ABSTRACT
OBJECTIVE: To evaluate the therapeutic efficacy of bevacizumab and cetuximab, alone and in combination, in an orthotopic model of anaplastic thyroid carcinoma (ATC) in athymic nude mice. STUDY DESIGN AND SETTING: This was a randomized, controlled in vivo study. MATERIALS AND METHODS: The ATC cell line, ARO, was used to establish orthotopic xenografts of ATC in athymic nude mice. Mice were randomized to therapy for 4 weeks in one of four treatment groups: placebo, cetuximab, bevacizumab, or the combination of cetuximab and bevacizumab. A second study compared the antitumor efficacy of the cetuximab-bevacizumab combination with doxorubicin. In both studies, tumor volumes on completion were measured and compared. Immunohistochemical analysis was performed with antiCD31 and antiproliferating cell nuclear antigen (PCNA) antibodies to assess the in vivo mechanisms of action of these agents. RESULTS: Cetuximab decreased the production of vascular endothelial growth factor by ATC cell lines in vitro. Mean tumor volumes for the control, bevacizumab, cetuximab, and combination groups at the end of the in vivo study were 291, 213, 94, and 42 mm(3), respectively. The differences in mean tumor volume for the control versus treatment groups were statistically significant. Immunohistochemical analysis showed decreased microvessel density and PCNA positivity in the treatment groups. In the doxorubicin comparison study, mean tumor volumes for control, doxorubicin, and combination antibody treatment groups were 175, 162, and 22 mm(3), respectively. CONCLUSIONS: Cetuximab and bevacizumab alone and in combination inhibit tumor growth and angiogenesis in an in vivo model of ATC. Also, this therapy was superior to doxorubicin therapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Thyroid Neoplasms/drug therapy , Animals , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bevacizumab , Blotting, Western , Carcinoma/immunology , Carcinoma/pathology , Cell Count , Cell Line, Tumor , Cetuximab , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , ErbB Receptors/antagonists & inhibitors , Immunohistochemistry , Male , Mice , Mice, Nude , Proliferating Cell Nuclear Antigen/immunology , Random Allocation , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Thyroid Neoplasms/immunology , Thyroid Neoplasms/pathologyABSTRACT
OBJECTIVE: To determine the prevalence of radiographic empty sella in patients with spontaneous cerebrospinal fluid (CSF) otorrhea. STUDY DESIGN AND SETTING: Retrospective case series of adult patients with CSF otorhinorrhea at an academic tertiary medical center. Patients with history of skull base surgery, trauma, tumor, or chronic ear disease were excluded. Available imaging studies were reviewed with attention to the sella turcica. RESULTS: Eight patients were diagnosed with spontaneous CSF otorrhea. Five of seven patients with adequate imaging studies (71%) had a radiographic empty sella. Seven of eight patients were clinically obese, with a body mass index BMI>30 kg/m2. CONCLUSIONS: Empty sella is a common radiologic finding in patients with spontaneous CSF otorrhea. This supports the theory that increased intracranial pressure contributes to development of spontaneous CSF otorrhea. SIGNIFICANCE: Radiographic empty sella predicts elevated intracranial pressure, which may require further evaluation and treatment in patients with spontaneous CSF otorrhea. EBM RATING: C-4.
Subject(s)
Cerebrospinal Fluid Otorrhea/etiology , Sella Turcica/diagnostic imaging , Adult , Aged , Cerebrospinal Fluid Otorrhea/diagnosis , Cerebrospinal Fluid Otorrhea/physiopathology , Female , Follow-Up Studies , Humans , Intracranial Pressure/physiology , Magnetic Resonance Imaging , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Sella Turcica/pathology , Tomography, X-Ray ComputedABSTRACT
PURPOSE: Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against epidermal growth factor receptor, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. EXPERIMENTAL DESIGN: The in vitro antiproliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. RESULTS: Cetuximab alone did not show any antiproliferative or proapoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro antiproliferative and proapoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. CONCLUSIONS: Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study.
