Faculty Bibliography

BACKGROUND: Patients with ulcerative colitis are at increased risk for developing colorectal cancer. We have shown that Toll-like receptor-4 (TLR4) is overexpressed in human colitis-associated cancer (CAC) and that mice deficient in TLR4 are markedly protected against colitis-associated neoplasia. We wished to elucidate the specific contributions of TLR4 signaling by myeloid cells and colonic epithelial cells (CEC) in colitis-associated tumorigenesis. METHODS: TLR4-deficient mice or wildtype littermates (WT) were transplanted with bone marrow (BM) cells: TLR4(-/-) BM-->WT mice (TLR4-expressing CEC) and WT BM-->TLR4(-/-) mice (TLR4-expressing myeloid cells). Colitis-associated neoplasia was induced by azoxymethane (AOM 7.3 mg/kg) injection and 2 cycles of dextran sodium sulfate (DSS) treatment. RESULTS: The number and size of dysplastic lesions were greater in TLR4(-/-) BM-->WT mice than in WT BM-->TLR4(-/-) mice (P < 0.005). Histologically, TLR4(-/-) BM-->WT mice had greater numbers of mucosal neutrophils and macrophages compared to WT BM-->TLR4(-/-) mice. The chemokines KC and CCL2, important in recruitment of neutrophils and macrophages, respectively, were induced in mice expressing TLR4 in CEC rather than the myeloid compartment. The lamina propria infiltrate of mice expressing TLR4 in CEC was characterized by macrophages expressing Cox-2. Moreover, mice expressing TLR4 in CEC rather than the myeloid compartment had increased production of amphiregulin and EGFR activation. CONCLUSIONS: These findings indicate that TLR4 signaling on CEC is necessary for recruitment and activation of Cox-2-expressing macrophages and increasing the number and size of dysplastic lesions. Our results implicate innate immune signaling on CEC as a key regulator of a tumor-promoting microenvironment.

OBJECTIVE: We report a case of allergic fungal sinusitis causing bone erosion and diplopia. CASE REPORT: A 43-year-old man presented with a four-month history of increased nasal congestion and progressive diplopia. Clinical examination revealed bilateral nasal polyposis and a right lateral gaze deficit, consistent with a VIth cranial nerve palsy. Computed tomography of the paranasal sinuses demonstrated a large sellar mass with extensive bony erosion and both supra- and infra-sellar extension. An endoscopic approach to the sphenoid sinus, clivus and posterior cranial fossa with image guidance was performed, enabling surgical treatment involving nasal polypectomy, wide marsupialisation of the sphenoid sinus and removal of the extensive allergic fungal mucin. The patient awoke from anaesthesia with complete resolution of his diplopia. CONCLUSION: Otolaryngologists should be aware that approximately 20 per cent of patients with allergic fungal sinusitis demonstrate paranasal sinus expansion and bone erosion involving surrounding anatomical structures. Such patients may have clinical findings involving the orbit and cranial vault

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.

The role that otolaryngologist Ross McIntire, MD, played in the care of Franklin Delano Roosevelt, 32nd President of the United States, was documented by reviewing primary source material pertaining to the relationship of McIntire and Roosevelt. This included material from various archives including the Franklin D. Roosevelt Presidential Library at Hyde Park, New York; United States National Archives; and numerous autobiographies and diaries. McIntire's belief in the value of confidentiality and to provide information only on a need-to-know basis is consistent with the strategy that he had devised earlier for protecting his patient's privacy. In the context of his time and his position, Dr McIntire served his patient and his country well by making appropriate medical and wise personal judgments. The career of Dr Ross T. McIntire, otolaryngologist and personal physician to the 32nd president of the United States, engenders a sense of honor to our profession.

The preponderance of pancreatic tumors is adenocarcinoma of the ductal type; carcinomas with multiple lineage differentiation are extremely rare. We report an unusual case of pancreatic carcinoma with combined acinar and neuroendocrine differentiation and minor ductal component with concurrent acinar-ductal metaplasia (ADM), an early lesion implicated in ductal carcinogenesis. The patient is a 56-year-old man with vague complaints of dull left upper quadrant pain with radiation across the mid-portion of his abdomen. A computer tomography scan revealed an irregular enlargement of the distal 3.2 cm of the pancreatic body. A distal pancreatectomy was then performed. Histologic examination revealed a pancreatic carcinoma with cellular features of eosinophilic granular cytoplasm and salt-pepper nuclei. The acinar differentiation of the carcinoma was confirmed by positivity on periodic acid-Schiff stain resistant to diastase digestion (dPAS), positivity for antitrypsin on immunohistochemistry (IHC), and presence of zymogen granules on electron microscopy (EM). The neuroendocrine differentiation was evident by positive synaptophysin and chromogranin stain on IHC and neuroendocrine granules on EM. The ductal component was only visible by PAS stain and immunostains for CEA and CK19A and accompanied by a number of the acinar-ductal metaplasia lesions adjacent to the main tumor. Thus, the histological, histochemical, immunohistochemical and electron-microscopic evidence all suggested that the pancreatic carcinoma underwent trilineage differentiation

Pruritus is a common symptom in patients with Philadelphia chromosome-negative myeloproliferative disorders (MPDs). The pathophysiology of MPD-associated pruritus is unclear. We have demonstrated that MPD mast cells (MCs) are involved by the malignant process. In the present study, we explored the hypothesis that MCs play an important role in the development of pruritogenesis in MPDs. We found that MPD MCs released significantly greater amounts of pruritogenic factors, including histamine, leukotrienes, and interleukin-31 (IL-31) than normal MCs. Elevated levels of IL-31 were also observed in MPD CD3(+) cell-conditioned media. MPD MCs exhibited increased migratory behavior in response to stem cell factor or interleukin-8, which was associated with increased filamentous-actin content. Furthermore, the presence of pruritus in MPDs was statistically correlated with a greater number of MCs being generated by CD34(+) cells, a greater number of MC colonies being formed by CD34(+) cells, decreased apoptosis and prostaglandin D(2) release by cultured MCs, and higher plasma levels of IL-31. These data demonstrate that functional abnormalities of MPD MCs probably lead to pruritogenesis in patients with MPDs. These studies provide cellular and molecular targets for the development of antipruritus drugs for patients with MPDs.

Pharyngeal manometry complements the modified barium swallow with videofluoroscopy (VFS) in diagnosing pressure-related causes of dysphagia. When manometric analysis is not feasible, it would be ideal if pressure information about the swallow could be inferred accurately from the VFS evaluation. Swallowing function was examined using VFS and concurrent manometry in 18 subjects (11 head and neck patients treated with various modalities and 7 healthy adults). Nonparametric univariate and multivariate analyses revealed significant relationships between manometric and fluoroscopic variables. Increases in pressure wave amplitude were significantly correlated with increased duration of tongue base to pharyngeal wall contact, reduced bolus transit times, and oropharyngeal residue. Pharyngeal residue was the most important VFS variable in reflecting pharyngeal pressure measurements. Certain VFS measures were significantly correlated with measures of pressure assessed with manometry. Further research is needed before observations and measures from VFS alone may be deemed sufficient for determining pressure-generation difficulties during the swallow in patients who are unable or unwilling to submit to manometric testing

OBJECTIVE: To report the adverse effects associated with prolonged high-dose prednisone for the treatment of autoimmune inner ear disease (AIED). STUDY DESIGN: Prospective data collected as part of a multicenter, randomized, controlled trial for the treatment of corticosteroid-responsive AIED with methotrexate. SETTING: Tertiary referral centers. PATIENTS: One hundred sixteen patients with rapidly progressive, bilateral sensorineural hearing loss. INTERVENTION: All patients completed a 1-month course of prednisone (60 mg/d). In Phase 2, 67 patients with improvement in hearing underwent a monitored 18-week prednisone taper, resulting in 22 weeks of prednisone therapy at an average dose of 30 mg per day. Thirty-three patients were randomized to receive methotrexate in Phase 2. Thirty-four patients received prednisone and placebo. MAIN OUTCOME MEASURE: Adverse events (AE) in patients treated with prednisone only. RESULTS: Of 116 patients, 7 had to stop prednisone therapy during the 1-month challenge phase due to AE. Of 34 patients, 5 were unable to complete the full 22-week course of prednisone due to AE. The most common AE was hyperglycemia, which occurred in 17.6% of patients participating in Phase 2. Weight gain was also common, with a mean increase in body mass index of 1.6 kg/m2 (95% confidence interval, 0.77-2.3) during the 22-week steroid course. Patients entering Phase 2 were followed for a mean of 66 weeks. No fractures or osteonecrosis were reported. CONCLUSION: Although high-dose corticosteroids are associated with known serious side effects, prospective data in the literature are limited. The present study suggests that with appropriate patient selection, monitoring, and patient education, high-dose corticosteroids are a safe and effective treatment of AIED

To date, major works on tracheomalacia have assumed a structural etiology and have proposed therapies as such. We describe a possible neurologic etiology for tracheomalacia in a child with clinically significant tracheomalacia that resolved in synchrony with each treatment of his recurring hydrocephalus. Endoscopy confirms remarkable expansion of tracheal diameter 7 days after decreasing intracranial pressure. The possibility of a neurologic etiology for tracheomalacia casts this condition in a new light with potential therapeutic implications.

Nasal obstruction from a deviated septum is one of the more frequent complaints bringing patients into an otolaryngology office. Despite the significant number of septoplasties performed each year, complications after this procedure are relatively uncommon. Most complications result from inadequate surgical planning or poor technique and often can be prevented. Surgeons should discuss these risks with patients before surgery as part of the informed consent process. This article reviews how complications of septoplasty can occur, compromising the functional and aesthetic aspects of a patient's life, and how attention to detail can reduce the risk for these complications. The septoplasty surgeon must be aware of all the possible complications that may arise so as to convey the benefits and risks of surgery effectively to prospective patients.