The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2.

Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.

Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma.

Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we use two "knock-in" Cre-estrogen receptor alleles to inducibly express K-RasG12D in CC10(+) epithelial cells and Sftpc(+) type II alveolar cells of the adult mouse lung. Analysis of these mice identifies type II cells, Clara cells in the terminal bronchioles, and putative bronchoalveolar stem cells as cells of origin for K-Ras-induced lung hyperplasia. However, only type II cells appear to progress to adenocarcinoma.

Bilateral renal cell carcinoma metastasis in the oral cavity.

Cancer metastases to the oral cavity are reported infrequently. Renal cell carcinoma has a high metastatic potential, with approximately one third of patients presenting with metastatic disease. New lesions in the oral cavity often rely on preoperative biopsy to establish the diagnosis. However, we report an unusual case in a setting of known renal cell carcinoma disease, where initial pathology and culture data were misleading. Appropriate follow-up and a high index of suspicion will remain necessary. Surgical excision is the treatment of choice.

The role of adenotonsillectomy in graft-versus-host disease.

OBJECTIVE: The aim of this study was to better characterize the impact of pre-transplant adenotonsillectomy in the development of graft-versus-host disease in pediatric patients undergoing allogeneic stem cell transplantation. METHODS: This retrospective study involved 211 children undergoing stem cell transplantation at Duke University. Patients who had undergone transplant were characterized by age at transplant, age at adenotonsillectomy (if applicable), age at graft-versus-host disease (if applicable), average length of follow up and other factors. Statistical analyses were performed to determine the relative risks associated with each variable. RESULTS: A total of 136 patients developed graft-versus-host disease and 75 did not. Average length of follow up was 2 years for GVHD and 1.7 years for non-GVHD patients. The relative risk (RR) of graft-versus-host disease was significantly increased under univariate analysis if the donor and recipient were unrelated (RR=2.1, p<0.0001) and if the HLA match was not identical (RR=1.6, p<0.001). A history of adenotonsillectomy prior to transplant did not affect the risk of developing graft-versus-host disease (RR=1.1, p=0.70). CONCLUSIONS: Adenotonsillectomy prior to bone marrow transplant has no significant impact either protectively or adversely on the risk of developing graft-versus-host disease after transplantation in pediatric patients. Future studies are needed to further examine the impact of otolaryngologic surgery on pediatric patients in terms of immune system modification. Research should specifically focus on the immunological effects of surgery on patients who will be undergoing bone marrow transplant.

Qualities of residency applicants: comparison of otolaryngology program criteria with applicant expectations.

OBJECTIVES: To evaluate the criteria used by otolaryngology programs in ranking residency candidates and to compare residency candidate ranking criteria among otolaryngology programs and applicant expectations. DESIGN: Cross-sectional, anonymous survey administered during the 2009 and 2010 match cycles. SETTING: Otolaryngology residency programs. PARTICIPANTS: Otolaryngology residency program applicants (PAs) and otolaryngology program directors (PDs). MAIN OUTCOME MEASURES: The PDs were asked to rank the importance of 10 criteria in choosing a residency candidate on a 20-point scale (with 1 indicating utmost importance; 20, not important at all). The PAs were asked to express their expectations of how candidates should be ranked using those same criteria. RESULTS: The interview and personal knowledge of the applicant (mean rank, 3.63) were the most important criteria to PDs, whereas the interview and letters of recommendation (mean rank, 3.65) were the most important criteria among PAs. Likelihood to rank program highly and ethnicity/sex were the least valued by PDs and PAs. CONCLUSIONS: Although PDs and PAs agree on the least important criteria for ranking otolaryngology residency candidates, they disagree on the most important criteria. This information provides insight into how programs select residency candidates and how this compares with applicant expectations. Furthermore, this information will assist applicants in understanding how they might be evaluated by programs. Improved understanding of the match process may increase the likelihood of having a good fit between otolaryngology programs and matched applicants.

Comparison of applicant criteria and program expectations for choosing residency programs in the otolaryngology match.

OBJECTIVE: To evaluate criteria used by residency applicants in ranking otolaryngology residency programs and to compare applicant criteria with program expectations of ranking otolaryngology residency programs. STUDY DESIGN: Cross-sectional survey. SETTING: 2009 and 2010 match cycles. SUBJECTS AND METHODS: Program applicants and otolaryngology program directors. MAIN OUTCOME MEASURES: Applicants were asked to rank the importance of 10 criteria in choosing a residency program (1 = criterion was of the utmost importance and 20 = not important at all). Program directors were asked to express expectations of how applicants should rank programs using those same criteria. The Mann-Whitney U test was used to analyze responses between groups. RESULTS: Comprehensiveness of subspecialties and resident satisfaction were the most important criteria for both groups; salary, call schedule, and likelihood to rank the resident highly were least valued. Four criteria were significantly different between groups. Applicants significantly valued location (4.36 vs 8.9, P < .0001) and call schedule (9.85 vs 12.73, P = .002) more than program directors did. Program directors valued didactic schedule (6.1 vs 9.18, P < .0001) and comprehensiveness of subspecialties (2.53 vs 3.02, P = .007) more than applicants did. Forty-one of 105 (39%) program directors completed the survey. CONCLUSION: While applicants and program directors agree on the most and least important criteria for ranking residency programs, there are several significant differences in these criteria. This study provides insight on ranking criteria that may improve the resident match process and subsequent training experience. However, the ability to generalize the results is limited by the low response rate.