Adrian Münscher

Human epidermal growth factor receptor 2 (HER2) in salivary gland carcinomas

Background: HER2 is a target for antibody-based treatment of breast and gastric carcinoma which is highly successful in advanced disease as well as in the adjuvant setting. To determine the potential applicability of such therapies, salivary gland tumours were analysed for HER2 overexpression/amplification in this study. Methods: A tissue microarray (TMA) was constructed from 994 carcinomas and 205 adenomas of the salivary gland. Slides were analysed for HER2 overexpression and gene amplification using FDA approved reagents for immunohistochemistry (IHC; Hercep-Test; Dako) and fluorescence in situ hybridisation (FISH; PathVysion; Vysis-Abbott). Results: HER2 was found overexpressed in 39 of 915 (4.26%) and amplified in nine of 915 interpretable salivary gland carcinomas (0.98%). HER2 overexpression was mostly found in salivary duct carcinoma. All other entities were mainly HER2 negative. HER2 was overexpressed in 34 of 319 (10.65%) mucoepidermoid carcinomas, one of 170 (0.59%) acinic cell adenocarcinomas and three of 14 (21.43%) salivary duct carcinomas. HER2 amplification was seen in three of 294 (1.01%) mucoepidermoid carcinomas, three of 14 (21.43%) salivary duct carcinomas, one of 81 (1.23%) adenocarcinomas (NOS), one of 12 (8.33%) cystadenocarcinomas and one of 19 (2.08%) myoepithelial carcinomas. HER2 amplification was found in seven of 39 immunohistochemically HER2 positive (2+ and 3+) tumours (17.95%) but in only two of 849 (0.24%) IHC negative tumours (p < 0.0001). No amplification/overexpression was found in adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous low grade carcinoma, basal cell carcinoma, myoepithelial carcinoma, cystadenocarcinoma and oncocytic carcinoma. Conclusion: HER2 overexpression caused by gene amplification was observed in about 20% of patients with salivary duct cancers but was rare in salivary adenomas and other carcinomas. Therefore, anti-HER2 therapy may represent a therapeutic option only in a small subgroup of salivary gland tumours.

11q21 rearrangement is a frequent and highly specific genetic alteration in mucoepidermoid carcinoma.

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Translocation t(11;19)(q21;p13) involving the MECT1 and MAML2 genes has been suggested as a diagnostic marker in these tumors. To determine the specificity of 11q21 locus rearrangements for MEC, fluorescence in situ hybridization analysis with specific MEC-I Dual Color Break Apart Probe was performed on a tissue microarray containing samples from almost 1200 salivary gland adenomas and carcinomas. Rearrangements of 11q21 were observed in 40% of 217 MECs. The frequency of rearrangements decreased with tumor grade and was found in 53% of G1, 43% of G2, and 31% of G3 tumors (P=0.015). There were no 11q21 rearrangements found in other salivary gland carcinomas including 142 adenoid cystic carcinomas, 104 acinic cell adenocarcinomas, 76 adenocarcinoma not otherwise specified, 38 epithelial-myoepithelial carcinomas, 15 polymorphous low-grade adenocarcinomas, 18 basal cell adenocarcinomas, 19 myoepithelial carcinomas, 12 papillary cystadenocarcinomas, 6 salivary duct carcinomas, and 10 oncocytic carcinomas. Furthermore, all analyzed salivary gland adenomas, including 39 cases of Warthin tumor and control samples, either from the salivary gland or from other organs were negative for 11q21 rearrangements. It is concluded that MECT1-MAML2 gene fusion is a highly specific genetic alteration in MEC with predominance in low-grade and intermediate-grade tumors.

Epidermal growth factor receptor (EGFR) in salivary gland carcinomas: Potentials as therapeutic target

AIMS Epidermal growth factor (EGFR) is involved in angiogenesis, cell differentiation, proliferation and progression of many cancers and is an important therapy target in lung and colorectal cancer. To determine the potential applicability of EGFR targeted therapies, EGFR status of over 800 salivary gland tumors of different entities were analyzed on DNA and protein level by FISH and IHC. MATERIALS AND METHODS A tissue microarray was constructed from 721 carcinomas and 205 adenomas of the salivary gland. EGFR expression and EGFR gene copy number was assessed by means of immunohistochemistry and fluorescence in situ hybridization (FISH). EGFR mutation analysis of exon 19 and 21 was performed in a subset of 107 carcinomas. RESULTS Positive immunohistochemical staining (definition?) for EGFR was shown in 324 of 663 (48.9%) salivary gland carcinomas. The frequency was dependent on the tumor entity and ranged from 17.9% (30 of 168 cases) positive immunostaining in acinic cell adenocarcinomas to 85.7% (42 of 49 cases) in Warthin tumors. No EGFR amplification was found by FISH. EGFR mutation analysis of Exon 19 and 21 in 107 salivary gland carcinomas revealed mutations in two acinic cell adenocarcinomas. CONCLUSION EGFR protein expression is common in salivary gland tumors but is not associated with gene amplification. Activating mutations of EGFR are rare. Nonetheless, selected cases of patients with salivary gland carcinomas might potentially benefit of anti-EGFR therapy.

Expression of insulin-like growth factor II mRNA-binding protein 3 in squamous cell carcinomas of the head and neck

BACKGROUND Insulin-like growth factor II mRNA-binding protein 3 (IMP3) was found overexpressed in various cancer types suggesting its possible role in carcinogenesis. Analysis of IMP3 expression in head and neck squamous cell carcinomas (HNSCC) is rare so that we evaluated it using tissue microarray method. METHOD Immunohistochemical analysis of IMP3 was performed on samples from over 400 patients. The expression was measured semiquantitative, subsequently divided into four categories (negative, weak, medium, or strong) and correlated with several available clinicopathologic parameters. RESULTS For HNSCC, positive IMP3 expression was observed in patients with all tumor stages (pT1-4) and nodal stages (pN0-3), showing also significant statistical correlation (P=0.023 and P=0.0013, respectively). No further correlations were found. Separate analysis according to tumor localization (oral cavity, oropharyngeal, and laryngeal) showed a significant correlation of positive IMP3 expression and overall survival (P=0.038) only in patients with tumors of the oral cavity. Multivariate analysis showed IMP3 as an independent predictive marker for oral squamous cell carcinomas (OSCC). CONCLUSION Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression might be used as an independent prognostic factor in the subgroup of OSCC.

A novel tool in laryngeal surgery: Preliminary results of the picosecond infrared laser

Conventional lasers ablate tissue through photothermal, photomechanical, and/or photoionizing effects, which may result in collateral tissue damage. The novel nonionizing picosecond infrared laser (PIRL) selectively energizes tissue water molecules using ultrafast pulses to drive ablation on timescales faster than energy transport to minimize collateral damage to adjacent cells.

Current studies of immunotherapy in head and neck cancer

Recently, enormous progress in cancer therapy has been achieved by the use of immune checkpoint inhibitors. Activating the bodys own immune system has added a novel and powerful therapeutic option for the treatment of melanoma and lung cancer. Furthermore, the potential use of immunotherapy is being extensively explored also in other malignancies.

Comparative study of wound healing in rat skin following incision with a novel picosecond infrared laser (PIRL) and different surgical modalities

As a result of wound healing the original tissue is replaced by dysfunctional scar tissue. Reduced tissue damage during surgical procedures beneficially affects the size of the resulting scar and overall healing time. Thus the choice of a particular surgical instrument can have a significant influence on the postoperative wound healing. To overcome these problems of wound healing we applied a novel picosecond infrared laser (PIRL) system to surgical incisions. Previous studies indicated that negligible thermal, acoustic, or ionization stress effects to the surrounding tissue results in a superior wound healing.

Survival and overall treatment time after postoperative radio(chemo)therapy in patients with head and neck cancer.

Generally, overall treatment time for patients with locally advanced head and neck cancer should be as short as reasonably possible. This analysis was undertaken to determine at what overall treatment time additional survival/locoregional control benefits could be achieved compared to a 100‐day cutoff.

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

BACKGROUND AND PURPOSE HPV-positive HNSCC cells are characterized by radiosensitivity, inefficient DNA double-strand break repair and a profound and prolonged arrest in G2. Here we explored the effect of clinically relevant inhibitors of Chk1 and Wee1 to inhibit the radiation-induced G2-arrest in order to achieve further radiosensitization. MATERIAL AND METHODS Assessment of Chk1 activity by Western blot; assessment of cell cycle distribution by propidium iodide staining and flow cytometry; assessment of cell survival by colony formation assay. HPV+ HNSCC cell lines: UD-SCC-2, UM-SCC-47 and UPCI-SCC-154; Chk1 inhibitors: LY2603618, MK8776; Wee1 inhibitor: AZD1775. RESULTS Specific Chk1 inhibitors efficiently abrogated the radiation-induced G2-arrest and caused radiosensitization. Wee-inhibition by AZD1775 resulted in the activation of Chk1. This feedback mechanism is likely to counteract some of the effects of Wee1 inhibition but could be antagonized through the combined inhibition of both kinases. Combined inhibition was effective using profoundly reduced concentrations of both inhibitors and resulted in more efficient radiosensitization of the HPV-positive cell lines compared to p53 proficient normal human fibroblasts. CONCLUSIONS Specific Chk1 inhibitors as well as the combined inhibition of Chk1 and Wee1 radiosensitize HPV-positive HNSCC cells.

Pituitary hormone mRNA in null cell adenomas and oncocytomas by in situ hybridization comparison with immunohistochemical and clinical data.

Null cell adenomas and oncocytomas are clinically inactive adenomas of the pituitary gland. They do not show any significant hormone content detectable by immunohistochemistry. This study aimed at demonstrating mRNAs for all main pituitary hormones in 32 null cell adenomas and 31 oncocytomas by non-isotopic in situ hybridization using digoxigenin-labeled oligonucleotide probes. The results were compared with immunohistochemical and clinical data. Immunohistochemistry (ABC method) was done with monoclonal antibodies against PRL, GH, FSH, LH, TSH, ACTH, alpha-subunit, and Ki-67 (mib-1). The signals for hormone production were detected in both adenoma types in a range from 42% for GH in oncocytomas to 78% for beta-FSH in null cell adenomas. However, these signals are apparently not effective on hormone production, as was shown by almost negative immunostaining. Owing to the simultaneous detection of at least two mRNAs in 78% of null cell adenomas and in 94% of oncocytomas, we assume that both tumor types originate from pluripotential precursor cells that are capable of producing various hormones. According to our data, it is unlikely that the signals influence the clinical behavior.