to know                                                                           or near-homologous DNA sequences.

                                                                                                                                            Fall 2006

These microRNAs (miRNA) are normal,            HIGH SPEED LARYNGEAL                                   Quantitative analysis of vocal fold
and derive from pre-miRNA genes within         IMAGING & THE VIRTUAL                                  dynamics using High Speed Digital
us, and the RNA-protein machinery all          LARYNGOSCOPE                                           Imaging (HSDI)
organisms use for this is being increas-
                                               Yuling Yan, PhD & Edward Damrose MD                    HSDI with simultaneously acquired acous-
ingly identified. MiRNA gene chips are
                                               The primary objective of our research                  tic recordings are being used to charac-
available, and abnormal quantities of
                                               program is to understand the mecha-                    terize vocal fold dynamics. We have
selected miRNAs have begun to be iden-
                                               nism of phonation for normal and for                   developed new methods and software
tified in a few malignancies. That miRNAs
                                               pathological voice conditions. We                      platforms to generate comprehensive,
are stable in paraffin will allow investiga-
                                               employ an interdisciplinary approach to                functional analysis of vocal fold vibra-
tion of archived material as well as easier
                                               these studies that borrows and inte-                   tions from HSDI and acoustic recordings.
investigation of fresh tumor-banked
material.                                      grates concepts and methodologies                           For example, our analytical platform that
                                               from bioengineering, biophysics, mathe-                     integrates automatic image segmenta-
The recognition of cancer stem cells in
                                               matical modeling and physiology.                            tion of the vocal folds and detection of
solid tumors, including head and neck
carcinomas, and the advances in DNA                                                                        vocal fold edge (Figure 1) with the gen-
                                               Functional Analysis and Modeling of                         eration of glottal waveforms that include
control by miRNAs suggest reasons for          Phonation in Normal and Diseased States the glottal area waveform, glottal width
optimism that fundamental insights will
lead to genetic therapies targeting can-       Vibration of the vocal folds is an essential function and displacements of the left-
cer stem cells in the future. Our lab, as      yet poorly understood event in human                        right vocal fold edges at specific anteri-
well as others, will investigate whether       voice production. An important aspect of or-medial-posterior locations. The
CD44 (a complex molecule, with multiple        our research program is to characterize                     approach also integrates our ‘Nyquist’
splice variants, that is involved in cell      the dynamic behavior of the vocal folds                     plot based waveform analysis (Yan et al.,
adhesion and mobility) is simply a mark-       during phonation – the ultimate goal for 2005. J. Voice), which provides not only
er for CSCs, or whether it plays an essen-     these studies is to understand the mech- an at-a-glance assessment of the vibrato-
tial function. More specific markers are                                                                                              ry properties of
likely to be found, which in aggregate                                                                                                the vocal fold (Fig-
will better identify the stem cell pool. As                                                                                           ure 1, bottom right)
identification of stem cells becomes                                                                                                  but a comprehen-
more precise, investigation of abnormal                                                                                               sive and quantita-
miRNAs will be a goal. As abnormalities                                                                                               tive, high-resolu-
in cell-cell signaling pathways become                                                                                                tion description of
better understood, it will be of interest to                                                                                          the vibratory
look at differences between tumors and                                                                                                properties of the
pre-malignant conditions such as dyspla-                                                                                              vocal fold for
sia and inverted papilloma, as well as the                                                                                            diagnosing specif-
differences in pathways associated with                                                                                               ic voice disorders
motility between primary tumors and                                                                                                   and assessment of
both nodal and distant metastases.                                                                                                    therapies. A relat-
                                                                                                                                      ed analysis has
In summary, the initial validation of can-                                                                                            been described
cer stem cells in head and neck carcino-                                                                                              for acoustic sig-
mas offers myriad opportunities both to                                                                                               nals (Yan et al,
understand the fundamental nature of                                                                                                  2006. J. Voice).
cancer and to develop stem cell targets                                                                                               These studies are
for genetic in the future.                                                                                                            advancing to-
                                                 Figure 1 – (Top) A montage of 10 image frames from an HSKI recording of a normal     wards a better
                                                 subject while producing a sustained vowel phonation; (Bottom) Spatially resolved
                                                 vocal fold vibration representing diplophonic voice, and Nyquist pattern showing the understanding of
                                                 bifurcation (transition from a normophonic [red] to a diplophonic phase [black]).    voicing and are
                                                                                                                                      currently under
                                               anism of phonation in terms of the gen-                     clinical evaluation for the differential
                                               eration and interaction of sound waves                      diagnosis of voice disorders associated
                                               in the vocal system; these studies will                     with neurological disease and the aging
                                               lead to the development of quantitative                     process. A near-term research goal is to
                                               biomechanical models of vocal fold                          develop a large, comprehensive and
                                               dynamics and acoustic interactions in                       comparative database of dynamic char-
                                               the vocal tract for the detection, diagno-                  acteristics of vocal folds derived from our
                                               sis and assessment of treatments for spe- image and acoustic-based analyses that
                                               cific voice disorders.                                      will be used to correlate changes in the

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


vibratory properties of the vocal fold                      RHINOLOGY RESEARCH AT THE                              AUDITORY FUNCTION IN THE
with specific voice condition and pathol-                   STANFORD SINUS CENTER                                  DEVELOPING HUMAN NEONATE
ogies. The database can be used for on-
                                                            Peter H. Hwang, MD                                     Gerald Popelka, PhD, David Stevenson, MD
line clinical diagnoses and for training
voice researchers, clinicians and medical                   We are evaluating the role of retinoic                 The overall research effort centers on
students.                                                   acid in mucosal wound healing and cilio-               increasing our understanding of auditory
                                                            genesis. The process of mucosal wound                  function in the developing human
Virtual Laryngoscopy                                        healing in the nose and paranasal sinus-               neonate. This effort is driven by the criti-
Endoscopy is a routine, minimally inva-                     es is complex yet poorly understood.                   cal role audition plays in the normal
sive imaging technique for evaluating                       Retinoids have been shown to be impor-                 development of language and speech
the three-dimensional (3D) features and                     tant co-factors in regulating the differen-            and the need to optimize all interven-
properties of the inner surface of the                      tiation and proliferation of ciliated                  tions for pre-lingual hearing loss includ-
larynx. We are extending principles and                     epithelial cells of the respiratory tract.             ing hearing aids and cochlear implants.
methods from Virtual Endoscopy (VE), to                     Using a rabbit model of sinus surgery, we
develop a virtual laryngoscope (VL) for                     are studying reciliation patterns of
non-invasive exploration of the laryngeal                   regenerated sinus mucosa after surgical
system for specific applications in medi-                   demucosalization of the maxillary sinus.
cine, medical education and surgery. The                    When evaluated by scanning electron
VL uses software to assemble data from                      microscopy, rabbits receiving topical
diverse imaging techniques (e.g., CT and                    retinoic acid showed greater density and
MRI) to reconstruct the internal anatomy                    uniformity of regenerated cilia compared
in 3D. Computer rendering provides a                        to controls. We are also evaluating func-              Human auditory development differs
continuous luminal view, within which                       tional aspects of regenerated mucosa                   significantly from that of most other
one can navigate along inner surfaces,                      through studies of ciliary beat frequency              organisms necessitating innovative
just as in conventional laryngoscopy                        and mucociliary transport times. In addi-              experiments be carried out directly on
(Figure 2). In addition, the VL can display                 tion, we are pursuing quantitative analy-              newborns in well baby, special care and
a perspective global view in 3D and a                       sis of marker proteins associated with cil-            intensive care nurseries. Measurement
view of the related CT and MRI slices for                   iogenesis in this model of mucosal                     systems must be non-invasive, integrat-
informative and interactive examination                     wound healing.                                         ed, very small and insensitive to the
for diagnosis and treatment of disease.                                                 5000x scanning elec-       many forms of ambient acoustic and
The VL offers several benefits over opti-                                               tron micrographs show      electrical noise found in these environ-
cal endoscopes that include both inter-                                                 a) normal rabbit maxil-    ments, yet remain precise and repeat-
nal unconventional views and external                                                   lary sinus mucosa          able. Under a series of carefully con-
anatomical views of the airway and the                                                                             trolled experiments we recently showed
sub-glottal cavity in patients with infec-                                                                         that the auditory system undergoes sys-
tion, inflammation and neoplasia of the                                                                            tematic and repeatable neural matura-
                                                                                        b) regenerated mucosa
lumen. VL maybe especially useful for                                                   without topical retinoic
                                                                                                                   tion during the first two days after birth,
patients with stenosis, congenital defects                                              acid                       both across subjects and in individual
or those unfit for general anesthesia. We                                                                          neonates.
are exploiting the advantages of the VL                                                                            This effect clearly is associated with
for applications in surgical examinations                                                                          neural development at the level of the
of sub-glottal cavity and diagnoses of                                                                             brainstem because the experimental
                                                                                        c) regenerated mucosa
laryngeal and airway diseases.                                                          with topical retinoic      approach allowed control of matura-
                                                                                        acid. Retinoic acid-       tional effects associated with other audi-
                                                                                        treated sinuses showed     tory structures such as the external ear,
                                                                                        improved ciliary mor-
                                                                                        phology, density, and      the middle ear and the cochlea, non-
                                                                                        orientation compared       auditory developmental factors such as
                                                                                        to controls.               birth weight, gestational age, and gener-
                                                            We are also actively engaged in a variety              al health of the neonate, and a variety of
                                                            of clinical research topics. Among these               exogenous variables such as exposure to
                                                            include longitudinal outcomes of endo-                 maternal anesthetic at delivery. This early
Figure 2 – Conventional endoscopic view (left) and                                                                 auditory neural maturation may be asso-
the virtual endoscopic view (right) of the vocal folds in   scopic sinus surgery for chronic rhinosi-
a patient with laryngeal tumor.                             nusitis; novel drug delivery technologies;             ciated with apoptosis (programmed cell
                                                            efficacy of sublingual immunotherapy                   death) or dendritic pruning. Current
                                                            for seasonal allergic rhinitis; and histo-             research involves understanding the
                                                            logic correlates of symptomatic improve-               relationship between auditory function
                                                            ment after endoscopic sinus surgery.                   and exposure to bilirubin, a molecule
                                                                                                                   that results from the normal catabolism

                                                                                                                           Fall 2006

of maternal senescent red blood cells          OTOBIOMECHANICS GROUP                        than with previous models. The computa-
and a potential detriment to normal                                                         tional framework will allow modification
                                               Sunil Puria PhD, Charles Steele PhD,
auditory development. Significant biliru-                                                   of structural parameters and provide the
                                               Richard L. Goode, MD
bin exposure is experienced by 60% of                                                       power to analyze resulting functions in a
well babies and much higher percent-           The OtoBiomechanics Group at Stanford        fast and efficient manner on a desktop
ages in the remaining neonates. This           is developing three-dimensional and          computer. The bio-computational frame-
molecule is known to permanently affect        multiscale bio-computational models of       work will be used to systematically under-
auditory function at extremely high            the middle ear and the inner ear and         stand a variety of inner ear pathologies.
exposures. However, its chronic or acute       their applications to understanding dis-
effects at lower exposures are largely         ease processes and interventions.
unknown.                                       Middle Ear Mechanics – Our goal is to
Our experimental approach is to meas-          understand the relationship between
ure auditory function simultaneously           anatomical structures and physiological
with precise measures of bilirubin expo-       responses of the human middle ear. We
sure at several points in time during the      combine dynamical measurements of
first few days after birth. A correlation of   the middle ear with advances in medical
these two measures, after compensating         imaging of anatomical structures, and
for normal neural development, will            three-dimensional bio-computational
establish the relation between auditory        modeling tailored to the anatomy and
neural function and bilirubin exposure.        physiology of individual ears. This
Several related projects support these         approach allows us to asses quantitative-
experiments. We are developing a life-         ly the effect of the middle ear anatomy
sized neonatal hearing simulator that          on sound transmission in the forward         We also plan to integrate the cochlear
contains computers, electronics and            and reverse directions, from high-resolu-    model with the human middle ear
transducers that can be programmed to          tion microCT imaging based morphome-         model. Such a unified model can be used
simulate normal and impaired neonatal          try, tailored to the individual anatomy.     to better understand the generation and
cochlear and auditory neural responses.        Such an approach allows quantification       detection of otoacoustic emissions and
This device will help us to understand         of precise causes of conductive hearing      how pathology of the organ of Corti can
the measurement process by determin-           loss due to damage, based on imaging         affect their clinical measurements in the
ing the effects of known sources of            data and computational biomechanics. It      ear canal. With our model, the mechani-
acoustic and electrical noise and by           also allows the possibility to predict the   cal etiology of inner ear disease and
investigating interactions among the           outcome of a particular surgical plan to     potential strategies for its repair can be
various measures. We also are develop-         repair the damage, or reconstruct it with    explored systematically. An important
ing and incorporating measures of biliru-      a passive or active prosthetic.              future technology is the regeneration of
bin production derived from measures of                                                     cochlear sub structures through the
carbon monoxide concentration in the                                                        introduction and differentiation of stem
breath and measures of bilirubin accu-                                                      cells. The yet unknown mechanical con-
mulation derived from transcutaneous                                                        sequences of these regeneration efforts
optical techniques.                                                                         on hearing also can be explored in the
                                                                                            proposed biomechanical framework.
Future efforts will involve the develop-
ment of improved non-invasive meas-                                                         The research being performed by the
ures of bilirubin production and accumu-                                                    OtoBiomechanics Group at Stanford and
lation and improved auditory neural                                                         funded in part by the NIDCD of NIH, are
measures. Potentially useful clinical pro-                                                  therefore the core foundation for multi-
cedures resulting from this research                                                        ple projects that are expected to funda-
include improvements in neonatal hear-                                                      mentally alter our understanding of mid-
ing screening achieved from simulator-                                                      dle and inner ear function, pathology
based training of nursery personnel,           Inner-ear Mechanics – Our plan is to         and intervention.
expansion of neonatal breath analysis to       build a three-dimensional and multiscale
include other hemolytic conditions,            computational model of the human
improvements in non-invasive measures          organ of Corti with associated vestibular
of bilirubin concentration, and the use of     canals and ducts on a mm scale, the
non-invasive auditory neural measures          hair cell soma on a um scale and hair cell
for early detection of impending toxic         tip links on a nm scale. This will be the
bilirubin exposure to improve interven-        first biomechanical model valid for both
tion for hyperbilirubinemia                    air and bone conducted sound, a vital
                                               distinction, because of its application to
                                               a broader scope of hearing health issues

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


THE EVALUATION, MANAGE-                                                        (including the Intergroup Hepatoblas-                         CLINICAL RESEARCH IN SLEEP
MENT, AND PREVENTION                                                           toma Study P9645 and the ARAR0331                             SURGERY
OF CISPLATIN OTOTOXICITY IN                                                    Nasopharyngeal Carcinoma Study). This                         Richard L. Goode, MD, Jose E. Barrera, MD,
PEDIATRIC PATIENTS.                                                            grading system has been a valuable tool                       Nelson Powell, MD, Robert Riley, MD
                                                                               and has helped to improve methodolo-
Kay Chang, MD                                                                                                                                The Division of sleep surgery aims to
                                                                               gies for accurately assessing and charac-
Cisplatin is a commonly administered                                           terizing ototoxic effects. This is particu-                   develop improved diagnostic methods
chemotherapeutic agent in multiple                                             larly important since children seem to be                     in evaluating site of obstruction in sleep
pediatric neoplasms. The ototoxicity of                                        much more susceptible to ototoxicity                          apnea patients. We are taking two
this agent is well-documented, though                                          than adults. Furthermore, while the effects                   approaches to improve our understand-
poorly characterized. Reports of ototoxic-                                     of ototoxicity may be quite limited in                        ing of the anatomic reasons for collapse
ity rates in children vary from 1% to 82%.                                     adults who have mastered speech and                           of the upper airway in obstructive sleep
This disparity is due to extreme variabili-                                    language, in pre-lingual young children,                      apnea. A protocol which is being coordi-
ty between institutions in the audiologic                                      ototoxicity may result in severe speech                       nated with Dr. Gerald Popelka will utilize
assessment of sick pediatric patients, as                                      delay and the inability to ever assume a                      cine real-time MRI scanning of the upper
well as the lack of a well established and                                     normal role in society. So while the chil-                    airway in patients with sleep disordered
clinically validated classification for                                        dren may be cured of their cancer, they                       breathing and normal volunteers, and
degrees of ototoxicity. The Common Ter-                                        really never fully recover from their treat-                  correlate these findings with the endo-
minology Criteria for Adverse Events                                           ment to live normal unhindered lives.                         scopic evaluation of patients before and
(CTCAE v3.0) widely used by oncologists,                                                                                                     after surgery. Electroencephalogram,
fails to classify ototoxicity in a clinically                                  While accurately monitoring cisplatin
                                                                               ototoxicity may provide some insights                         actigraphy, and pulse oximetry data in
consistent, or relevant manner.                                                                                                              combination with MRI images will be
                                                                               into improved dosing strategies for
Due to a lack of a robust grading system                                       reducing adverse effects in children, a                       collected from patients with upper air-
for ototoxicity, it is difficult to design oto-                                more exciting approach is actual preven-                      way resistance syndrome, obstructive
toxicity studies in patients that can be                                       tion of ototoxicity by administering vari-                    sleep apnea, and normal controls. We ex-
easily compared to other studies. I have                                       ous “otoprotective” agents. In the course                     pect to be able to significantly improve
developed a more clinically useful grad-                                       of investigating the protective effect of                     our understanding of the anatomic rea-
ing system for pediatric ototoxicity and                                       the anti-oxidant N-acetylcysteine in the                      sons for a given patient’s obstructive
have validated it to a large 5-year cohort                                     guinea pig cochlea, my laboratory dis-                        symptoms, and thus improve clinical
of children treated by the Lucile Packard                                      covered a novel otoprotective effect                          staging and surgical decision-making.
Children’s Hospital (LPCH) at Stanford                                         induced by the transtympanic adminis-
Pediatric Oncology department. By exam-                                        tration of lactate to the middle ear. In
ining details such as dose delivery sched-                                     this experiment, guinea pigs treated with
ule and co-administered drugs, a number                                        cisplatin that were administered either
of interesting revelations regarding opti-                                     lactated Ringer’s solution or N-acetylcys-
mal methods of reducing ototoxicity in                                         teine had significantly improved cochlear
children have been discovered, and will                                        function, as measured by DPOAE, com-
be presented at the next ASCO meeting.                                         pared to the normal saline and negative
As an active member of the Children’s                                          control groups (see figure). Currently,
Oncology Group (COG), a national organ-                                        with the collaboration the LPCH Pediatric
ization involved in improving the onco-                                        Oncology department, standardized pro-
logic care of children, I have been inti-                                      tocols utilizing my grading scale are
mately involved in the ototoxicity                                             being developed to investigate these as
assessment of multiple large multi-insti-                                      well as other otoprotective agents, in-                       Real time MRI scan
tutional studies administered by COG                                           cluding EPO and several gene therapy                          Our second project aims to evaluate
                                                                                       agents. Our goal is with these                        functional obstruction during sleep as a
                  Post-Treatment DPOAEs                                                efforts is to eliminate this most                     measure of pressure manometry. The use
  15                                                                                   devastating late-effect of chemo-                     of a multi-site pressure probe tube that
  10                                                                                   therapy in young children.                            is worn during sleep will be utilized to
     5                                                                         Legend      Mean post-treatment DPOAE data. Stimulus          determine the site of obstruction based
                                                                                 IR        parameters were L2 = 55 dB and F2 ranging         on pressure changes across five trans-
     0                                                                           N-AC      from 2 to 16 kHz. Error bars represent one
dB                                                                               NS        SEM, and are plotted for the Control and LR       ducers within the probe tube precisely
                                                                                 Control   groups; however they were comparable              located in the upper airway. We hope to
  -10                                                                                      across all 4 groups (average SEM across fre-      characterize what causes multi-site
                                                                                           quencies measured 2.88, 3.27, 2.93, and 2.78      obstruction and to what degree patients
  -15                                                                                      for the 4 groups). The light dotted line at the
                                                                                           bottom of the graph represents the average        with with obstructive sleep apnea are
                                                                                           noise floor during emission recording.            affected.
         2000 2378 2828 3364 4000 4757 5657 6727 8000 9514 11314 13454 16000

                                                                                                                                                  Fall 2006

EVIDENCE-BASED MEDICINE IN                                                                              CLINICAL RESEARCH IN
FACIAL PLASTIC SURGERY                                                                                  LARYNGOLOGY
Sam P. Most, MD                                                                                         Edward Damrose, MD and Yuling Yan, PHD
The primary goal of this research pro-                                                                  The Division of Laryngology is currently
gram is to develop a higher standard of                                                                 performing research in several fields.
care for facial plastic surgery patients.                                                               Since the arrival of Dr. Yuling Yan, PhD,
The approach to this goal is two-fold. The                                                              we have begun investigations into vocal
first involves development of prospec-                                                                  fold vibration using high-speed digital
tive studies that examine the efficacy of                                                               imaging. High-speed digital imaging can
new or existing surgical techniques in                                                                  capture motion at a rate of more than
facial plastic surgery. One clinical prob-                                                              2000 frames per second, allowing the
lem we have already begun to examine                                                                    resolution of a single vibration of the
is nasal obstruction. Functional rhino-                                                                 vocal folds. Because pathological voicing
                                               Anterior septal reconstruction, a modified extracorpo-
plasty techniques have been a mainstay         real septoplasty technique.
                                                                                                        represents the generation of an aperiod-
of otolaryngology, and facial plastic sur-                                                              ic signal, traditional laryngostroboscopy
gery in particular, for decades. While                                                                  has been somewhat limited in allowing
many have attempted, with mixed suc-                                                                    extensive analysis of the factors that
cess, to examine nasal function using                                                                   cause abnormal voicing. Coupled with
quantitative measures, few prospective                                                                  algorithms developed by Dr. Yan, high-
studies of quality of life have been per-                                                               speed imaging techniques can resolve
formed. To this end, we have begun to                                                                   the vibratory properties of an individual
examine prospectively various functional                                                                vocal cord through individual cycles,
rhinoplasty techniques.                                                                                 affording us insight into the mechanism
                                                                                                        of voice production that has never been
The second approach to development of
                                                                                                        possible before (Figure 1).
a higher standard of care for our patients
is 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 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 pro-
vide valuable information about product
efficacy to physicians and patients alike.
Facial Nerve Recovery after Injury –
Facial nerve injury after trauma or extir-
pative surgery can be devastating to                                                                    Figure 1 – A single cycle of vocal fold vibration as seen
patients. The Division seeks to develop a                                                               by high-speed digital imaging.
clinical and basic research program
studying facial nerve recovery after such                                                               When multiple vibratory cycles are ana-
injuries. The basic research program                                                                    lyzed in regards to symmetry and regu-
within the Division will use a previously                                                               larity, a visual graphic of periodicity
                                               A) Murine facial nerve nucleus (outlined with arrow-     can be generated, called a Nyquist plot
developed animal (mouse) model for             heads); B) Facial motor neurons stained with anti-bcl2
facial nerve injury to examine the age-                                                                 (Figure 2).
                                               antibody (arrows).
dependence of motor neuron survival in                                                                  With the incorporation of these new ana-
the facial nucleus and its correlation to                                                               lytical tools into the armamentarium of
facial nerve recovery. Furthermore, the                                                                 the Stanford Voice Center, it is hoped
role of apoptotic cell death in the facial                                                              that new insight may be provided into
nerve nucleus will be studied, with the                                                                 the causes and treatments of a variety of
hope that anti-apoptotic processes may                                                                  voice disorders.
aid in facial nerve recovery. The clinical
research program will study quality of                                                                  Our division is also partnering with the
life issues in facial nerve injury patients.                                                            Departments of Electrical Engineering
                                                                                                        and Radiology to apply an experimental

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


                                                          CLINICAL RESEARCH IN
                                                          Nikolas H. Blevins and Robert K. Jackler
                                                          Planned Subtotal Resection and
                                                          Stereotactic Radiotherapy for Acoustic
                                                          The advent of stereotactic radiosurgery
                                                          has provided the clinician with a non-
                                                          surgical option to control the growth of
                                                          acoustic tumors. With the development
                                                          of the Cyberknife linear accelerator sys-
                                                          tem, Stanford has long been a pioneer in                The Stanford Cyberknife.
                                                          the non-surgical management of skull
                                                          base disease. Despite considerable expe-                The Use of Stacked ABR for the
Figure 2 – Generation of the Nyquist plot, an objective
representation of normal vocal fold vibration.            rience with small acoustic tumors, the                  Assessment of Hearing Preservation in
                                                          role of radiosurgery into the treatment                 Acoustic Neuroma Resection
form of high-resolution MRI imaging for
                                                          of large tumors remains to be fully                     Patients with small acoustic neuromas
the detection of early invasive cancer of
                                                          defined. The potentially synergistic effect             and good hearing are faced with a
the vocal cords (Figure 3). High-resolu-
                                                          of combined microsurgical resection and                 choice of treatment options. Whether
tion MRI scanning may allow images of
                                                          stereotactic radiotherapy could offer                   they choose to undergo microsurgical
the larynx at 8 to 10 times the resolution
                                                          effective new options to individuals who                resection or stereotactic radiotherapy
of standard MRI, and a clinical trial is cur-
                                                          remain at most risk given conventional                  (such as with Cyberknife) can be largely
rently underway to determine its role in
                                                          treatment.                                              influenced by the likelihood of hearing
predicting invasion of the cartilage by
cancer.                                                   The Stanford Department of Otolaryn-                    preservation. The short-term rates of
                                                          gology in collaboration with the depart-                hearing preservation with stereotactic
Earlier detection of advanced disease                                                                             radiation are excellent, but given the per-
                                                          ments of Neurosurgery and Radiation
may afford higher rates of laryngeal con-                                                                         sistence of tumor and possible long-term
                                                          Oncology, is leading a prospective multi-
servation in the future.                                                                                          neurovascular changes, hearing levels
                                                          center trial to assess the efficacy of man-
                                                          aging large acoustic neuromas (over 3                   may deteriorate with time. Microsurgery
                                                          cm) with a combination of planned                       in contrast, often places additional risks
                                                          subtotal resection followed by stereotac-               to hearing in the short term. However,
                                                          tic radiosurgery. Patients enrolled in the              the expectation for maintaining hearing
                                                          protocol will undergo planned subtotal                  that is present post-operatively is quite
                                                          resection avoiding potentially injurious                favorable. Unfortunately, there is a cur-
                                                          dissection of the facial nerve from the                 rent lack of preoperative predictors of
                                                          tumor capsule. Patients will be followed                which patients are more likely to retain
                                                          with serial MRI scans, and will receive                 hearing through a surgical procedure.
                                                          stereotactic radiation to the tumor rem-                The Stanford Departments of Otolaryn-
                                                          nant if growth is detected.                             gology and Audiology are engaged in a
                                                          The prospective nature of this study will               prospective clinical trial to assess innova-
                                                          provide valuable data towards establish-                tive of electrophysiologic testing to pre-
                                                          ing optimal treatment of advanced dis-                  dict the success of hearing-preservation
                                                          ease, while minimizing the risk of post-                attempts. The study applies highly sensi-
Figure 3 – High-resolution MRI of the human larynx.                                                               tive auditory brainstem response tech-
                                                          operative facial nerve dysfunction.
                                                                                                                  niques (“stacked ABR”) that may be an
                                                                                                                  accurate predictor of the potential for an
                                                                                                                  involved cochlear nerve to withstand sur-
                                                                                                                  gical manipulation and tumor extraction.
                                                                                                                  The development of such non-invasive
                                                                                                                  preoperative predictors will substantive-
                                                                                                                  ly assist with patient counseling and
                                                                                                                  treatment planning in patients with
                                                                                                                  acoustic neuromas. Given this additional
                                                          Planned subtotal resection of an acoustic neuroma
                                                                                                                  information, patients and their clinicians
                                                                                                                  may make better-informed decisions
                                                                                                                  about the pursuit of treatment options.

                                                                                                                              Fall 2006

Non-invasive Diagnosis of                        CLINICAL RESEARCH IN                         enough for routine clinical use. It is
Cholesteatoma using High-Resolution              AUDIOLOGY                                    hoped that the improved procedure will
Diffusion-Weighted MRI Sequences                                                              provide a repeatable and useful indica-
                                                 Gerald Popelka, PhD
                                                                                              tion of cochlear fluid pressure.
The Department of Otolaryngology, in
                                                 Clinical research in Audiology comple-
conjunction with the Department of Radi-                                                      Our current rehabilitative research proj-
                                                 ments the services that are provided and
ology, is engaged in a prospective study                                                      ects center on the development of
                                                 consequently covers both diagnostics
to establish the efficacy of innovative MRI                                                   advanced digital signal processing that
                                                 and rehabilitation. All clinical audiology
techniques in the diagnosis of cholestea-                                                     can be implemented with contemporary
                                                 research is performed under strict IRB
toma. Standard diffusion-weighted MRI is                                                      digital hearing aids. These advanced
                                                 protocols with patients providing signed
capable of detecting intratemporal squa-                                                      hearing aids now constitute over 90% of
                                                 consents and receiving compensation in
mous epithelium. However, it is subopti-                                                      all hearing aids sold nationally and 100%
                                                 most cases and complete protection of
mal in its anatomic resolution and is                                                         of those dispensed in our clinic and con-
                                                 patient privacy
subject to significant artifacts, both of                                                     tinue to add new functionality such as
which limit its clinical utility.                                                             incorporating cell phone capability.
Our protocol involves the use of new sig-                                                     Current research projects involve both
nal processing techniques (SENSE-DWI).                                                        the development of new digital process-
The resulting improved images have the                                                        ing for improving speech understanding
potential to make MRI clinically useful in                                                    in noise and measuring and understand-
treatment planning for patients with                                                          ing the sources of alterations in other
possible occult cholesteatoma. Patients                                                       auditory tasks caused by the specific dig-
in whom a second-look procedure is                                                            ital processing such as errors in locating
contemplated may benefit greatly from                                                         sounds in the environment. We wish to
this non-invasive imaging modality.                                                           make sure that an enhancement in one
                                                                                              type of auditory performance, improved
Innovations in Cochlear Implant
                                                                                              understanding in noise, eg, is not
                                                                                              obtained at the expense of a detriment
In 1964, the first human multichannel                                                         in another type of auditory performance,
cochlear implant was placed at Stanford.                                                      poor speech understanding through the
The Department of Otolaryngology con-                                                         internal cell phone function, eg. We also
tinues this long history of innovation in                                                     wish to determine if the particular digital
                              the develop-                                                    processing interacts with the individual
                                                  Our current auditory diagnostic research
                              ment and                                                        hearing status such that a particular pro-
                                                 projects center around the development
                              application                                                     cessing may be beneficial for certain
                                                 and improvement of clinical information
                              of inner ear                                                    types of hearing impairment but detri-
                                                 derived from auditory evoked potentials.
                              prostheses.                                                                             mental for other
                                                 A new auditory evoked potential meas-
                              Related                                                                                 types of hearing
                                                 ure reported last year has the possibility
                              basic science                                                                           impairment.
                                                 of indicating whether cochlear fluid
                              projects                                                                                Patients with well
                                                 pressure is abnormally high. The meas-
                              include the                                                                             documented hear-
                                                 ure is based on the theory that a promi-
                              application                                                                             ing loss are
                                                 nent peak in the waveform of the audito-
of stem-cells for inner ear regeneration,                                                                             recruited to listen
                                                 ry brainstem response will shift in
computational modeling of inner ear                                                                                   to speech and
                                                 latency (about 1 msec) with selective
function, and inner ear microendoscopy                                                                                other sounds
                                                 stimulation of different portions of the
for therapeutics and inner ear microro-                                                                               processed digitally
                                                 basilar membrane. This latency shift is
botics.                                                                                                               under highly-con-
                                                 due primarily to the normal stiffness gra-
The LPCH/Stanford Cochlear Implant                                                                                    trolled conditions
                                                 dient along the length of the basilar
Center is actively involved in clinical tri-                                                                          either in real time
                                                 membrane. High fluid pressure such as
als for cochlear implants. We are a center                                                                            or with pre-
                                                 that associated with endolymphatic
for the clinical trial of the Nucleus Electri-                                                                        recorded record-
                                                 hydrops is expected to eliminate this
cal-Acoustic Hybrid implant.These devices                                                                             ings. It is hoped
                                                 gradient stiffness and therefore elimi-
offer the potential benefits of cochlear                                                                              that this systemat-
                                                 nate the latency shift. Currently, several
implantation to the vast number of indi-                                                      ic approach will result in an understand-
                                                 parametric variables are being investi-
viduals who suffer from high frequency                                                        ing of the optimal digital processing for
                                                 gated including electrode location, auto-
hearing loss, since residual acoustic hear-                                                   individual patients allowing us to fulfill
                                                 mated response quantification, methods
ing in the lower frequencies can be                                                           our goal of providing customized and
                                                 for reducing electromyogenic artifacts,
maintained.                                                                                   optimized solutions for our hearing
                                                 and other practical considerations before
                                                                                              impaired patients.
                                                 the method can be deemed reliable

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             FALL 2006



                                  The Departments of Otolaryngology –
                                                                                           The Department of Otolaryngology –
                                  Head & Neck Surgery and Neurosurgery,
                                                                                           Head & Neck Surgery
                                  Stanford University School of Medicine
                                                                                           Stanford University School of Medicine
                                  and Stanford Hospital and Clinics
                                  STANFORD COURSE IN                                       OTOLOGY
                                  CRANIAL BASE SURGERY:                                    & NEUROTOLOGY
                                  Minimally Invasive Approaches                            UPDATE 2006
                                  to Inaccessible Intracranial Lesions                     Stanford Court Hotel, San Francisco
                                                                                           November 2-4, 2006
                                  Friday and Saturday
                                  March 4th and 5th, 2005

                                  Clark Center Auditorium
                                  Stanford Campus

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.

S TA N F O R D O T O L A R Y N G O L O G Y D E PA R T M E N T 2 0 0 6

801 Welch Road, Palo Alto, CA 94304
(650) 723-5281 (clinic) • (650) 725-6500 (academic)

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