Prognostic significance of cyclooxygenase-2 overexpression in glottic cancer.

PURPOSE: Cyclooxygenase-2 (COX-2) overexpression has been associated with a poor prognosis in many cancers. However, the role of COX-2 overexpression in head and neck cancers remains undetermined. The objective of this study was to evaluate whether COX-2 is a prognostic factor in glottic cancer. EXPERIMENTAL DESIGN: This study was part of a phase III placebo-controlled randomized trial evaluating the efficacy of alpha-tocopherol in reducing second primary cancers (SPC) in head and neck cancer patients. Immunohistochemical analyses were conducted on pretreatment biopsies of 301 patients with early-stage glottic cancer treated by radiotherapy. The median value of 50% of positive tumor cells was the cutoff point used to define COX-2 overexpression. Outcomes considered in the statistical analysis were recurrence, SPC, and death. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and their 95% confidence intervals (95% CI). RESULTS: The HR associated with COX-2 overexpression was 0.94 (95% CI, 0.55-1.62) for recurrence. The HR associated with SPC was 2.63 (95% CI, 1.32-5.23) for the first 3.5 years of follow-up and 0.55 (95% CI, 0.22-1.32) for the following 3.5 years. The HR associated with COX-2 overexpression was 1.57 (95% CI, 1.01-2.45) for overall mortality. CONCLUSIONS: COX-2 overexpression in glottic cancer was associated with increased overall mortality and an increased risk of SPC during the early follow-up period. Future studies are needed to explain observed effects on SPC. COX-2 expression may prove helpful in defining an individual patient's prognosis.

Central tolerance to myogenic cell transplants does not include muscle neoantigens.

BACKGROUND: Duchenne muscular dystrophy is a fatal genetic disease caused by lack of dystrophin. Myogenic cell transplantation (MT), a potential therapy for Duchenne muscular dystrophy, can restore dystrophin expression in muscles. Because allogeneic MT is highly resistant to peripheral tolerance, we proposed to induce central tolerance. However, given its immunogenicity, we asked whether central tolerance to donor major histocompatibility complex would allow long-term expression of dystrophin, a tissue-specific neoantigen in dystrophic recipients. METHODS: Central tolerance was induced in C57BL/10J mdx (dystrophic) mice by allogeneic bone marrow transplantation (BMT) after conditioning with either lethal total body irradiation (TBI) or an established nonmyeloablative protocol (anti-CD154, anti-CD8 mAbs, and low-dose TBI). Recipients subsequently received donor-strain MT or skin grafts. RESULTS: Long-term hematopoietic chimeras generated using either lethal TBI or the nonmyeloablative regimen were tolerant to donor skin grafts and both primary and secondary donor MT (>90 days). Myogenic cell transplantation survival was decreased when chimerism was transient, which was most common with nonmyeloablative conditioning and fully rather than haplo-mismatched donors. Interestingly, regardless of conditioning, MT was associated with localized muscle infiltration with Foxp3CD4, CD25CD4, and PerforinCD8 cells, whereas skin grafts lacked infiltration. CONCLUSIONS: Central tolerance achieved using regimens that eliminate nearly all endogenous peripheral lymphocytes (i.e., lethal irradiation) or a nonmyeloablative protocol that depleted peripheral CD8 cells, results in lymphocytic infiltration in muscles that received MT but not in skin allografts. This suggests that muscle-specific infiltration may result from lack of negative selection for peripheral neoantigens in the thymus after BMT and that tolerance after MT may rely on peripheral regulatory mechanisms.

Diagnostic concordance of histologic lung cancer type between bronchial biopsy and cytology specimens taken during the same bronchoscopic procedure.

CONTEXT: The diagnosis of lung cancer is often confirmed by cytology and biopsy specimens obtained during a bronchoscopic procedure. At our institution, these specimens are read by different pathologists, and the rate of concordance was not known. OBJECTIVES: To evaluate the concordance rate in the diagnosis of lung cancer types between cytology and biopsy specimens and to correlate discordance with patient outcome. DESIGN: Specimens obtained during the same procedure, between January 1, 2000, and December 31, 2005, were identified. Cases with cytology and biopsy specimens positive for cancer were evaluated for concordance of histologic type, small cell versus non­small cell lung carcinoma. Cases with different types were considered discordant, and slides were reviewed. RESULTS: Of 231 cases, 225 (97.4%) had concordant diagnoses. Discordance was the result of misinterpretation of undifferentiated carcinoma, overinterpretation of squamous dysplasia, interpretation of suboptimal specimens with necrosis and crush artifact, and sampling error. CONCLUSIONS: Even though the cytology and biopsy specimens were reviewed by different pathologists, the concordance rate for histologic type at our institution was high, emphasizing that this is a safe practice. The few discordant cases did not affect the patient's outcome.

Enhanced lung disease and Th2 response following human metapneumovirus infection in mice immunized with the inactivated virus.

Human metapneumovirus (hMPV) is a paramyxovirus that causes acute respiratory-tract infections in humans. The histopathological and immunological responses to hMPV infection in BALB/c mice immunized with inactivated hMPV were characterized. Animals were immunized intraperitoneally with PBS, supernatant from non-infected LLC-MK2 cells and from heat-inactivated influenza A- or hMPV-infected cells, all in incomplete Freund's adjuvant, or with heat-inactivated hMPV without adjuvant, and then infected intranasally with 10(8) TCID50 virus. Following infection, lung samples and bronchoalveolar lavages were collected for determination of viral titre and cytokine levels and for histopathological studies. On day 1, 26 % of mice immunized with inactivated hMPV and adjuvant died, compared with none in the other groups. There was more significant lung inflammation associated with eosinophilic infiltration, as well as increased levels of interleukin-4 (IL-4) and IL-5, in the bronchoalveolar lavages of mice immunized with hMPV alone or with the adjuvant. Mice from the last two groups had a 4-5 log10 decrease in their pulmonary viral titres compared with controls. Our data demonstrate the risks associated with immunization using inactivated hMPV in this animal model and that this aberrant response should be considered in the development of hMPV vaccines.