MicroRNA expression correlates with disease recurrence and overall survival in oral squamous cell carcinoma.

OBJECTIVES: Locoregional disease recurrence and metastatic events are the leading causes of death and the most important prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). A major goal of oncology is the identification of clinical and molecular parameters to evaluate the individual risk of recurrence. MicroRNAs (miRNAs) have been shown to correlate well with tumor size and differentiation. Therefore, they are candidate biomarkers for estimating clinical outcomes. MATERIALS AND METHODS: In this study, the expression levels of distinct miRNAs extracted from formalin-fixed, paraffin-embedded (FFPE) samples of oral squamous cell carcinoma were compared. RESULTS: Statistical analysis revealed significant correlations between distinct miRNAs and disease recurrence (miR-99*, miR-194*; p < 0.05) and overall survival (miR-99*; p < 0.05). The results were then validated via data from The Cancer Genome Atlas (TCGA). CONCLUSIONS: Our data show that miR-99* and miR-194* can possibly serve as biomarkers for clinical outcome in HNSCC. These findings may help to identify high-risk patients, who could profit from a more individualized treatment and follow-up.

SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as type II enteropathy associated T-cell lymphoma (type II EATL), is a rare, aggressive primary intestinal T-cell lymphoma with a poor prognosis and an incompletely understood pathogenesis. We collected 40 cases of MEITL and 27 cases of EATL, formerly known as type I EATL, and comparatively investigated the T-cell receptor (TCR) itself and associated signaling molecules using immunohistochemistry, amplicon deep sequencing and bisulfite pyrosequencing. The TCR showed both an αß-T-cell origin (30%) and a γδ-T-cell derivation (55%) resulting in a predominant positive TCR phenotype in MEITL compared with the mainly silent TCR phenotype in EATL (65%). The immunohistochemical expression of the spleen tyrosine kinase (SYK) turned out to be a distinctive feature of MEITL (95%) compared with EATL (0%). Aberrant SYK overexpression in MEITL is likely caused by hypomethylation of the SYK promoter, while no common mutations in the SYK gene or in its promoter could be detected. Using amplicon deep sequencing, mutations in DNMT3A, IDH2, and TET2 were infrequent events in MEITL and EATL. Immunohistochemical expression of linker for activation of T-cells (LAT) subdivided MEITL into a LAT expressing subset (33%) and a LAT silent subset (67%) with a potentially earlier disease onset in LAT-positive MEITL.

Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report.

BACKGROUND: Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases. CASE PRESENTATION: The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved. CONCLUSIONS: Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.

Co-treatment of wild-type EGFR head and neck cancer cell lines with afatinib and cisplatin.

Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging. Non­surgical approaches typically comprise radiotherapy and antineoplastic chemotherapy, of which platinum­based agents are the most common. Similar to other malignancies, targeted therapies have an increasing role in the treatment of head and neck cancer. The overexpression of epidermal growth factor receptor (EGFR) is a useful target for specific therapeutic strategies. Resistance to EGFR­directed therapies, including cetuximab, is partly mediated by the activation of alternative receptors and pathways. Therefore, other members of the ErbB family, including human epidermal growth factor receptor (HER)2 and HER4, may have important therapeutic roles. The aim of the present study was to investigate the efficacy of afatinib, an EGFR/HER2/HER4 tyrosine kinase inhibitor, in combination with cisplatin in HNSCC cell lines. The cisplatin concentration used was set at cell line­specific half maximal inhibitory concentration values. Since the vast majority of head and neck cancers do not exhibit any EGFR tyrosine kinase domain mutations, five human EGFR wild­type HNSCC cell lines were used in the present study. For statistical analyses, non­parametric Mann­Whitney tests were conducted. The present study detected a concentration­dependent efficacy of afatinib. In three out of the five cell lines (PCI­9, PCI­52 and PCI­68), 0.625 µM afatinib in combination with cisplatin exerted significant antiproliferative effects. In the two other cell lines (PCI­1 and PCI­13), significant effects were observed following treatment with ≥1.25 µM afatinib. Notably, compared with the findings of previous studies, cell lines (PCI-9 and PCI-52) less vulnerable to erlotinib or gefitinib were more vulnerable to the afatinib/cisplatin combination, and vice versa. Differences in the treatment success of erlotinib/gefitinib (targeting only EGFR) and afatinib (targeting EGFR, HER2 and HER4) may be explained by mutations in the EGFR. Therefore, afatinib treatment may be considered an important therapeutic option for patients failing cetuximab treatment. In addition, the present study demonstrated significant enhancement of platinum­based therapies upon the addition of various afatinib concentrations. These results provide preclinical evidence to advocate further in vivo studies and clinical trials.

Erlotinib and gefitinib responsiveness in head and neck cancer cell lines--a comparing analysis with cetuximab.

OBJECTIVE: The objective of this study is to examine the efficacy of erlotinib and gefitinib with respect to epidermal growth factor (EGF) and cetuximab response in head and neck cancer cell lines. MATERIALS AND METHODS: Five human head and neck carcinoma cell lines were treated with EGF, cetuximab, erlotinib, and gefitinib, and the effects were measured with a crystal violet assay. The efficacies of cetuximab, erlotinib, and gefitinib in clinically relevant concentrations were statistically analyzed. The expression of the epidermal growth factor receptor (EGFR) and phosphorylation patterns were detected with fluorescence-activated cell sorting (FACS) analysis and western blot analysis. The endogenous production of EGF by the cells was detected with an enzyme-linked immunosorbent assay. Finally, EGFR, KRAS, BRAF, and PI3K mutation analyses were performed. RESULTS: All of the cell lines had a poor or no response to EGF but exhibited distinct EGFR phosphorylation and EGFR expression. Compared to cetuximab, erlotinib and gefitinib demonstrated a greater impact on the majority of the cell lines. The only cell line that showed a concentration-dependent behavior toward EGF and strong EGFR phosphorylation was entirely resistant to cetuximab, erlotinib, and gefitinib. The production of EGF in all cell lines was very low. Mutational analysis of all cell lines revealed wild-type EGFR, KRAS, BRAF, and PI3K. CONCLUSIONS: The prediction of anti-EGFR treatment cannot be based on responsiveness to EGF or EGFR activation. CLINICAL RELEVANCE: Erlotinib and gefitinib show good response in EGF-independent cell lines and might be useful drugs in tumors that are less responsive to cetuximab.

Oral brush biopsy and melanoma-associated antigens A (MAGE-A) staining in clinically suspicious lesions.

PURPOSE: In oral cancer and in other tumor entities, melanoma-associated antigens are present. These antigens contribute to tumor progression and poor prognosis, and reduce the cytotoxicity of antineoplastic drugs. The aim of this study was to investigate the diagnostic potential of these antigens in combination with oral brush biopsies. MATERIAL AND METHODS: We analyzed 72 oral brush biopsy specimens for melanoma-associated antigens A (MAGE-A) expression by immunocytologic staining with the MAGE-A 57B antibody. A total of 24 healthy specimens, 15 lichen ruber cases, 18 leukoplakia cases, and 15 invasive carcinomas were studied. Incisional biopsy served as the gold standard. RESULTS: In total, 66 of 72 specimens (91.6%) could be assessed. Twelve of 15 (80%) carcinomas stained positive for MAGE-A. MAGE-A staining was detected in four of 51 nonmalignant specimens, resulting in a false-positive rate of 7.8%. However, MAGE-A positive staining was significantly correlated with oral squamous cell carcinoma (p < 0.0005). Sensitivity and specificity for MAGE-A staining and carcinoma were 80% and 92.2%, respectively. The diagnostic accuracy was 89.4%. CONCLUSION: Our results indicate that oral brush biopsy with MAGE-A staining serves as an additional tool for use in oral cancer diagnosis. These findings might help to facilitate an easier and more representative surveillance of the mucosa, particularly for large areas of altered mucosa.