Faculty Bibliography

OBJECTIVE: To attempt to mitigate the effects of irradiation on murine skin after high-dose radiation using a novel transcutaneous topical delivery system to locally inhibit gene expression with small interfering RNA (siRNA) against Smad3. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: Twenty-five wild-type C57 mice. INTERVENTION: In an isolated skin irradiation model, the dorsal skin of C57 wild-type mice was irradiated (45 Gy). Just before irradiation, Smad3 and nonsense siRNA were applied to 2 separate dorsal skin areas and then reapplied weekly. Skin was harvested after 1 and 4 weeks. Smad3 expression were assessed by immunohistochemistry, and collagen deposition and architecture was examined using picrosirius red collagen staining. MAIN OUTCOME MEASURES: Epidermal thickness was measured semiquantitatively at 4 weeks. Radiation-induced fibrosis was measured quantitatively via tensiometry. The Young modulus, a measure of cutaneous rigidity inversely related to elasticity, was determined, with normal irradiated skin serving as a control specimen. RESULTS: Murine skin treated with topical Smad3 siRNA demonstrated effective Smad3 inhibition at 1 week and persistent suppression at 4 weeks. Collagen deposition and epidermal thickness were significantly decreased in skin treated with Smad3 siRNA compared with control irradiated skin. Tensiometry demonstrated decreased tension in Smad3 siRNA-treated skin, with a Young modulus of 9.29 MPa (nonirradiated normal skin, 7.78 MPa) compared with nonsense (control) siRNA-treated skin (14.68 MPa). CONCLUSIONS: Smad3 expression can be effectively silenced in vivo using a novel topical delivery system. Moreover, cutaneous Smad3 inhibition mitigates radiation-induced changes in tissue elasticity, restoring a near-normal phenotype

Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs

Early in life, neural circuits are highly susceptible to outside influences. The organization of the primary auditory cortex (A1) in particular is governed by acoustic experience during the critical period, an epoch near the beginning of postnatal development throughout which cortical synapses and networks are especially plastic. This neonatal sensitivity to the pattern of sensory inputs is believed to be essential for constructing stable and adequately adapted representations of the auditory world and for the acquisition of language skills by children. One important principle of synaptic organization in mature brains is the balance between excitation and inhibition, which controls receptive field structure and spatiotemporal flow of neural activity, but it is unknown how and when this excitatory-inhibitory balance is initially established and calibrated. Here we use whole-cell recording to determine the processes underlying the development of synaptic receptive fields in rat A1. We find that, immediately after the onset of hearing, sensory-evoked excitatory and inhibitory responses are equally strong, although inhibition is less stimulus-selective and mismatched with excitation. However, during the third week of postnatal development, excitation and inhibition become highly correlated. Patterned sensory stimulation drives coordinated synaptic changes across receptive fields, rapidly improves excitatory-inhibitory coupling and prevents further exposure-induced modifications. Thus, the pace of cortical synaptic receptive field development is set by progressive, experience-dependent refinement of intracortical inhibition

BACKGROUND: Xeroderma pigmentosum, an autosomal recessive disease that occurs with a frequency of 1:250,000, is caused by a genetic defect in nucleotide excision repair enzymes. Mutation of these enzymes leads to the development of multiple basal cell and squamous cell carcinomas. OBJECTIVES: We present a case of xeroderma pigmentosum in a patient with cervical and intraparotid metastatic disease from recurrent cutaneous squamous cell carcinomas of the face and scalp, treated with neck dissection and re-irradiation. With the illustrative case report, we include a literature review of diagnosis, prognostic factors, and treatment, with emphasis on surgical and radiation treatment of cervical metastatic disease from recurrent skin carcinomas. CASE PRESENTATION: A xeroderma pigmentosum patient presented to our clinic with a 2-cm right submental and 1-cm right infra-auricular mass after resection of multiple squamous cell carcinomas of the scalp and face, and external-beam radiation therapy to the right face and neck. Fine-needle aspiration biopsy of the submental mass revealed poorly differentiated squamous cell carcinoma. The patient was brought to the operating room for a right modified radical neck dissection and excision of the right submental and intraparotid mass. Surgical pathology revealed 3 level ia and supraclavicular lymph nodes that were positive for metastatic squamous cell carcinoma. Re-irradiation to the entire right hemi-neck and left submandibular nodal region was performed using opposed oblique portals for the upper neck and a low anterior en face hemi-neck portal. The left parotid region was also included in the re-irradiation volume. Treatment was completed without delayed complications or recurrences to date. CONCLUSIONS: To our knowledge, this is the first case report in the literature of a patient with xeroderma pigmentosum who subsequently developed metastatic disease from recurrent cutaneous squamous cell carcinoma. Because of the rarity of xeroderma pigmentosum, this case report is also the first to describe re-irradiation to treat cervical and intraparotid metastatic disease in a xeroderma pigmentosum patient

PURPOSE: Perineural invasion (PNI) in oral squamous cell carcinoma (SCC) is recognized as a significant predictor of outcome. PNI is associated with locoregional recurrence and decreased survival of patients with head and neck SCC. Nerve growth factor (NGF) has been shown to be involved in PNI in several malignancies, including breast, prostate, and pancreatic cancers. We investigated the hypothesis that NGF and its high-affinity receptor tyrosine kinase A (TrkA) are highly expressed in cases of oral SCC that have histologic evidence of PNI. MATERIALS AND METHODS: We performed immunohistochemistry on archived oral tongue SCC specimens from the established oral and general pathology databases at the University of California, San Francisco. The following groups were evaluated: 1) 21 T1/T2 oral tongue SCC cases with PNI and 2) 21 T1/T2 oral tongue SCC cases without histologic evidence of PNI. RESULTS: Strong homogeneous cytoplasmic staining for NGF and TrkA was detected in the malignant cells in the PNI-positive group of tumors. In group II (PNI negative) NGF and TrkA were detected in the stroma cells or were very weakly expressed by the malignant cells. We were able to show the presence of NGF and TrkA in the cytoplasm of malignant squamous cells in tumors with histologic evidence of PNI. Immunostaining for NGF (P = .0001) and TrkA (P = .039) was significantly higher in the PNI-positive oral SCC group than in the PNI-negative oral SCC group. CONCLUSION: This study shows that oral SCC with evidence of PNI shows increased expression of NGF and TrkA and suggests that NGF and TrkA are involved with the mechanism leading to PNI. Further investigations are warranted to determine the potential for use of NGF and TrkA as candidate biomarkers to predict progression and outcome

A retrospective study was conducted to assess outcomes of reconstruction of the oral cavity with the platysma myocutaneous flap, in terms of flap survival, complications, and quality of life. Included were 10 patients with squamous cell carcinoma (stage T1 to T4; nodal status N0 to N2) of the oral cavity who were treated between 2002 and 2006. Each patient underwent tumor resection, modified radical neck dissection, and primary reconstruction with a platysma myocutaneous flap. Operating time, length of stay, time to swallow, and complications were assessed, and the University of Washington Quality of Life questionnaire was administered. Mean operating time was <4 hours, mean length of stay was 11 days, and mean time to swallow was 9 days. One patient had distal flap necrosis and one had wound dehiscence. No total flap failures or fistulas occurred. The authors conclude that the platysma myocutaneous flap provides thin, pliable, reliable tissue for use in the oral cavity. The additional operating room time is negligible, the surgical complications minimal, and the overall quality of life very good. This flap should be used more frequently in the reconstruction of oral cavity defects

This case study presents a report of inflammatory pseudotumor of the inner ear in a child, discusses radiographic findings and clinical management, and reviews the current literature on this rare disease. A 2.5-year-old presented with otalgia, transient vertigo, and fluctuating facial palsy partially responsive to myringotomy with tube. Work-up for infectious and neoplastic processes was negative. Computed tomography (CT) of the temporal bone showed a very unusual, expansile, erosive appearance to the otic capsule, and magnetic resonance imaging of the temporal bone revealed soft tissue enhancement of the middle ear, mastoid, and inner ear. The patient's symptoms were transiently responsive to tympanomastoidectomy. Inner ear histopathology after labyrinthectomy revealed changes consistent with pseudotumor. Inflammatory pseudotumor of the inner ear is extremely rare but needs to be considered in cases of refractory otitis media with facial palsy, particularly when certain changes appear on CT of the temporal bone.

OBJECTIVE:The objectives of this study were to 1) evaluate anatomical relationships and 2) develop technical correlates for endoscopic anterior skull base (ASB) surgery. STUDY DESIGN/METHODS:Cadaver study. SETTING/METHODS:Minimally invasive surgery laboratory. SUBJECTS AND METHODS/METHODS:Ten adult fresh-frozen cadaver heads were dissected from December 2006 to December 2007. The endoscopic trans-cribriform, trans-ethmoid approach to the anterior cranial base was refined over these consecutive dissections. Endoscopic orientation along the ventral axis was assessed with 0 degrees , 30 degrees , and 70 degrees rigid telescopes. Anatomical dimensions of the ASB window were measured in the anteroposterior (posterior table of frontal sinus to planum sphenoidale) and transverse (orbit-to-orbit) dimensions at the anterior ethmoid artery (AEA) and posterior ethmoid artery (PEA). RESULTS:Endoscopic cadaveric dissections confirmed technical feasibility of ASB surgery and greatly enhanced understanding of ASB anatomical concepts. The 30 degrees rigid endoscope provided the most optimal view from the frontal sinus to the planum sphenoidale with the least distortion, relative to 0 degrees and 70 degrees scopes. Careful identification of the AEA and PEA was requisite for proper orientation at the ASB. The posterior one third of the ASB was thickest and always required drilling for resection. The mean boundaries of the ASB window were 33.7 mm (anterior to posterior) and 23.5 and 19.1 mm at the AEA and PEA (orbit to orbit), respectively. CONCLUSION/CONCLUSIONS:This prospective cadaveric study outlined key correlates for endoscopic ASB surgery. It serves to highlight the requisite technical steps and anatomical dimensions when the trans-nasal endoscopic route is employed for ASB pathology.