IL-23 stabilizes an effector Treg cell program in the tumor microenvironment.

Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (Treg) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in Treg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity.

Bilateral spontaneous hemotympanum secondary to chemotherapy-induced thrombocytopenia.

OBJECTIVE: To present a case of spontaneous, bilateral hemotympanum secondary to chemotherapy-induced thrombocytopenia. METHODS: Case report and review of the literature. RESULTS: Bilateral spontaneous hemotympanum is an exceedingly rare event. We present the first case of nontraumatic bilateral hemotympanum secondary to chemotherapy-induced thrombocytopenia in a patient with acute myelogenous leukemia. The patient presented with a 7-day history of progressive bilateral hearing loss and a platelet count of 10 × 10(9)/L after receiving his first dose of induction chemotherapy. A small, left-sided subdural hematoma was present in this patient though no extra-aural sources of bleeding to explain the bilateral hemotympanum were identified. CONCLUSION: Full resolution of symptoms was achieved with conservative management.

Sinonasal undifferentiated carcinoma (SNUC): the Alberta experience and literature review.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare malignancy with often dismal outcomes. This study set to determine provincial and literature-wide survival outcomes based on treatment modality. METHODS: Retrospective chart review of all SNUC patients in the province of Alberta from 1986-2010 was conducted. A review of the literature of SNUC patients was also performed. Patient/tumor characteristics, treatment, and follow-up/survival data were collected. Kaplan-Meier and Cox regression survival analyses were performed. RESULTS: 20 patients were treated for SNUC in Alberta and 140 patients were identified in the literature. Pooled median disease-free survival was 12. 7 months and 5-year survival estimate was 6.25%. Cox-Regression analysis demonstrated an overall survival advantage with multimodality treatments (Log-Rank test: p = 0.015). However, no statistically significant differences in disease-free and overall survival were identified between patients treated with chemoradiation or surgery followed by adjuvant therapy. CONCLUSIONS: Treatment of SNUC remains challenging with poor survival outcomes. There appears to be no statistically significant difference in overall, or disease-free survival between treatment modalities.

HPV status and second primary tumours in oropharyngeal squamous cell carcinoma.

INTRODUCTIONS: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCCs) is rising in developed nations. Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer. OBJECTIVE: The purpose of this study was to evaluate the rate of second primary tumors and the diagnostic yield of field cancerization work up in the upper aerodigestive tract in patients with HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma. DESIGN: Retrospective review. SETTING: Tertiary cancer care centers in Alberta. METHODS: Retrospective review of 406 patients diagnosed with OPSCC in Alberta between 2005 and 2009. HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16. PRIMARY OUTCOME: incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC. SECONDARY OUTCOMES: diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients. RESULTS: The overall rate of SPTs was 7.4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02). CONCLUSIONS: Patients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways.

Trends in level of evidence in facial plastic surgery research.

BACKGROUND: Evidence-based medicine has increasingly become an integral part of clinical research and practice. The purpose of this study was to assess the trends in the level of evidence in leading facial plastic surgery journals in recent years. METHODS: All scientific articles within the field of facial plastic surgery published in The Laryngoscope, Archives of Facial Plastic Surgery, Otolaryngology-Head and Neck Surgery, Journal of Plastic Surgery, and Plastic and Reconstructive Surgery from 1999, 2002, 2005, and 2008 were rated for level of evidence. The presence of p values and confidence intervals was also noted. RESULTS: Of 975 articles reviewed, 88 percent were clinical and 88 percent were therapy articles. Overall, there was an increase in the average level of evidence of articles published from 1999 to 2008. There was also a significant increase in the proportion of articles reporting p values and confidence intervals. However, the number of articles containing level 1 or 2 evidence remains low. CONCLUSIONS: With the increased demand for evidence-based medicine, facial plastic surgery literature has seen an overall increase in the quantity of higher level evidence research published. However, articles representing level 1 and 2 evidence remain rare.

Structural and functional characterization of transmembrane segment VII of the Na+/H+ exchanger isoform 1.

The Na(+)/H(+) exchanger isoform 1 is an integral membrane protein that regulates intracellular pH by exchanging one intracellular H(+) for one extracellular Na(+). It is composed of an N-terminal membrane domain of 12 transmembrane segments and an intracellular C-terminal regulatory domain. We characterized the structural and functional aspects of the critical transmembrane segment VII (TM VII, residues 251-273) by using alanine scanning mutagenesis and high resolution NMR. Each residue of TM VII was mutated to alanine, the full-length protein expressed, and its activity characterized. TM VII was sensitive to mutation. Mutations at 13 of 22 residues resulted in severely reduced activity, whereas other mutants exhibited varying degrees of decreases in activity. The impaired activities sometimes resulted from low expression and/or low surface targeting. Three of the alanine scanning mutant proteins displayed increased, and two displayed decreased resistance to the Na(+)/H(+) exchanger isoform 1 inhibitor EMD87580. The structure of a peptide of TM VII was determined by using high resolution NMR in dodecylphosphocholine micelles. TM VII is predominantly alpha-helical, with a break in the helix at the functionally critical residues Gly(261)-Glu(262). The relative positions and orientations of the N- and C-terminal helical segments are seen to vary about this extended segment in the ensemble of NMR structures. Our results show that TM VII is a critical transmembrane segment structured as an interrupted helix, with several residues that are essential to both protein function and sensitivity to inhibition.