The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide, with a poor prognosis and limited treatment options. Molecularly targeted therapies for HNSCC are still lacking. However, recent reports provide novel insights about many molecular alterations in HNSCC that may be useful in future therapies. Therefore, it is necessary to identify new biomarkers that may provide a better prediction of the disease and promising targets for personalized therapy. The poor response of HNSCC to therapy is attributed to a small population of tumor cells called cancer stem cells (CSCs). Growing evidence indicates that the Hedgehog (HH) signaling pathway plays a crucial role in the development and maintenance of head and neck tissues. The HH pathway is normally involved in embryogenesis, stem cell renewal, and tissue regeneration. However, abnormal activation of the HH pathway is also associated with carcinogenesis and CSC regulation. Overactivation of the HH pathway was observed in several tumors, including basal cell carcinoma, that are successfully treated with HH inhibitors. However, clinical studies about HH pathways in HNSCC are still rare. In this review, we summarize the current knowledge and recent advances regarding the HH pathway in HNSCC and discuss its possible implications for prognosis and future therapy.

Prognostic Value of WNT1, NOTCH1, PDGFRß, and CXCR4 in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: The biological behaviour of oral squamous cell carcinoma (OSCC) might be an effect of aberrant activation of several signalling pathways, like WNT and NOTCH pathways. The purpose of this study was to investigate the prognostic significance of WNT1 and NOTCH1 in patients with OSCC in relation to pro-angiogenic factors (PDGFRß, CXCR4). MATERIALS AND METHODS: Immunohistochemistry was performed in 60 OSCC tissue samples to compare WNT1, NOTCH1, PDGFRß, and CXCR4 expression and correlate it with clinicopathological parameters. RESULTS: Immunoreactivity of WNT1, NOTCH1, PDGFRß, and CXCR4 was found in 51.7%, 25.0%, 63.3%, and 70.0% of the patients, respectively. WNT1 expression was positively correlated with NOTCH1 (r=0.269, p=0.037) and CXCR4 (r=0.268, p=0.038). Positive correlation was observed also between NOTCH1 and CXCR4 (r=0.493, p<0.001). WNT1 and PDGFRß expression was significantly associated with shorter overall survival (p=0.042, p=0.033, respectively). Multivariate Cox regression model revealed that WNT1 and CXCR4 were independent prognostic factors (p=0.009, p=0.021, respectively). CONCLUSION: WNT1 and NOTCH1 expression is associated with CXCR4 expression in OSCC, suggesting that WNT and NOTCH pathways are important in oral tumour angiogenesis. Moreover, WNT1 and CXCR4 could serve as independent prognostic factors for patients with OSCC.

Comparison of p53, HSP90, E-cadherin and HPV in oral lichen planus and oral squamous cell carcinoma.

OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory disease. There are no markers that can be used to identify the risk of a malignant transformation of OLP to oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemical staining was performed among 56 patients with OLP and 66 patients with OSCC for p53, HSP90 and E-cadherin expression and presence of HPV16/18. RESULTS: Significant differences in p53 and HSP90 expression between OLP and OSCC were found (p = 0.01 and p = 0.006, respectively). A positive correlation between HSP90 and p53 expression was seen in OLP (p = 0.017). Univariate analysis identified HSP90 expression and HPV16/18 presence as prognostic factors for overall survival time (OS) (p < 0.05). In multivariate analysis, only HSP90 expression was an independent prediction factor for shorter OS of OSCC patients (p = 0.016). CONCLUSIONS: The present study suggests that cooperation between p53 and HSP90 as well as between HPV16/18 and HSP90 exists in OLP and may affect the biological behaviour of OLP. The observed expression of HSP90 and p53 in OLP and their increase in OSCC suggests that these proteins participate in the malignant transformation of OLP. HSP90 may be a potential independent prognostic biomarker that can predict poor prognosis in OSCC.

SHH Expression Is Significantly Associated With Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a highly invasive malignancy with poor prognosis. Recent reports suggest that Sonic Hedgehog (SHH) plays a key role in tumor progression and worsens the response to therapy, possibly through an association with a cancer stem cell (CSC) phenotype. The objective of our study was to investigate the relationship between SHH expression and CSC markers in OSCC. MATERIALS AND METHODS: A total of 67 OSCC specimens were immunostained for SHH and CSC markers using specific antibodies and expression was correlated with clinicopathological parameters. RESULTS: SHH expression was significantly correlated with CD133 (p=0.026, r=0.272) and SRY-box transcription factor 2 (SOX2; p<0.001, r=0.793). SHH and SOX2 expression were associated with worse survival in OSCC (p=0.003 and p=0.003, respectively). In multivariate analysis SHH and CD44 were independent prognostic biomarkers in patients with OSCC (p=0.001 and p=0.008, respectively). CONCLUSION: Our study revealed that SHH overexpression is closely associated with CSC markers, contributing to tumor progression and worse outcomes of patients with OSCC.

Sonic Hedgehog is a novel prognostic biomarker in patients with oral squamous cell carcinoma.

Recent studies revealed that Sonic Hedgehog (SHH) signaling pathway plays an important role in initiation and tumor progression in various malignancies, however, its role in oral squamous cell carcinoma (OSCC) remains unclear. The objective of this study was to investigate the prognostic significance of SHH expression in patients with OSCC in relation to p53 protein expression and human papillomavirus (HPV) presence. SHH, p53, HPV expression was analyzed in surgical specimens from 70 patients with primary OSCC by immunohistochemistry (IHC) and correlated with clinicopathological parameters. The presence of SHH, p53, HPV was found in 51/70 (72.9%), 32/70 (45.7%), 11/70 (15.7%) cases, respectively. No correlation between SHH, p53 overexpression, and HPV presence was found. SHH expression was associated with tumor stage (p=0.026). P53 immunoreactivity correlated with tumor grade (p=0.040). By Kaplan-Meier analysis, SHH expression was significantly associated with shorter overall survival (p=0.005). Multivariate cox regression analysis showed that SHH was an independent prognostic factor for overall survival (HR=2.93; 95% CI=1.40-6.13; p=0.004). Our findings revealed that the SHH signaling pathway contributes to the poor survival of patients with OSCC and should be considered as a new prognostic biomarker in patients with OSCC. Inhibition of the SHH pathway may be used as a new potential target in cancer therapy.

Surgical Correction of Pectus Excavatum by the Nuss Procedure: A 15-Year Experience Study.

Pectus excavatum is the most common congenital deformity of the chest. The Nuss procedure is minimally invasive surgical correction of this defect, using retrosternal metal bars. The purpose of the present study was to describe a 15-year experience with the Nuss surgery, and to evaluate the long-term clinical results of the procedure. We retrospectively evaluated 239 patients, aged 14-34, who underwent the Nuss surgery in the years 2002-2016. Postoperative complications were observed in 40/236 (16.9%) patients. The most common complication was pneumothorax in 14/239 patients. Less common were the following: wound infection in 4, pleural effusion in 3, allergy to nickel in 1, lung atelectasis in 1, and ventricular failure in 1 patient. Three patients were treated because of severe postoperative pain, and in one case the implant had to be removed. Postoperative complications associated with the number of bars inserted, but not with the patient age or gender. A satisfactory and long lasting corrective effect of surgery was observed in 231/239 (96.7%) of patients. There was no perioperative mortality. We conclude that the Nuss surgery is a safe surgery that demonstrates excellent and long-lasting esthetic results, with a low risk of severe complications.

PDGFRα/HER2 and PDGFRα/p53 Co-expression in Oral Squamous Cell Carcinoma.

AIM: The purpose of this study was to explore the parallel expression of platelet-derived growth factor receptor α (PDGFRα) and human epidermal growth factor receptor 2 (HER2) or p53 in relation to clinicopathological parameters of oral squamous cell carcinoma (OSCC) to define their role in progressive growth of tumor. MATERIALS AND METHODS: Expression of PDGFRα, HER2 and p53 was evaluated in 71 OSCC samples by immunohistochemistry. HER2 status was verified by fluorescence in situ hybridization. RESULTS: PDGFRα and p53 expression were associated with tumor grade (p=0.043 and p=0.040, respectively). HER2 expression was more frequent in advanced (III/IV) cancer (p=0.006). A positive correlation of PDGFRα with HER2 (r=0.267; p=0.024) and with p53 (r=0.266; p=0.025) was noted. PDGFRα/HER2 and PDGFRα/p53 co-expression was found more often in G3 than in G1 and G2 tumors (p=0.008 and p=0.015, respectively). CONCLUSION: Our study revealed that PDGFRα/HER2 and PDGFRα/p53 co-expression exists in poorly differentiated OSCCs, suggesting that cooperation between these proteins might enhance aggressive behavior of tumor.

Influence of Obesity on the Course of Malignant Neoplastic Disease in Patients After Pulmonary Metastasectomy.

BACKGROUND/AIM: The aim of the study was to determine whether increased body mass index (BMI) in patients operated on for lung metastases influences the course of the disease. MATERIALS AND METHODS: The retrospective data of 97 patients previously operated on for different malignancies were analyzed. There were 40 obese patients (BMI >30 kg/m2, mean 33.9±4.5) and 57 non-obese patients (BMI 25.8±2.7 kg/m2, p<0.001). Disease-free interval (DFI), the overall survival (OS) and survival after pulmonary metastasectomy were analyzed. RESULTS: DFI and OS were longer in obese than in non-obese patients (82.1±83.5 months vs. 43.0±44.4, p<0.01 and 110.7±81.3 months vs. 69.9±52.9 p<0.005, respectively). Survival after pulmonary metastasectomy was 27.2±25.6 months and was longer in obese and overweight patients than in normal weight patients (20.2±18.4 months vs. 29.4±26.5, p<0.05). CONCLUSION: Being obese or overweight is a favorable prognostic factor in patients after surgical resection of lung metastases of different malignancies.