Traumatic brain injury-induced ependymal ciliary loss decreases cerebral spinal fluid flow.

Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle.

Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells.

OBJECTIVES: To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM). METHODS: Synovial biopsies from affected joints of two patients with MM and amyloid arthropathy were examined with light and electron microscopy, and immunohistochemically for expression of CD3, CD8, CD20, CD38, CD68, Ki-67 and vWF. Results were compared to values from osteoarthritis (OA, n = 26), rheumatoid arthritis (RA, n = 24) and normal (n = 15) synovial membranes. RESULTS: There was no or only mild lining hyperplasia. Vascular density was not elevated, and there were few Ki-67+ proliferating cells in the stroma. The Krenn synovitis score classified one specimen as "low-grade" and one as "high-grade" synovitis. CD68+ and CD3+ cells were the predominant mononuclear inflammatory cells, whereas CD20+ and CD38+ cells were absent from both synovial membrane and synovial fluid sediment. Electron microscopy demonstrated amyloid phagocytosis by synovial macrophages. In hierarchical clustering the two amyloid arthropathy specimens were more closely related to OA than to RA or normal synovium. CONCLUSIONS: This first detailed immunohistological analysis of MM-associated amyloid arthropathy suggests that it is a chronic synovitis that evolves despite the loss of humoral immunity seen in advanced MM. Instead, amyloid phagocytosis by synovial macrophages likely triggers and perpetuates local disease.

Synchronous verrucous carcinoma and inverted papilloma of the lacrimal sac: case report and clinical update.

Inverted papilloma is a benign epithelial tumor of the nasal cavity. It is known to coexist with malignancy in 5 to 13% of cases, with squamous cell carcinoma being the most common malignancy. Another associated malignancy, one that is extremely rare, is verrucous carcinoma. To the best of our knowledge, no case of verrucous carcinoma occurring alone or in association with another neoplasm has been described in the nasolacrimal system. We report a case of synchronous verrucous carcinoma and inverted papilloma of the lacrimal sac in a 47-year-old man. The patient presented with epiphora, nasal obstruction, swelling of the left medial canthus, and drainage of a foul-smelling fluid from the left nostril. Computed tomography and magnetic resonance imaging detected the presence of a large mass occupying the left nasal cavity and sinuses with extension into the nasopharynx. In addition, bony invasion of the anteroinferomedial wall of the left orbit was noted with extension of the tumor into the orbit itself, which resulted in lateral displacement of the left medial rectus muscle. The patient underwent endoscopic debulking of the left sinonasal lesion. Of note, the surgery had to be completed in stages because of excessive blood loss. Histopathologic examination of the intranasal component of the tumor identified it as an inverted papilloma. One month after the intranasal resection, a left dacryocystectomy was performed; histopathologic examination revealed that an invasive verrucous squamous cell carcinoma had arisen within the inverted papilloma.

Cellular adaptive inflammation mediates airway granulation in a murine model of subglottic stenosis.

OBJECTIVE: To determine the contribution of B- and T-cell-mediated inflammation in a murine airway granulation model. STUDY DESIGN: Pilot study in a modified murine model. SETTING: Philadelphia VA Medical Center Research Building. SUBJECTS AND METHODS: Laryngotracheal complexes (LTCs) from 54 donor C57BL/6 mice were harvested and divided into 3 groups: (1) uninjured, (2) mechanically injured using a wire brush, and (3) chemically injured using hydrochloric acid. One donor LTC from each group was placed in deep dorsal subcutaneous pockets of either severe combined immunodeficiency (SCID)- or C57BL-recipient mice, for a total of 3 transplanted tracheas per recipient mouse. After 3 weeks, the transplanted LTCs were harvested from both C57BL- and SCID-recipient mice. Tissues were fixed, sectioned, and stained with hematoxylin and eosin. Representative slides were reviewed by a blinded pathologist to determine the formation of granulation tissue and graded as to the degree of formation of granulation tissue. RESULTS: Despite significant granulation formation in C57BL-recipient mice, direct airway injury did not induce the formation of granulation tissue under the disrupted epithelium of airway mucosa in SCID mice 3 weeks after injury. CONCLUSION: The data indicate that the immune response that results in the formation of granulation tissue is mediated by circulating B- and/or T-cell processes rather than resident airway immune cells. Further studies focusing on cellular adaptive immune processes in response to airway injury may provide a novel treatment modality for subglottic stenosis.

Atypical carcinoid of the larynx and potential complications of the carcinoid syndrome: a case report.

A 47-year-old man with a history of allergic rhinitis presented with a several-month history of nasal symptoms and gastroesophageal reflux disease. He also had clinical depression, for which he had been taking a selective serotonin reuptake inhibitor (SSRI). During evaluation, flexible laryngoscopy incidentally detected a left interarytenoid polyp. Biopsy identified the lesion as a moderately differentiated neuroendocrine carcinoma. In addition to conducting a metastatic workup, we determined that it was necessary to evaluate the functional status of the tumor prior to excision because the SSRI could precipitate a carcinoid syndrome. We discuss the characteristics and management of different neuroendocrine carcinomas of the larynx, and we review the potential complications of the carcinoid syndrome.

Prognostic significance of tumor-infiltrating lymphocytes in oropharyngeal cancer.

The presence of tumor-infiltrating lymphocytes has been shown to significantly improve clinical outcomes in many types of cancer. However; their effects on outcomes in patients with oropharyngeal cancer specifically have yet to be elucidated. We conducted a retrospective study in an effort to shed light on this issue. We reviewed the records of 48 consecutively presenting patients with oropharyngeal cancer; and we performed immunohistochemistry to analyze their archived paraffin-embedded tissue samples for the presence of CD3-positive tumor-infiltrating lymphocytes. We also used real-time polymerase chain reaction testing to look for human papillomavirus type 16 (HPV-16) in the tumors. We found that patients with large numbers of tumor-infiltrating lymphocytes (CD3high) had a significantly lower incidence of metastasis at presentation than did those with low numbers of tumor-infiltrating lymphocytes (CD31low) (40.0 vs. 88.5%; p = 0.001), regardless of HPV status. When HPV status was taken into account, the correlation between a high CD3 count and a lower rate of metastasis was maintained in the HPV-positive patients but not in the HPV-negative patients. We also found that the CD3high patients had higher rates of overall survival and disease-free survival at 3 and 5 years than did the CD3low patients; however; these differences only approached but did not reach statistical significance.

BRAF and RAS mutations in human lung cancer and melanoma.

BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.

Metastatic breast cancer to 4 eyelids: a clinicopathologic report.

A 47-year-old woman presented complaining of progressive, painless swelling of all 4 eyelids for 6 weeks. Her medical history was significant for breast cancer 14 months prior. Examination results showed a diffuse, firm thickening of all 4 eyelids with mild erythema of the overlying skin. Orbital computer tomography revealed extensive preseptal infiltration of soft tissue of all 4 eyelids, which enhanced with contrast. Results of a bilateral biopsy of the upper eyelids demonstrated extensive infiltration of the orbicularis muscle. Histologic features were consistent with metastatic breast cancer. Results of both the primary breast cancer biopsy taken 14 months previously and the eyelid biopsies were the same histologic type. Presentation of metastatic breast cancer to the eyelids is rare, but a recurrence must be considered in any patient with a history of breast cancer, despite the length of tumor-free survival. Bilateral involvement should not exclude metastases from diagnostic consideration, but rather, the diagnosis requires a high degree of clinical suspicion and recognition of the various cutaneous forms.