Downregulation of the α1- and ß1-subunit of sGC in Arterial Smooth Muscle Cells of OPSCC Is HPV-Independent.

The nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is a heterodimeric enzyme with an α and ß subunit. NO binds to heme of the ß1-subunit of sGC, activates the enzyme in the reduced heme iron state in vascular smooth muscle cells (VSMCs), and generates cGMP-inducing vasodilatation and suppression of VSMC proliferation. In the complex tumor milieu with higher levels of reactive oxygen species (ROS), sGC heme iron may become oxidized and insensitive to NO. To change sGC from an NO-insensitive to NO-sensitive state or NO-independent manner, protein expression of sGC in VSMC is required. Whether sGCα1ß1 exists at the protein level in arterial VSMCs of oropharyngeal squamous cell carcinoma (OPSCC) is unknown. In addition, whether differences in the genetic profile between human papillomavirus (HPV)-positive and HPV-negative OPSCC contributes to the regulation of sGCα1ß1 is unclear. Therefore, we compared the effects of HPV-positive and HPV-negative OPSCC on the expression of sGCα1ß1 in arterial VSMCs from tumor-free and tumor-containing regions of human tissue sections using quantitative immunohistochemistry. In comparison to the tumor-free region, we found a decrease in expression of both α1- and ß1-subunits in the arterial VSMC layer of the tumor-containing areas. The OPSCC-induced significant downregulation of the α1- and ß1-subunits of sGC in arterial VSMC was HPV-independent. We conclude that the response of sGC to NO in tumor arterial VSMCs may be impaired by oxidation of the heme of the ß1-subunit, and thus, α1- and ß1-subunits of sGC could be targeted to degradation under oxidative stress in OPSCC in an HPV-independent manner. The degradation of sGCα1ß1 in VSMCs may result in increased proliferation of VSMCs, promoting tumor arteriogenesis in OPSCC. This can be interrupted by preserving the active heterodimer sGCα1ß1 in arterial VSMCs.

The relevance of the lymph node ratio as predictor of prognosis is higher in HPV-negative than in HPV-positive oropharyngeal squamous cell carcinoma.

OBJECTIVES: Lymph node ratio (LNR) is an established predictor in different entities of carcinoma, including head and neck malignancies. In oropharyngeal squamous cell carcinoma (OPSCC), lymph node involvement differs between human papilloma virus (HPV)-positive and HPV-negative tumours. Herein, we evaluate the impact of HPV association on the concept of LNR. METHODS: 88 surgically treated patients were included in this retrospective chart review. HPV-positive and HPV-negative OPSCC were evaluated for prediction of outcome by LNR separately. The endpoints were 5-year overall survival (OS) and recurrence-free survival (RFS). RESULTS: The OS of all patients was 60.1%. In univariate analysis, LNR was a significant predictor of overall survival rate (P=.008) in OPSCC independently of the HPV status, as well as extracapsular spread (ECS). T-classification was only a significant predictor in the univariate analysis in HPV-positive OPSCC carcinoma. However, in the multivariate analysis LNR remained predictor of prognosis in all OPSCC and in HPV-negative OPSCC. In patients with HPV-positive OPSCC, only T-classification reached significance to predict OS. CONCLUSION: Prognosis of primarily operated HPV-positive patients might be more dependent on the extent of primary tumour site, whereas prognosis of HPV-negative patients is based more on cervical metastatic spread, represented by LNR.

Prediction of outcome by lymph node ratio in patients with parotid gland cancer.

OBJECTIVE: Lymph node ratio (LNR) has been shown to be an independent predictor of recurrence risk and survival in different entities of carcinoma. METHODS: In this retrospective chart review, 128 patients with parotid gland cancer (PGC) subsequently treated by primary surgery were included. About 64% (n = 82) of these patients were additionally treated with adjuvant radiotherapy. Five-year overall survival rates were determined by subgroups based on LNR value. RESULTS: Lymph node ratio was found to be significantly associated with overall survival rate (P < 0.001). Using univariate analyses, pathological tumour-node-metastasis (TNM)-stage, UICC-stage grouping and extracapsular spread were found to be significant predictors of overall survival (P < 0.001). However, with a multivariate analyses, LNR remained the only independent predictor of overall survival (P = 0.043). CONCLUSIONS: After surgery for PGC, evaluation of the neck using LNR was found to reliably stratify the overall survival rate.

[Update on HPV-induced oropharyngeal cancer]. / Aktuelles zu HPV-induzierten Oropharynxkarzinomen.

Oropharyngeal squamous cell carcinoma (OSCC) is associated with oncogenic human papillomavirus (HPV) infection in 30-40% of all cases in Germany. The use of PCR and / or in situ hybridisation to detect HPV in tumour tissue is used in combination with p16 immunohistochemistry to reliably distinguish HPV-related and HPV-unrelated OSCC. The distinct biological behaviour of the HPV-related subset of OSCC results in a more favourable prognosis. This might be the result of a greater response to chemotherapy and radiotherapy as seen in recent studies. Ongoing and future clinical trials will stratify for HPV status. If the results of these prospective, randomized trials are consistent with the preliminary results of recent studies, HPV status will be of enormous clinical relevance in the future.