Ulrich Hauser

IL-5 synthesis is upregulated in human nasal polyp tissue

BACKGROUND In most nasal polyps, tissue eosinophilia is a striking finding, the pathologic mechanism of which is not understood. OBJECTIVE This study was performed to investigate a possibly distinct cytokine and chemokine pattern that could explain the characteristic tissue eosinophilia in nasal polyps. METHODS Polyps from 23 patients and turbinate tissue from 18 control subjects were investigated. The cytokine protein content (IL-1 beta, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, IL-1RA, RANTES, GRO-alpha) of tissue homogenates was measured by ELISA. Immunohistochemistry was performed in selected samples to detect IL-5+, major basic protein-positive, and EG2+ cells. RESULTS IL-5 was detectable in only one sample of tissue from 18 control subjects but was found in 18 of 23 nasal polyps. Immunohistochemistry revealed an abundant number of IL-5+ cells, of which 69.5% could be identified as eosinophils by morphology. IL-6, IL-8, IL-10, tumor necrosis factor-alpha, GRO-alpha, and RANTES were detected in all specimens, without significant differences between groups (p > or = 0.05), whereas significnatly higher concentrations of IL-1 beta and IL-1RA were found in turbinate mucosa (p < or = 0.05). IL-3 was not detectable: granulocyte-macrophage colony-stimulating factor could only occasionally be found. CONCLUSION This study indicates that IL-5 plays a key role in the pathophysiology of eosinophilic nasal polyps and may be produced by eosinophils.

The dilemma of follow-up in head and neck cancer patients

Abstract The aims of tumor follow-up in head and neck cancer patients are (1) evaluation of therapeutic efficacy, (2) management of impairments, (3) detection of new tumor manifestations, and (4) psychosocial care. In general standardized 5-year-protocols are used for all such patients. However, it is questionable whether a rigid follow-up schedule is optimal for a very heterogeneous tumor population. Therefore 603 patients with sqamous cell carcinoma of the oral cavity, pharynx or larynx, or with cervical metastasis from an unknown primary site (CUP syndrome), who had been diagnosed and treated curatively by an operation with or without radiotherapy (n = 523) or just by radio(chemo)therapy (n = 80) between 1985 and 1994, and who had been followed-up regularly according to a standardized plan, were worked-up retrospectively. Data were evaluated for the manifestation and prognosis of curable new tumor manifestations as well as for tumor-specific factors likely to select groups which should be followed more or less intensively. Within a 5-year follow-up period new tumor growth was detected in 152/603 (25%) patients: 79 local and 31 regional recurrences, 18 systemic metastases and 24 second primary cancers. Where follow-up was extended beyond the 5th year, 168/603 (28%) patients presented a new tumor manifestation. One hundred and sixteen of the 152 (28%) patients had another operation with or without radiotherapy or had radio(chemo)therapy alone. So far 18/116 (14%) patients have survived their new tumor manifestation for more than 5 years and 30/116 for more than 2 years. Tumor-specific data on the initial tumors (T stage, N stage, site) did not indicate the risk of a new tumor manifestation, but 87% of patients who survived their new tumor manifestation for more than 2 years initially had T1 or T2 tumors and only 30% initially had N+ necks. Occurrence of distant metastasis or a second primary outside the head and neck region limited survival to ≤ 2 years after detection. In terms of survival, follow-up efforts should therefore concentrate on detection of locoregional recurrence, particularly if an option for further curative local therapy exists. The limited success of detection of new tumor manifestations in terms of survival does not justify a reduction in tumor-follow-up examinations, since the benefit of the other efforts cannot be determined from survival figures.

Proinflammatory Cytokines: Measurement in Nasal Secretion and Induction of Adhesion Receptor Expression

We recently demonstrated that interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, IL-6 and IL-8 can be found in nasal secretions from allergic rhinitis patients under artificial and natural conditions. By ELISA measurements, significantly elevated baseline levels for IL-1 beta, IL-6 and IL-8 were found in seasonal allergic compared to control subjects. Within the first 2 h after nasal allergen challenge, IL-1 beta and TNF are secreted, whereas IL-6 and IL-8 showed a slow increase over 6-8 h. All cytokine levels returned to baseline within 24 h after exposure. Repeated measurements at 4-week intervals in perennial allergic rhinitis subjects (n = 27) showed significant correlations between IL-1 and IL-8, IL-6 and IL-8 and IL-6 and the symptom score (visual analogue scale). The IL-1 receptor antagonist IL-1ra was found in great molar excess in the secretions and correlated significantly with IL-8, but not IL-1 beta. In an in vitro assay using fresh nasal mucosa of grass-pollen-allergic subjects, we were able to demonstrate a strong and rapid induction of E-selectin adhesion receptor expression on endothelial cells by allergen, IL-1 beta and TNF. The adhesion receptor expression was markedly inhibited by soluble IL-1 receptors, sTNF-R and IL-1ra. These data indicate a key role for inflammatory cytokines in the regulation of allergic inflammation.

Proinflammatory cytokines in allergic rhinitis

Allergic diseases such as allergen-induced rhinitis represent an inflammatory reaction that is characterized by the chemotaxis and activation of various cell populations. A high degree of cell-to-cell communication is needed to orchestrate this inflammatory immune response. A variety of cytokines and adhesion receptors seem to play an important role in the allergic late phase reaction. Here we demonstrate that proinflammatory cytokines such as interleukin(IL)-1, IL-8 and TNF-α (tumor necrosis factor-alpha) can be detected in nasal secretions and mucosa by enzyme-linked immunosorbent assay and immunohistochemistry. The increased expression of adhesion receptors in mucosa specimens of patients with seasonal allergic rhinitis points to their role in regulating the cellular migration and probably represents a key event in allergic inflammation. We established an in vitro model using freshly taken nasal mucosa to study the induction of adhesion receptors by proinflammatory cytokines. E-selectin, an endothelial receptor, was strongly upregulated by IL-1β, TNF-α and allergen. The induction due to allergen exposure of the mucosa was markedly inhibited by soluble cytokine receptors (sIL-1R, TNF-BP) or by a receptor antagonist (IL-Ira) and prednisolone, These findings indicate that proinflammatory cytokines may be key factors for the upregulation of adhesion processes in human nasal mucosa and the activation of various cell populations involved in the allergic inflammation. They therefore represent a main target for new therapeutic strategies.

Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma

Chemotherapy and/or radiotherapy are established measures in treatment protocols of head and neck squamous cell carcinoma (HNSCC). However, we still lack reliable predictive markers for the response to radio- and chemotherapy. The p53 pathway is involved in stress response and thus might influence chemo-/radiosensitivity. Using 29 HNSCC cell lines previously characterized for p53 mutations, we simultaneously analyzed several key players in the p53 pathway by RT-PCR, transcript sequencing and immunohistochemistry, and investigated their association with chemosensitivity and radiosensitivity. Cell lines with p53 mutations were slightly more sensitive to cisplatin than those with wild-type p53. The type of mutation did not influence radio- or chemosensitivity. p14(ARF), an activator of p53, was lost or mutated in all cell lines. Three cell lines showed overexpression of HDM-2, a major negative regulator of p53; however, HDM-2 levels did not correlate with radio- or chemosensitivity. HPV-16 oncoproteins were detected in one highly chemoresistant cell line. Our findings suggest that molecular events resulting in the inactivation of the p53 pathway occur in all HNSCC cell lines. However, single alterations in the p53 pathway are not reliable predictors for the response to radio- or chemotherapy in HNSCC.

Reliable detection of p53 aberrations in squamous cell carcinomas of the head and neck requires transcript analysis of the entire coding region.

Aberrations of the p53 tumor suppressor gene are common events in squamous cell carcinomas of the head and neck (SCCHN). However, reported frequencies range considerably, and the predictive value of aberrant p53 is continuing to be an issue of controversy. These inconsistencies are possibly caused by methodical limitations.

Comments on the publication: Haas I. et al. (2001) The dilemma of follow-up in head and neck cancer patients. Eur Arch Otorhinolaryngol 258: 177-183

concerning the topic of the above-mentioned article by mistake is not mentioned in the references. Therefore, I would like to correct this: the respective article is presented by de Visscher, A.V.M. and Manni, J.J. (1994) in Arch Otolaryngol Head Neck Surg 120: 934–939. Its title is: “Routine long-term follow-up in patients treated with curative intent for squamous cell carcinoma of the larynx, pharynx and oral cavity.”

Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines

Protein kinase C (PKC) plays a pivotal role in signal transduction involved in the control of cell proliferation, differentiation and apoptosis. Interference with such signaling pathways may result in altered tumor cell response to antineoplastic drugs. We investigated the effects of two selective PKC inhibitors as single agents and in combination with cisplatin in cell lines derived from squamous cell carcinomas of the head and neck (SCCHN). Safingol (Saf) is directed against the regulatory domain, whereas chelerythrine (Che) interacts with the catalytic domain of PKC. In six SCCHN cell lines (UM-SCC 11B, 14A, 14C and 22B, 8029NA, and a 5-fold cisplatin-resistant subline 8029DDP). PKC activities ranged between 1 and 158 IU/1×107 cells, and they were inversely proportional to the amount of cellular epidermal growth factor receptor. Using the colorimetric MTT assay, PKC inhibitors Saf and Che showed comparable dose-dependent growth inhibition. The 50% inhibitory concentrations (IC50) were between 3.8–8.6 μ M for Saf and 8.5–13.6 μ M for Che with no relationship to PKC activity or cisplatin sensitivity of the respective cell lines. Combinations of cisplatin (IC50 = 0.4–5.8 μ g/ml) and either PKC inhibitor (5 μ M Saf, 10 μ M Che) led to a significant decrease of cisplatin IC50 values in most cell lines. However, comparison with theoretical additive dose–response curves showed additive rather than synergistic effects for both PKC inhibitors.

Specific Immunotherapy Suppresses IL-1β and IL-8 Levels in Nasal Secretions: A Possible Explanation for the Inhibition of Inflammatory Cell Migration

The efficacy of specific immunotherapy in the treatment of allergic rhinitis is now clearly established. The fundamental principle of this form of therapy is still not fully understood, although consi

Argon plasma coagulation (APC) in palliative surgery of head and neck malignancies

Objectives Surgical reduction of bulky disease is an important treatment option in patients with incurable head and neck malignancies. In general, conventional tumor ablation is associated with significant hemorrhage, and the resulting tumorous wound surface entails aftercare problems. Argon plasma coagulation (APC) represents a novel technique providing effective hemostasis and wound sealing. Thus, APC features requirements of particular interest in palliative surgery of the head and neck.