Weibel W. Braunius

Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma: A systematic review

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV). HPV-positive OPSCC is considered a distinct molecular entity with a better prognosis than HPV-negative cases of OPSCC. However, the exact pathogenic mechanisms underlying the differences in clinical and molecular behavior between HPV-positive and HPV-negative OPSCC remain poorly understood. Epigenetic events play an important role in the development of cancer. Hypermethylation of DNA in promoter regions and global hypomethylation are 2 epigenetic changes that have been frequently observed in human cancers. It is suggested that heterogeneous epigenetic changes play a role in the clinical and biological differences between HPV-positive and HPV-negative tumors. Unraveling the differences in methylation profiles of HPV-associated OPSCC may provide for promising clinical applications and may pave the road for personalized cancer treatment. This systematic review aims to assess the current state of knowledge regarding differences in promoter hypermethylation and global methylation between HPV-positive and HPV-negative OPSCC.

HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV) in a proportion of tumors. HPV‐positive OPSCC is considered a distinct molecular entity with a prognostic advantage compared to HPV‐negative cases. Silencing of cancer‐related genes by DNA promoter hypermethylation may play an important role in the development of OPSCC. Hence, we examined promoter methylation status in 24 common tumor suppressor genes in a group of 200 OPSCCs to determine differentially methylated genes in HPV‐positive versus HPV‐negative primary OPSCC. Methylation status was correlated with HPV status, clinical features, and patient survival using multivariate methods. Additionally, methylation status of 16 cervical squamous cell carcinomas (SCC) was compared with HPV‐positive OPSCC. Using methylation‐specific probe amplification, HPV‐positive OPSCC showed a significantly higher cumulative methylation index (CMI) compared to HPV‐negative OPSCC (P=0.008). For the genes CDH13, DAPK1, and RARB, both HPV‐positive and HPV‐negative OPSCC showed promoter hypermethylation in at least 20% of the tumors. HPV status was found to be an independent predictor of promoter hypermethylation of CADM1 (P < 0.001), CHFR (P = 0.027), and TIMP3 (P < 0.001). CADM1 and CHFR showed similar methylation patterns in OPSCC and cervical SCC, but TIMP3 showed no methylation in cervical SCC in contrast to OPSCC. Methylation status of neither individual gene nor CMI was associated with survival. These results suggest that HPV‐positive tumors are to a greater extent driven by promotor hypermethylation in these tumor suppressor genes. Especially CADM1 and TIMP3 are significantly more frequently hypermethylated in HPV‐positive OPSCC and CHFR in HPV‐negative tumors.

Outcome and toxicity of radiotherapy combined with chemotherapy or cetuximab for head and neck cancer: Our experience in one hundred and twenty‐five patients

Simultaneous radiotherapy and chemotherapy improve survival in patients with locally advanced head and neck squamous cell carcinoma compared to radiotherapy alone. Addition of cetuximab (an anti-EGFR antibody) to radiotherapy combined with cetuximab also improves survival. Postoperative (adjuvant) radiotherapy combined with chemotherapy improves (disease-free) survival in patients with a microscopically incomplete resection and/or extracapsular spread of nodal disease compared to adjuvant radiotherapy alone. We previously published our experience with primary radiotherapy combined with chemotherapy for locally advanced head and neck squamous cell carcinoma in the period 1998–2002. We found an overall long-term survival of 30–40%. Since then, we adjusted the following: all patients receiving primary radiotherapy combined with chemotherapy receive nutritional support using a percutaneous endoscopic gastrostomy (PEG)-tube tube; radiotherapy technique has changed; patients unfit for radiotherapy combined with chemotherapy receive radiotherapy combined with cetuximab; radiotherapy combined with chemotherapy and occasionally radiotherapy combined with cetuximab are also given in the adjuvant setting. The aim of this study is to assess the feasibility, effectiveness and toxicity of radiotherapy combined with chemotherapy or cetuximab in patients with locally advanced head and neck squamous cell carcinoma treated in our institute between 2008 and 2010 and to compare the results with the updated data of the previous cohort. Patients and methods

Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma

Current conventional treatment modalities in head and neck squamous cell carcinoma (HNSCC) are nonselective and have shown to cause serious side effects. Unraveling the molecular profiles of head and neck cancer may enable promising clinical applications that pave the road for personalized cancer treatment. We examined copy number status in 36 common oncogenes and tumor suppressor genes in a cohort of 191 oropharyngeal squamous cell carcinomas (OPSCC) and 164 oral cavity squamous cell carcinomas (OSCC) using multiplex ligation probe amplification. Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival. The 11q13 region showed gain or amplifications in 59% of HPV‐negative OPSCC, whereas this amplification was almost absent in HPV‐positive OPSCC. Additionally, in clinically lymph node‐negative OSCC (Stage I–II), gain of the 11q13 region was significantly correlated with occult lymph node metastases with a negative predictive value of 81%. Multivariate survival analysis revealed a significantly decreased disease‐free survival in both HPV‐negative and HPV‐positive OPSCC with a gain of Wnt‐induced secreted protein‐1. Gain of CCND1 showed to be an independent predictor for worse survival in OSCC. These results show that copy number aberrations, mainly of the 11q13 region, may be important predictors and prognosticators which allow for stratifying patients for personalized treatment of HNSCC.

The value of postoperative anticoagulants to improve flap survival in the free radial forearm flap: a systematic review and retrospective multicentre analysis.

Free radial forearm flap (FRFF) reconstruction is a valuable technique in head and neck surgery, which allows closure of large defects while striving to maintain functionality. Anticoagulative drugs are often administered to improve flap survival, although evidence regarding effectiveness is lacking.

A systematic review of computed tomography detection of cartilage invasion in laryngeal carcinoma.

This systematic review aimed to assess the diagnostic value of computed tomography (CT) in detecting cartilage invasion among patients with laryngeal carcinoma.

Prognostic significance of the EGFR pathway in nasopharyngeal carcinoma: a systematic review and meta-analysis

OBJECTIVE To evaluate the prognostic impact of the EGF receptor (EGFR) pathway molecules and assess their clinical usefulness. METHODS We conducted a systematic review. Pubmed and EMBASE were searched January 2014. The prognostic relevance of EGFR, JAK, PI3K, PIK3CA, STAT3, STAT5, PTEN, AKT, mTOR, GRB2, SOS, RAF, RAS, MAPK, ERK, MEK and CCND1 in nasopharyngeal carcinoma was assessed. The outcomes considered were overall survival, disease-free survival and tumor-node-metastasis stage. Twenty-two studies were included. Risk of bias was evaluated. Meta-analysis for which pooled hazard ratios and 95% CIs were calculated. CONCLUSION EGFR overexpression predicts a worse overall survival and disease-free survival in nasopharyngeal carcinoma, but no specific causal pathway molecule could be identified.

Prognostic role of tumor infiltrating lymphocytes in EBV positive and EBV negative nasopharyngeal carcinoma

OBJECTIVES Tumor infiltrating lymphocytes (TILs) correlate with both better and worse prognosis in solid tumors. As therapeutic modalities for nasopharyngeal carcinoma (NPC) are limited, immunotherapy could be a potential alternative. Up till now there is limited prognostic data on the role of TILs in NPC, so we assessed the prognostic role of TILs in Epstein-Barr-virus (EBV) positive and negative NPC. METHODS Tissue of 92 NPCs was assessed for CD3, CD4, CD8, PD1 and PDL1 expression in the tumors micro-environment. Correlations between clinicopathological characteristics was assessed using the Pearson X2 test, Fishers exact test and ANOVA. Survival was analyzed with the Kaplan-Meier method and Cox regression. Differences in CD3, CD4, CD8, PD1, PDL1 counts/(co)expression between EBV positive and negative NPCs were evaluated using the Mann-Whitney U test. Two-tailed P values below 0.05 were considered statistically significant. RESULTS EBV positive NPC contains significantly more CD3, CD4 and CD8 TILs than EBV negative NPC. In the whole NPC group, increased CD8 count is associated with better overall survival (OS) (HR 0.219 (95%CI 0.075-0.640)), but also in cases with PDL1 co-expression (HR 0.073 (95%CI 0.010-0.556)). In EBV positive NPC co-expression of CD8 and PDL1 showed better disease free survival (HR 0.407 (95%CI 0.195-0.850)) and OS (HR 0.170 (95%CI 0.037-0.787)). CONCLUSIONS Although TILs are significantly different between EBV positive and negative NPCs, it is especially composition of the infiltrate which determines prognosis. Effects of PD1 and CD8 need more study, because these findings show much potential in using immunotherapeutic modalities in NPC treatment.

Grade of dysplasia and malignant transformation in adults with premalignant laryngeal lesions.

The purpose of this systematic review was to determine the significance of the grade of dysplasia in the development of invasive carcinoma.

The Co-Expression of Kallikrein 5 and Kallikrein 7 Associates with Poor Survival in Non-HPV Oral Squamous-Cell Carcinoma

Objective: Oral squamous-cell carcinoma (OSCC) still has a poor prognosis. Lymph node metastasis (LNM) is a major determinant of treatment decisions and prognosis. Serine protease inhibitor Kazal-type 5 (SPINK5) is the inhibitor of kallikrein 5 (KLK5) and KLK7. SPINK5, KLK5 and KLK7 are three of the genes of a recently validated LNM-predicting gene expression profile in OSCC. This study evaluates their clinicopathological role and value as biomarkers in OSCC. Methods: Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papillomavirus (HPV) status was determined by an algorithm for HPV-16. Protein expression for KLK5, KLK7 and SPINK5 was semi-quantitatively determined in all 83 tumours by immunohistochemistry. All expression data were correlated with clinicopathological parameters. Results: Concurrent loss of KLK5 and KLK7 correlates with worse disease-specific and overall survival (DSS and OS). Multivariate analysis proved that co-expression is an independent prognostic factor for DSS (p = 0.029) and OS (p = 0.001). Conclusion: This report demonstrates that concurrent loss of KLK5 and KLK7 associates with a poor clinical outcome in OSCC and could therefore serve as prognostic marker in this disease.