Prognostic value of p16 expression in Epstein-Barr virus-positive nasopharyngeal carcinomas.

BACKGROUND: Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear. METHODS: Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining. RESULTS: EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02). CONCLUSION: P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459-E1466, 2016.

Angiotensin II inhibits interleukin-6 mRNA expression of LPS-stimulated macrophages through down-regulating calcium signaling.

BACKGROUND: The renin-angiotensin system plays a key role in the regulation of blood pressure following hemorrhage and shock. Recent studies also suggest renin-angiotensin system regulates inflammatory mediator production although the amechanism is largely unknown. This purpose of the study was to examine the effect of angiotensin II on macrophage (MØ) IL-6 messenger RNA (mRNA) expression induced by lipopolysaccharide (LPS) and on the alterations in the calcium influx. METHODS: J774A.1 cells, a mouse MØ cell line, were exposed to E. coli LPS (1 or 10 µg/ml) in the presence of angiotensin II (10 nM to 1 µM). IL-6 mRNA expression was determined by the reverse transcription polymerase chain reaction technique. IL-6 protein production was measured by ELISA. To examine the involvement of calcium signaling in IL-6 mRNA expression, MØ were exposed to various calcium agonists and antagonists in the presence of LPS stimulation. Changes of intracellular [Ca(2+)] by LPS stimulation and angiotensin II treatment were determined by a fura-2 fluorescence ratio method. RESULTS: LPS stimulation increased MØ IL-6 mRNA expression, which was inhibited by Angiotensin II in a dose-dependent fashion. Both thapsigargin and A23187 augmented the IL-6 mRNA levels induced by LPS stimulation, but only thapsigargin was able to induce IL-6 mRNA directly. TMB-8 but not verapamil inhibited LPS-stimulated MØ IL-6 mRNA. Finally, angiotensin II significantly altered the changes in intracellular [Ca(2+)] levels induced by LPS stimulation by reducing both the peak and slope of calcium spikes. CONCLUSIONS: Our data show that calcium signaling is closely related to IL-6 mRNA expression. Angiotensin II inhibits IL-6 mRNA expression of LPS-stimulated MØ. The inhibitory effects of angiotensin II appear, at least in part, to be mediated through down regulating calcium dependent pathways.

Human papillomavirus and WHO type I nasopharyngeal carcinoma.

OBJECTIVES: Nasopharyngeal carcinoma (NPC) is a rare cancer in the United States. An association between NPC and Epstein-Barr virus (EBV) is well-established for World Health Organization (WHO) types II and III (WHO-II/III) NPC but less well-established for WHO type I (WHO-I) NPC. Given the rise in oropharyngeal tumors positive for high-risk human papillomavirus (HPV) and the unique biology of WHO-I NPC, we examined the relationship between HPV and WHO-I NPC. STUDY DESIGN: Retrospective case-comparison study. METHODS: A search of a large multidisciplinary cancer center tumor registry identified 183 patients seen from January 1999 to December 2008 with incident NPC and no prior cancer. Available paraffin-embedded tumor specimens (N = 30) were analyzed for oncogenic HPV status by in situ hybridization (ISH) and polymerase chain reaction (PCR) for HPV-16 and HPV-18; EBV status by ISH; and p16 expression by immunohistochemistry. Demographic parameters, including race and smoking, were obtained from the medical records. RESULTS: Among the 18 WHO-I NPC patients, 66% (N = 12) were smokers and 17% (N = 3) Asian; among the 165 WHO-II/III NPC patients, 44% (N = 73) were smokers and 24% (N = 39) Asian. Eight WHO-I NPC patients had available paraffin blocks; five of six were HPV-16-positive by PCR and four of eight were HPV-positive by ISH; only two of eight (25%) were EBV-positive. Twenty-two WHO-II/III NPC patients had available paraffin blocks; only 1 was HPV-positive by ISH, and 13 of 22 (60%) were EBV-positive. CONCLUSIONS: These results suggest that WHO-I NPC is associated with oncogenic HPV, although larger studies are needed to verify these findings. Laryngoscope, 2010.

Human papillomavirus & WHO type I nasopharyngeal carcinoma.

OBJECTIVES: Nasopharyngeal carcinoma (NPC) is a rare cancer in the U.S. that has a well-established association with Epstein-Barr virus(EBV) for WHO types II/III but less so for WHO type I. Given the rise in oropharyngeal tumors positive for high risk human papillomavirus (HPV) and the unique biology of WHO type INPC, we chose to examine the relationship between HPV and WHO type I NPC. STUDY DESIGN: Retrospective case comparison study. METHODS: A search of a large multidisciplinary cancer center tumor registry identified 183 patients seen from January 1999 to December 2008 with incident NPC and no history of prior cancer. Available paraffin embedded tumor specimens (N=30) were analyzed for HPV status by in situ hybridization (ISH) and polymerase chain reaction (PCR) for HPV 16 and 18, EBV status by ISH, and p16 expression by immunohistochemistry. Demographic parameters, including race, smoking, and alcohol exposure were obtained from the medical records. RESULTS: Patients with incident WHO-I NPC (N=18) tended to be smokers (66%) and only 17% were Asian, while for patients with incident WHO-II/III NPC (N=165), 44% were smokers and 24% were Asian. For WHO-I NPC patients with available paraffin blocks (N=8), 5 of 6 were HPV 16+ by PCR and 4 of 8 had HPV identified by ISH, while only 2 of 8 were EBV+. Of patients with WHO II/III NPC and available archival tissue (N=22), 60% were EBV+ and only one was HPV positive by ISH. CONCLUSIONS: These results suggest that WHO type I NPC may be associated with oncogenic HPV, though larger studies are needed to verify these findings.