A related DNA fragment distinct from the epidermal growth factor receptor and ERBB2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNA. Characterization of the cloned DNA fragment mapped the region of v-erbB homology to three exons with closest identity of 64% and 67% to a contiguous region within the tyrosine kinase domains of the epidermal growth factor receptor and ERBB2 proteins, respectively. cDNA cloning revealed a predicted 148-kDa transmembrane polypeptide with structural features identifying it as a member of the ERBB gene family, prompting us to designate the gene as ERBB3. It was mapped to human chromosome 12q13 and was shown to be expressed as a 6.2-kilobase transcript in a variety of normal tissues of epithelial origin. Markedly elevated ERBB3 mRNA levels were demonstrated in certain human mammary tumor cell lines. These rmdings suggest that increased ERBB3 expression, as in the case of epidermal growth factor receptor and ERBB2, may play a role in some human malignancies.Protooncogenes encoding growth factor receptors constitute several distinct families with close overall structural homology. The highest degree of homology is observed in their catalytic domains, essential for the intrinsic tyrosine kinase activity of these proteins (1). Examples of such families include genes encoding epidermal growth factor receptor (EGF-R) and ERBB2, the colony-stimulating factor 1/ platelet-derived growth factor receptors, insulin/insulin-like growth factor 1 receptors, and EPH/ELK (2-12). Growth factor receptors in several of these families play critical roles in regulation of normal growth and development. Some of these molecules have been implicated in the neoplastic process as well. In particular, both the EGF-R gene and ERBB2 have been shown to be activated as oncogenes by mechanisms involving overexpression or mutations that constitutively activate the catalytic activity of their encoded proteins (13)(14)(15)(16) DNA and RNA Hybridization. High-stringency hybridization was conducted as described (20). Reduced-stringency hybridization of DNA was carried out in 30% (vol/vol) formamide followed by washes in 0.6x SSC, whereas intermediate stringency was achieved by hybridization in 40% (vol/vol) formamide and washing in 0.25x SSC.Molecular Cloning. An oligo(dT)-primed human placenta cDNA library was obtained from Clontech. The oligo(dT) primed MCF-7 cDNA library was constructed in ApCEV9 (21). After plaque purification, phage DNA inserts were subcloned into pUC-based plasmid vectors for further characterization.Nucleotide and Amino Acid Sequence Analysis. The nucleotide sequence was determined for both DNA strands by the dideoxy chain-termination method (22) using supercoiled plasmid DNA as template.t Amino acid sequence comparison was performed with the alignment program by Pearson and Lipman (23). Hydrophobic and hydrophilic regions in the predicted protein were identified according to Kyte and Doolittle (24).

Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development of cancer in humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed in tumor‐derived cell lines and that heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism for signal definition, diversification or amplification. In cells expressing HER2 and HER3, tyrosine phosphorylation of HER3 is markedly increased upon exposure to recombinant HRG. ATP binding site mutants of HER2 and HER3 demonstrate transphosphorylation of HER3 by HER2, but not vice versa. HRG‐induced transphosphorylation of HER3 results in a substrate phosphorylation pattern distinct from HER2 cells and enhances association of the receptor with SHC and phosphoinositol 3‐kinase in transfected 293 and mammary carcinoma‐derived MCF‐7 cells. The physiological relevance of HER2/HER3 heterodimerization is demonstrated by HRG‐dependent transformation of NIH 3T3 cells coexpressing the two receptors. These findings demonstrate the acquisition of expanded signaling capacities for HER2 by HRG‐induced heterodimerization with HER3 and provide a molecular basis for the involvement of receptor heteroactivation in the development of human malignancies.

In the treatment of LPR-related symptoms a high placebo effect can be observed. However, compared to control, twice-daily PPI treatment for three months demonstrated a significantly greater improvement in laryngeal appearance and LPR symptoms.

Carcinoma of unknown primary is defined as the histological diagnosis of metastasis without the detection of a primary tumor. In the literature, the incidence of CUP in all patients with a malignant disease is said to be between 3% and 15%. The most frequent histopathological results of CUP metastases are adenocarcinoma, followed by undifferentiated carcinoma and squamous cell carcinoma. In this retrospective investigation the clinical records of 167 patients were studied. All patients had been admitted and treated for cervical CUP at the Department of Otorhinolaryngology of the Grosshadern Clinic from 1979 to 1998. Cervical swelling was the first noted symptom in all cases, followed by pain and dysphagia. The study group comprised 134 men and 33 women with an average age of 55 years at admission. Squamous cell carcinoma (n=123) was the predominant histopathological finding of the cervical lymph nodes. During the 10-year follow-up, a primary tumor was detected in 36 (21.5%) of the 167 initially diagnosed CUP patients. In over 90% of these cases the tumor was localized in the head and neck region. The most frequent origin of the tumor was the tonsilla palatina (n=7). Neck dissection and additional postoperative radiotherapy was performed in 118 (70.7%) of the 167 CUP patients. Primary radiotherapy was the treatment of choice in 28 patients; eight patients received combined radio-chemotherapy as the primary treatment and seven patients were treated with chemotherapy alone. Six patients had no treatment. Comparison of different treatment protocols revealed a significant difference in patient survival: in comparison with primary radiotherapy alone or neck dissection and postoperative radiotherapy, the survival rate improved significantly in patients that received a bilateral tonsillectomy in addition to neck dissection and postoperative radiotherapy. The treatment of choice in patients with cervical CUP should be a surgical procedure including (radical) neck dissection and diagnostic bilateral tonsillectomy followed by postoperative radiation of the cervical lymph drainage. Bilateral tonsillectomy is especially important and is correlated with a significant improvement of the survival rate in CUP patients. Additional postoperative radiation of the entire pharyngeal and laryngeal mucosa should also be considered in order to treat a possible small primary tumor in this region.

Laryngopharyngeal symptoms can be predictors of gastroesophageal diseases and GERD because the most frequent underlying cause is supposed to be associated with posterior laryngitis. Medical antireflux treatment is effective for relief of symptoms and mucosal healing of posterior laryngitis.

After decades of rigorous investigations of chemotherapeutic cancer therapies, many cancers, including those of the head and neck, remain beyond our clinical ability to control them. From 3% to 5% of all patients initially cured of early-stage head and neck cancer will develop second primary tumors or local recurrences. 1 This phenomenon has been explained by the concept of field cancerization, which argues that certain risk factors such as alcohol and tobacco change the lining of the upper aerodigestive tract into a so-called condemned mucosa. In such a scenario, alcohol may represent the key risk factor for neoplastic transformation in the oral cavity, the oro-and hypopharynx. [2][3][4] An increasing amount of evidence suggests that alcohol intake and smoking play a synergistic role in the neoplastic progress.One of the most important achievements of molecular oncology has been the demonstration that cancer represents a genetic disease that begins with genetic damages in the genome of one cell in the form of point mutations, DNA rearrangement and gene amplification leading to the distortion of the expression and biochemical function of respective gene products. Growth factor receptors of the class I subfamily, which include the epidermal growth factor receptor (EGFR/HER1) and the related proteins HER2, HER3 and HER4, have shown that amplification or overexpression of those receptors, especially well documented for HER2 in patients with breast and ovarian cancers, plays an important role in carcinogenesis and tumor progression. [5][6][7][8] Multivariate survival analysis showed that HER2 amplification or overexpression is more predictive of clinical outcome than all other known prognosticators with the exception of positive lymph nodes. 9,10 These findings have validated the HER2 receptor as a target for therapeutic intervention. Moreover, recent clinical investigations have confirmed the benefit of antagonistic HER2 antibody therapy in breast cancer using herceptin. 11 Minute genetic changes such as point mutations have been found to cause constitutive activation of the HER2/neu kinase activity and to induce neoplastic disorders. 12 Similarly, the 2 amino acid substitutions Gly380Arg and Ala391Glu in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) have been shown to be responsible for 2 forms of human dwarfism, namely, achondroplasia and morbus crouzon. [13][14][15] Other mutations in the FGFR3 gene have been associated with bladder and cervix cancer. 16 The FGFR signaling system is composed of 4 receptor tyrosine kinases (RTKs) and more than 20 known ligands and has been implicated in the regulation of a multitude of both physiologic and pathophysiologic processes, including migration, wound healing, angiogenesis and cancer. 17 More recently, we have identified a single nucleotide polymorphism (SNP) in codon 388 of the FGFR4 gene, which plays a pivotal role in the progression of breast cancer. This SNP is present at a significantly higher rate in breast cancer patients with early relap...

We report a case of a 30-year-old, previously healthy man who presented at our clinic with complaints of increasing dysphagia and globus sensation for about 2 years. In addition, he noticed an increasing submental swelling. On examination, the patient revealed a massive swelling of the floor of the mouth, which had displaced the tongue cranially. MRI imaging showed the lesion to be a homogeneous, cystic lesion, clearly at a distance from the surrounding mucous tissue. Surgery was performed, and the tumor was resected completely. Histologic examination of the resected tissue was consistent with a dermoid cyst located in the floor of the mouth. Although dermoid cysts are rarely located in the oral cavity, it should be included in differential diagnosis. Surgery is the treatment of choice.

There is a lot of scepticism surrounding laryngopharyngeal reflux (LPR). Symptoms such as globus pharyngeus, constant throat clearing, chronic cough, idiopathic hoarseness, catarrh and choking episodes may be reflux-related. The aim of this survey was to highlight current treatment trends in LPR. Questionnaires were emailed to 260 members of the British Academy of Otolaryngology-Head and Neck surgery (BAO-HNS). Survey recipients were asked about type, duration and dose of antireflux treatment and length of follow-up appointments, if any. Finally, they were asked about awareness of any reflux symptom and reflux sign questionnaires. Survey response rate was 60%. The vast majority of the otolaryngologists surveyed believe in laryngopharyngeal reflux (90%) and more than 50% prescribe proton pump inhibitors (PPIs). The preferred duration of treatment is 2 months (37%). Only a minority will prescribe PPIs for 6 months or more. Most otolaryngologists will give the standard GORD dose (70%) (once daily) and only a few (20%) will prescribe more aggressive and prolonged doses. The commonest symptoms for which proton pump inhibitors are prescribed are globus (73%), followed by choking episodes (66%) and chronic cough (62%). If LPR is suspected, most of the otolaryngologists will follow-up the patients (61%) and approximately one third (31%) will discharge them back to the general practitioners. Only eight-percent 8% will refer to gastroenterologists. The three commonest laryngoscopic signs that makes them suspect LPR are erythema of the arytenoids (86%) or the vocal cords (57%) and granulomas (42%). The majority of the otolaryngologists (94%) do not use popular questionnaires such as the RFS or RSI. Despite the controversy surrounding laryngopharyngeal reflux, our results suggest that the majority of the otolaryngologists surveyed believe in LPR and attempt to treat it. Interesting findings are: the duration of treatment, the doses used, the length of follow-ups or the lack of, and the fact that the majority does not request any specific diagnostic tests. "symptoms and signs" questionnaires are rarely used.