Articles and Abstracts by Dr. Doherty

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Exostoses and osteomas are benign bony lesions of the auditory canal. Although common in the external auditory canal, they are rare and difficult to distinguish in the internal auditory canal (IAC). In this literature review and case presentation, we define radiologic and histologic criteria to differentiate exostoses from osteomas of the IAC.

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Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways.

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We have demonstrated that ERa expression in VS is equivalent to GAN. The phosphorylated form of the receptor is up-regulated compared with GAN, however, indicating a higher level of ERa activation in sporadic VS compared with normal nerve.

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The expression of PDGFR-Q and c-Kit in VS tissue may indicate novel molecular targets involved in the development of this tumor. Direct inhibition of these molecules by Gleevec may have relevant therapeutic applications.

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Merlin depletion results in deregulation of ErbB receptor signaling, promotes a dedifferentiated state, and increases Schwann cell proliferation, suggesting critical steps toward schwannoma tumorigenesis.

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Exostosis severity seems to correspond to the ear that is more exposed to the predominant coastal wind. We propose that evaporative cooling in a cold water environment contributes to greater progression of exostoses in the ear with more exposure to the predominant wind. Exostosis removal using the postauricular approach carries a low complication rate.

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A significant 1-year change in VS size and hearing occurred in NF2 patients. Clinically, tumor change or hearing deterioration on one VS cannot be used to predict changes in the other VS. This suggests that, although NF2 is a Mendelian disease, the germline genotype-phenotype relationship may resemble that of complex disorders.

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Gene therapy has considerable potential for the treatment of disorders of the inner ear. Many forms of inherited hearing loss have now been linked to specific locations in the genome, and for many of these the genes and specific mutations involved have been identified. This information provides the basis for therapy based on genetic approaches. This chapter will examine the potential for such targeting to deliver gene therapy to the inner ear in a precisely controlled manner.

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ER and PR expression in VS might have implications for development of a VS-specific drug delivery system using antihormone and ErbB pathway small molecule inhibitors, due to crosstalk between these receptors. These signals may be critical for re-establishing ErbB-mediated cell density dependent growth inhibition.

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These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.

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Nonvestibular cranial nerve schwannoma usually affect cranial nerves III and V, as was the case in our NF2 sample. Fortunately, neuropathies associated with these tumors are rare. In contrast, lower cranial nerve schwannomas, although also rare, are associated with swallowing difficulty, aspiration, and other sequelae.

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IIH is an enigmatic disease entity. Increased intracranial pressure usually presents with headache and pulsatile tinnitus and is occasionally associated with cranial neuropathies. Abducens palsy is most common, producing diplopia. Cranial nerve involvement is often asymmetric, producing false localizing signs. Facial paralysis is an uncommon sequela of IIH. Treatment of IIH consists of reducing intracranial pressure. Corticosteroids are recommended for treatment of facial paralysis.

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Internal auditory canal melanoma portends a grim prognosis, can occur up to 17 years after initial melanoma diagnosis/treatment, and can be detected with appropriate MRI sequences, especially enhanced fluid-attenuated inversion recovery images. In disseminated cases, diagnosis can be confirmed with lumbar puncture demonstrating malignant cells. Management includes tumor resection when melanoma seems to be solitary and malignant cells are not present in CSF. Intrathecal chemotherapy and radiation are recommended for dissemination, although the survival rate is still poor.

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Most otologists are aware of the potential for contralateral ear involvement and conversion from cochlear hydrops to Meniere’s disease after diagnosis. These changes are significant, require long-term follow-up for detection, and may necessitate further treatment. Patients should be counseled regarding this potential when interventions are considered, especially with respect to ablative treatments.

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Proteus syndrome (PS) is a rare hamartomatous disorder characterized by mosaic overgrowth of multiple tissues that manifests early in life and is progressive. The presence of unilateral external auditory canal exostoses in a patient who is not a swimmer or surfer is suggestive of PS. However, hearing loss is not a typical feature. Here, we describe exostoses and ossicular discontinuity with conductive hearing loss in a patient with PS. The treatment consisted of canalplasty and ossicular chain reconstruction. A postoperative reduction was demonstrated in the patient’s air-bone gap, from 21 dB to 13 dB for the pure tone average (four frequencies) and from 41 dB to 15 dB in the high-frequency range (6,000 to 8,000 Hz). Causes of ossicular discontinuity are discussed. Routine annual audiometric and otolaryngological evaluation should be considered in all patients with temporal bone involvement of PS.

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Data suggests that spiral ligament structure and function are essential for stria vascularis survival. In addition, dampened expression of ion transport molecules within the spiral ligament and stria vascularis may disrupt potassium ion recycling, resulting in loss of endocochlear potential and sensory hearing loss.

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The patulous eustachian tube (pET) presents a challenging management problem. Patients with the pET disorder are disturbed to the point of mental illness by their symptoms of aural fullness and autophony, especially the echo of their own voice. Thus far, described treatment methods are often temporary or ineffective. Here, we describe a minimally invasive method for the treatment of pET that involves cauterization with autologous fat graft plugging of the ET at its nasopharyngeal orifice, in conjunction with myringotomy and ventilation tube placement. This procedure has been successful for the treatment of refractory pET in 2 patients at the House Ear Clinic with at least 1-year follow-up and we propose that it may accomplish relief of symptoms by permanent stenosis of the ET.

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The four members of the EGF receptor family are capable of homomeric as well as heteromeric interactions. HER-2/neu (erbB-2) dominates as the preferred coreceptor that amplifies mitogenic signaling. An alternative HER-2/neu product, herstatin, consists of a segment of the ectodomain of p185HER-2 and an intron-encoded C-terminus. Recombinant herstatin was found to bind with nM affinity and inhibit p185HER-2. To further examine the impact on receptor activity, herstatin was expressed with various receptor tyrosine kinases. In CHO cells that overexpressed HER-2, herstatin caused a sevenfold inhibition of colony formation that corresponded to a reduction in the tyrosine phosphorylation of p185HER-2. Herstatin also prevented HER-2 mediated transactivation of the kinase impaired HER-3 as reflected in transphosphorylation of HER-3 and heteromers between HER-2 and HER-3. In EGF receptor-overexpressing cells, EGF induction of receptor dimerization and tyrosine phosphorylation were reduced more than 90%, and receptor down-regulation as well as colony formation were also suppressed by coexpression with herstatin. Inhibition was selective for the EGF receptor family since herstatin expression did not reduce tyrosine phosphorylation mediated by the FGF receptor-2 or by insulin-like growth factor -1. Herstatin bound to the EGF receptor as well as to p185HER-2 in pull-down assays suggesting that complex formation may be involved in receptor inhibition. Our findings indicate that herstatin has the capability to negatively regulate combinations of interactions between group I receptor tyrosine kinases that confer synergistic growth signals.

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HER-2/neu (erbB-2) encodes an 185-kDa orphan receptor tyrosine kinase that is constitutively active as a dimer and displays potent oncogenic activity when overexpressed. Here we describe a secreted protein of approximately 68 kDa, designated herstatin, as the product of an alternative HER-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185HER-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The recombinant product of the alternative transcript specifically binds to HER-2-transfected cells with a K(D) of approximately 14 nM and was chemically crosslinked to p185HER-2, whereas the intron encoded sequence alone also binds with high affinity to transfected cells and associates with p185 solubilized from cell extracts. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185HER-2 mRNA in carcinoma cells that contain an amplified HER-2 gene. Herstatin appears to be an inhibitor of p185HER-2, because it disrupts dimers, reduces tyrosine phosphorylation of p185, and inhibits the anchorage-independent growth of transformed cells that overexpress HER-2.

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The 8-kb transcript is generated from alternative polyadenylation site usage rather than gene rearrangement. Since the 8-kb transcript contains alternative sequence found at the 3′ end of the normal HER-2 gene, it could be expressed in other cells. Increased stability of the 8-kb transcript may confer a selective advantage for SKOV-3 cells by providing enhanced HER-2 expression.

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We identified an NH2-terminally truncated HER-2/neu product of M(r) 95,000 with in vitro kinase activity by Western blotting and immunoprecipitations using domain-specific antibodies. p95 levels correlated with the extracellular domain (ECD) shed from different cells under varied conditions. Both ECD and p95 were at approximately 20-fold lower levels in SKOV3 ovarian carcinoma cells, as compared to BT474 breast carcinoma cells. Both were stimulated by treatment of cells with the phorbol ester tumor promoter phorbol 12-myristate 13-acetate and the lysosomotrophic agent chloroquine. The hydroxamate inhibitor of metalloproteases, TAPI, suppressed both p95 and ECD in a dose-dependent fashion, with maximal inhibition at < or = 10 microM in BT474 cells. Cancer tissues were analyzed by Western blotting and scored for p95HER-2/neu and for p185HER-2/neu expression. Breast and ovarian cancer tissues were both found to express p95HER-2/neu in addition to p185HER-2/neu. Of 161 breast cancer tissues, 22.4% expressed p95, 21.7% overexpressed p185, and 14.3% were p95 positive and overexpressed p185. A higher proportion of node-positive patients (23 of 78) than node-negative patients (9 of 63) expressed p95 in all tumors combined (P = 0.032). In the group that overexpressed p185, those that contained p95 were associated with node-positive patients (15 of 21), whereas those that were p95 negative were associated with node-negative patients (8 of 11; P = 0.017). Neither p95- nor p185-rich patients significantly correlated with tumor size or with hormone receptor status in this study. Our findings show that breast cancers, which express the HER-2/neu oncogene, are heterogeneous with respect to HER-2/neu protein products. p95HER-2/neu appears to distinguish tumors that have metastasized to the lymph nodes from those in node-negative patients.

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