Miljenko Katunarić

EGFR and cyclin D1 in nodular melanoma: correlation with pathohistological parameters and overall survival.

Considering that nodular melanoma (NM) has the potential to show an early distant metastasis, there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate the protein expression of membrane and nuclear epidermal growth factor receptor (EGFR), cyclin D1, and the corresponding gene status in NM samples and correlate the results obtained with clinicopathological parameters and overall survival of patients. Immunohistochemical and fluorescence in-situ hybridization analyses were carried out on tissue microarrays constructed from 110 NM samples, 30 compound nevi, and 38 dysplastic nevi. NM samples showed 24% strong cyclin D1 and 37% strong Ki67 protein expression compared with 3 and 0% strong cyclin D1 and Ki67 expression in the control group. Membrane EGFR expression was detected in 50% of NM cases, whereas EGFR gene amplification was detected in only 4% of NM cases. Multiple NM samples presented simultaneous membrane and nuclear EGFR expression. We found a negative correlation between tumor thickness and membrane EGFR expression. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR-negative (0) NM samples. In univariate analysis, carried out on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++, +++) showed 3.06 and membrane EGFR (2+, 3+) showed 2.76 higher risk of mortality compared with patients with low and negative nuclear and membrane EGFR expression (P<0.05).

Modulating telomerase activity in tumor patients by targeting dyskerin binding site for hTR

Telomeres shortening, which leads to apoptosis, is prevented by telomerase adding small repeated segments of DNA to the telomeres. The telomerase level has been correlated with progression of several cancer types, including acute leukemia, breast, prostate, lung cancer and melanoma. Suppression of telomerase activity was found to reduce metastatic potential but could have serious side effects in normal proliferative cells. One of the proteins stabilizing the telomerase complex called dyskerin reduces the maximum telomerase activity. We suggest a possible therapeutic agent which would disable the interaction of dyskerin and telomerase, but would not completely inhibit telomerase activity.

Primary large-cell neuroendocrine carcinoma of the scrotum

ZusammenfassungDie vorliegende Arbeit berichtet über einen 78-jährigen Mann mit einem schnell wachsenden Knötchen am Skrotum und einer Schwellung in der Inguinalregion. Es bestanden sonst keine subjektiven Symptome. Die Familieanamnese für erbliche Tumoren war negativ. Sexuell übertragbare Krankheiten, Traumata, Pilzinfektionen oder chronische Reizung der Region wurden negiert. Ebenso hatte keine Radiotherapie, chemische oder Arsen-Exposition statt gefunden. Beide Hautveränderungen wurden 1,2 cm im Gesunden exzidiert. Die histologische Untersuchung zeigte ein umschriebenes, undifferenziertes großzelliges neuroendokrines Karzinom mit Metastasen in den inguinalen Lymphknoten. Drei Monate nach der Exzision fanden wir ein lokales Rezidiv. Die Histopathologie zeigte, dass das Rezidiv mit dem primären Tumor identisch war. Bisher ist unserem Wissen nach in der medizinischen Literatur noch nicht über einen neuroendokrinen Tumor des Skrotums berichtet worden.SummaryNeuroendocrine tumors (NETs) mostly develop from the neural crest cells but a few arise from neuroectoderm. They are common in the lungs and gastrointestinal tract but rare in the genitourinary tract. A 78-year-old man with no family history of malignant or hereditary diseases presented with a 3-month history of a rapidly growing asymptomatic scrotal nodule and swelling in the groin. He had a negative history of sexually transmitted disease and of trauma, fungal infection or chronic irritation in the scrotal area; there was no history of radiotherapy or exposure to chemicals or arsenic. Both the scrotal and groin lesions were excised with a minimum of 1.2 cm of normal skin. Examination of the specimen revealed a confined poorly differentiated large-cell neuroendocrine carcinoma with a metastasis to the inguinal lymph nodes. Three months after the excision we found a local recurrence. The recurrent tumor revealed tumor tissue concurrent with the primary lesion. To the best of our knowledge, there have been no previously published case reports on neuroendocrine tumor of the scrotum.

Cytoplasmic EGFR staining and gene amplification in glottic cancer - a better indicator of EGFR-driven signaling?

Although enhanced epidermal growth factor receptor (EGFR) signaling has been connected with glottic cancerogenesis, the precise mechanisms of its activation still remain unclear. The aim of the present study was to examine EGFR on protein level, confronting cellular pattern of expression and EGFR gene amplification in glottic carcinomas. Tissue microarray technology was applied for uniformity of results. Biopsy specimens of patients with glottic squamous cell carcinoma and simple hyperplasia (control samples) were immunostained for EGFR. Immunohistochemical EGFR reaction was analyzed as membrane and cytoplasm positive and compared with the presence of gene amplification obtained by fluorescent in situ hybridization (FISH) analysis, obtained previously on a large group of patients. The cytoplasmic distribution of the EGFR staining appeared as a primary property of some squamous carcinoma cells; different from the membranous reaction, the reactions were mutually exclusive. Significantly higher scores of cytoplasmic EGFR staining were found in carcinomas with gene amplification when the cell reaction was examined in the basal and suprabasal layer. Our results suggest that EGFR expression in squamous cell carcinoma is different with regard to tumor cell position in carcinoma with ERGF gene amplification, which could be a new indicator of differently driven EGFR signaling in glottic cancer. Such results with cellular pattern distribution of EGFR protein are worthy of further research.

EGFR activated cell mobility - A link to melanoma ulceration.

Melanoma ulceration is the third most powerful survival predictor in the analysis for the currently valid 2010 AJCC melanoma staging system. However, there is still no detailed explanation for melanoma ulceration mechanism. Although thicker tumors are more commonly ulcerated, ulceration is a factor that predicts the disease outcome independently of melanoma thickness. It is our hypothesis that EGFR activates melanoma cell mobility. Melanoma cells with increased mobility move through tissue in diverse direction. Cells moving toward the epithelium weaken the intercellular bonds between the cells causing the loss of epithelium and subsequently ulceration.