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In patients with cervical cancer of an unknown primary (CUP), no established concept exists for the necessary diagnostic procedures. In order to find the primary tumor, extensive diagnostic steps are generally recommended; however, they are often not performed consistently. In the current study, we consistently used a diagnostic algorithm and analyzed its consequences on patients' prognoses. We retrospectively studied 57 patients who were found to have a cervical metastasis of the upper- or midneck and an unknown primary tumor after routine examination of the head and neck region. Patients were analyzed for the value of applied diagnostic measures, tumor classification, survival rates and frequencies of subsequent lymph node or distant metastases after the initial treatment. Our results showed that a diagnostic algorithm (lymph node biopsy, rigid panendoscopy with systematic biopsies of suspect regions as well as blind biopsies of endoscopically inconspicuous regions, including the tongue base and nasopharynx and bilateral tonsillectomy) led to the detection of 14 occult oropharyngeal and 5 nasopharyngeal primary tumors in the patients. These tumors were primarily diagnosed as CUP. Oropharyngeal tumors either grew submucosally or were so small that only microscopic evaluation of the entire tonsil uncovered the tumor. Imaging procedures (X-ray, ultrasound, CT, MRT and FDG-PET) as well as gynecological, urological and gastroenterological consultations did not reveal the primary tumors in any of the cases. The 3-year survival rate for the patients with occult oropharyngeal primary tumors was 100% after treatment, while the patients in which our diagnostic schedule did not reveal a primary tumor showed a survival rate of 58%. The prognosis of all of the patients with cervical carcinoma metastasis was dependent on the initial nodal stage. Metachronous metastasis after completion of the initial treatment was prognostically infaust, while secondary detection of the primary tumor was worthwhile during follow-up as long as further treatment options were offered. The prognosis of patients with cervical carcinoma metastases of the upper- and midneck is much more favorable than that of patients with a CUP syndrome of other localizations. Identification of an occult pharyngeal tumor is prognostically relevant, since it opens up the possibility of specific locoregional treatment. In patients with cervical CUP, blind but systematic pharyngeal biopsies, including bilateral tonsillectomy, should be performed.

Die stagnierenden Heilungsraten für Karzinome der Kopf-Hals-Region lassen sich möglicherweise durch Beeinflussung der Wachstumsregulation des Tumorgewebes verbessern, indem beispielsweise wachstumsstimulierende Einflüsse gehemmt oder vice versa wachstumshemmende Faktoren verstärkt werden. Voraussetzung für ein gerichtetes Eingreifen in derartige biologische Systeme ist die Kenntnis nicht nur der an ihr beteiligten Einzelkomponenten, sondern auch der Interaktionen innerhalb des Systems. Dabei sind einerseits die wechselseitigen Beziehungen zwischen den Tumorzellen selbst, andererseits aber auch die Interaktionen zwischen ihnen und dem Stroma zu berücksichtigen. Wir sind deshalb der Frage nachgegangen, welchen Einfluss Fibroblasten und eventuell auch Tumorzellen selbst auf die Proliferation von Plattenepithelkarzinom-Zellen ausüben. Unsere Ergebnisse werden unter Berücksichtigung des einschlägigen Schrifttums im Sinne einer Übersicht zusammenfassend dargestellt. Es wird gezeigt, dass in unterschiedlichen Experimentalsystemen sowohl Fibroblasten als auch Tumorzellen das Wachstum von Tumorzellen offensichtlich stimulieren wie auch behindern können. Fördernde und hemmende Aktivitäten können gleichzeitig von einundderselben Zellpopulation ausgehen, und es ist eine Frage der Zielzelle, ihrer Mikroumgebung und des Kultivationsmodells, welcher Einfluss überwiegt. Tumorwachstum ist demnach ein Wechselspiel gegenseitiger Beeinflussungen der daran beteiligten Zellen, wobei nicht nur der Fibroblast wachstumsfördernd oder -hemmend auf die Tumorzelle einwirkt, sondern auch die malignen Zellen selbst sich sowohl in ihrem Verhalten gegenseitig als auch das benachbarte Stroma beeinflussen.

BACKGROUND Inflammatory sinus diseases include acute sinusitis, chronic purulent sinusitis, and chronic polypoid rhinosinusitis. We investigated the cytokine profile of different types of rhinosinusitis in order to evaluate whether a distinct form of rhinosinusitis is associated with the expression of a specific cytokine profile. METHODS AND PATIENTS Fresh sinus mucosa obtained during routine surgery from patients with acute sinusitis (n = 10), chronic sinusitis (n = 7), antrochoanal polyp (n = 10), nasal polyps (n = 8), and controls of turbinate mucosa (n = 7) were homogenized. The cytokine protein content (IL-1 beta,IL-3,IL-5,IL-6,IL-8,GM-CSF) of tissue homogenates was measured using ELISA technique. RESULTS In the group of proinflammatory cytokines, the protein levels measured for interleukin IL-8, a proinflammatory cytokine, IL-1 beta, and IL-6 were elevated in acute sinusitis. In the group of eosinophil-activating cytokines interleukin-3, -5 and granulocyte an makrophage-colony stimulating factor, we measured a significantly elevated protein level of IL-5 in nasal polyp tissue in contrast to significantly elevated IL-3 protein level in chronic sinusitis. CONCLUSIONS These findings suggest that IL-8 plays a pivotal role in neutrophil-dominated and IL-5 in eosinophil-dominated sinusitis. IL-3 seems to sustain chronic inflammation.

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

Interaction of stroma and tumor cells within a carcinoma can influence tumor growth and progression. We investigated possible influences of allogeneic and autologous fibroblasts on established squamous cell head and neck carcinoma lines (SCHNCL) and freshly isolated cells from such tumors. Tumor cells were compared in their colony-forming ability, starting from low cell counts, in their ability to form multicellular spheroids (MCS) and in their capacity to form tumors in the subrenal capsule of nu/nu mice. All tumor cell lines tested had a weak plating efficiency, whereas the capacity to form MCS as well as growth and progression in the xenotransplantation model showed large differences. The fibroblasts produced soluble factor(s) which increased colony formation of all tumor cell lines tested to the same extent, whereas admixture of fibroblasts exhibited a different influence on the MCS size and growth. They accelerated growth of the slowly growing MCS but did hardly alter growth of the fast growing ones. Tumor cells growing invasively in the xenotransplantation model were not influenced by coinoculation with fibroblasts; other tumor cells did not produce detectable tumors in nude mice or formed nodules well separated from the renal tissue: adding fibroblasts to these cells caused invasive growth of xenografts. The growth-promoting effects of fibroblasts in these extracorporeal systems might be of prognostic or even therapeutic benefit if intervention of these properties were successful.

OBJECTIVE Assessment of a) the efficacy of hearing loss screening in baby check-ups at the age of 6 to 8 months b) the efficiency and efficacy using parent questionnaires about hearing loss risk factors and parents' concern about the child's hearing as part of baby check-up. METHODS The analyses are based on 7282 baby check-ups carried out in 47 pediatricians' offices in the Dusseldorf area from July 1991 to March 1993: 3385 of these check-ups were performed in the traditional manner (period A; July 1, 1991, to January 1, 1992; 3897 check-ups involved parent questionnaires (period B June 1, 1992, to March 31, 1993). All children who failed the tests and a random sample of those who had passed the test when tested in the traditional manner, were offered extensive hearing assessment. RESULTS In period A, 4.3% of the children failed the test as compared to 21.7% with the first version of the questionnaire and 14.3% with a revised questionnaire in period B. Compliance to the offer of extensive hearing assessment was unsatisfactory (53% in period A and 63% in period B). The first extensive hearing examination failed to distinguish healthy children from children with probable sensorineural hearing loss in about 30% of the patients, mainly because of glue ear. One child with sensorineural hearing loss was identified by the screening in period A as compared to six children in period B. CONCLUSIONS 1) The systematic use of parent questionnaires in baby check-ups at ages 6 to 8 months is likely to increase the efficacy of the screening. 2) The efficiency of the questionnaires currently in use, however, needs to be improved and can be improved with the data from the study. 3) The compliance with extensive hearing testing in children who have failed the screening test must be improved. 4) Due to the high prevalence of conductive hearing loss in this age group, treatment of potential glue ear problems is mandatory before referral for extensive testing for sensorineural hearing loss.

In der experimentellen Onkologie ist die Gewebekultur fur bestimmte Fragestellungen unverzichtbar. Sie kann als Zell- und Organkultur sowohl in vitro als auch in vivo etabliert werden. Die gebrauchlichen Systeme der Gewebekultur werden kurz beschrieben, ihre Vorzuge und Nachteile erlautert und ihre Nutzanwendung an einigen Beispielen dargestellt.

Mit InkurabilitAt ist gemeint, dass eine Heilung des Kranken aller Voraussicht nach weder durch eine Operation noch durch andere Massnahmen erzielt werden kann. InkurabilitAt bedeutet aber n

All epithelial, mesenchymal and lymphoepithelial neoplasias that occur in the rest of the aerodigestive tract may occur in the nasopharynx, but very much more rarely.

From 12 Ursinia species, in addition to known compounds, 31 new sesquiterpene lactones, 10 being germacranolides, 19 guaianolides, one eudesmanolide and a rearranged one, were isolated. Furthermore, seven sesquiterpene acids and methyl esters, including two fulvenes and a rearranged eudesmane, a nerolidol and seven farnesol derivatives, a furosesquiterpene derived from dehydrolasiospermane, three eudesmane and three eremophilane derivatives as well as a triynene were present. The structures were elucidated by high field NMR techniques. The chemistry supports the placement of the genus in the tribe Anthemideae, probably as a subtribe, together with related South African genera.

Investigation of 11 Aspilia species afforded several known kaurane derivatives and other diterpenes. From A. eenii a highly oxygenated germacrane bisepoxide was isolated. Comparison of the 1 H NMR data with those of several germacrane derivatives from Senecio and Ligularia species, spin decoupling and NOED led to corrections of the structures of several compounds.

Allergische Reaktionen an der Nase sind lAngst zu einem internationalen Forschungsgebiet von Allergologen und Immunologen geworden. Aufgmnd ihrer ZugAnglichkeit bietet sich die Nase fUr experimentelle Untersuchungen und die UberprUfung der Relevanz von In-vitro-Befunden fUr die «natUrliche» allergische Reaktion an. Diese Tatsache hat zu einem erheblichen Gewinn an Kenntnissen zum Pathomechanismus einer hAufigen Erkrankung, der allergischen Rhinitis, gefUhrt. IgE-vermittelte Reaktionen lOsen nicht nur Sofortsymptome aus, sondern werden von einer SpAtphase gefolgt, die durch die Einwanderung und Aktivierung verschiedener Zellpopulationen charakterisiert ist. Zu diesen Zellpopulationen sind basophile Granulozyten, Mastzellen, eosinophile und neutrophile Granulozyten, T-Lymphozyten, Makrophagen und Monozyten zu rechnen. Die Aktivierung dieser Zellen fiihrt zur Freisetzung von Mediatoren und zur konsekutiven Steigerung der spezifischen und unspezifischen Reaktionsbereitschaft des Organs. Der «zellulAre Anteil» der IgE-vermittelten Reaktion stellt damit das Bindeglied zwischen der akuten allergischen Phase und der chronischen EntzUndung der Schleimhaut dar. Dabei lAsst sich die SpAtphase heute nur ansatzweise in ihrer KomplexitAt und der Interaktion ihrer zellulAren Elemente erfassen: Mastzellen sind nicht nur Mediatorzellen, sondern transportieren IgE-AntikOrper und synthetisieren Lymphokine; sie haben damit auch immunologische und immunmodulierende Funktionen. T-Lymphozyten und Makrophagen sind nicht nur an der humoralen Immunantwort bzw. IgE-Synthese, sondern auch an der Modulation der allergischen SpAtphase beteiligt. Die mOglichen EinflUsse von Gewebszellen, wie z.B. den Epi-thelzellen, auf die lokale Immunpathologie sind in ersten AnsAtzen bekannt. Die weltweiten ForschungsbemUhungen schlagen sich allerdings schon jetzt in einer wachsenden Kenntnis der therapeutischen (medikamentOsen und allergenspezifischen) Ansatzpunkte nieder. Bereits heute sind die grundlegenden Pathomechanismen Bestandteile der therapeutischen Uberlegungen und ersetzen zunehmend empirische Erfahrungswerte. Gleichzeitig erOffnen sich neue Wege fUr den Einsatz spezifischer Antagonisten zur Reduktion einzelner krankheitsrelevanter Zellen oder Mediatoren.

Schkuhria pinnata afforded, in addition to several known sesquiterpene lactones, eight new ones. The structures were elucidated by high field NMR spectroscopy.

After a brief introduction into the basics of head and neck oncology, the current review focusses on potential predictive markers and predisposing factors for these kinds of cancers. Furthermore, prognosis and degree of disability of cancer patients are commented on. With a survival rate of approximately 50%, the prognosis of head and neck carcinomas seems rather good, but it is in fact unsatisfactory. Since the treatment of advanced head and neck cancers is often accompanied by profound functional (articulation, phonation, respiration, and deglutition) and aesthetic impairment, it repeatedly leads to a high degree of disability and occupational invalidity. Furthermore, special limitations of head and neck cancer patients are discussed as well as the consequences they may have on the qualification for certain jobs.

The diagnostic workup on esthesioneuroblastoma is more extensive than ever before. We have investigated whether improvements in diagnosis of sinonasal neuroectodermal tumors, including esthesioneuroblastomas (ENB), sinonasal neuroendocrine carcinomas (SNEC) and sinonasal undifferentiated carcinomas (SNUC), have had an impact on treatment and outcome.11 ENB, 7 SNEC and 1 SNUC in 13 men and 6 women (average age 52.9 years (range 26-82)), diagnosed between 1986 and 2001, were analyzed with regard to histopathologic and clinical diagnosis as well as outcome. Our results were compared with the available literature.According to the Morita classification considering endoscopy, CT and MRI scans, 2 tumors were staged D, 14 were found to be stage C, 2 were stage B and 1 was stage A. Lightmicroscopically only 4 of 19 showed higher differentiation and rosette-like structures, the others were poorly differentiated. 18 of 19 tumors were examined immunohistochemically. Neuronal markers (NSE, synaptophysin, chromogranin, S-100 and neurofilaments) were heterogeneously expressed in both ENB and NEC, only NSE stained all but 2 tumors. Coexpression of neuronal markers and cytokeratins was proven in all NEC and 5 of 11 ENB. Some tumors expressed atypical markers. Despite extensive diagnostic steps it was not possible to exclude a different histopathological diagnosis in 10 of 19 cases.For sinonasal neuroectodermal tumors no pathognomonic antigenic profiles are known. Immunohistochemical markers lack specificity and sensitivity. Nevertheless, in many sinonasal neuroectodermal tumors a panel of differentiation markers allows to specify the light-microscopic diagnosis. Until now no therapeutic consequence arises from a more extensive diagnostic workup. However, the histopathologic identification of subtypes (SNUC) and proliferation markers may help to identify patients with poor prognosis.

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 toor = 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.

Inflammatory sinus diseases include acute sinusitis, chronic purulent sinusitis, and chronic polypoid rhinosinusitis. We investigated the cytokine profile of different types of rhinosinusitis in order to evaluate whether a distinct form of rhinosinusitis is associated with the expression of a specific cytokine profile.Fresh sinus mucosa obtained during routine surgery from patients with acute sinusitis (n = 10), chronic sinusitis (n = 7), antrochoanal polyp (n = 10), nasal polyps (n = 8), and controls of turbinate mucosa (n = 7) were homogenized. The cytokine protein content (IL-1 beta,IL-3,IL-5,IL-6,IL-8,GM-CSF) of tissue homogenates was measured using ELISA technique.In the group of proinflammatory cytokines, the protein levels measured for interleukin IL-8, a proinflammatory cytokine, IL-1 beta, and IL-6 were elevated in acute sinusitis. In the group of eosinophil-activating cytokines interleukin-3, -5 and granulocyte an makrophage-colony stimulating factor, we measured a significantly elevated protein level of IL-5 in nasal polyp tissue in contrast to significantly elevated IL-3 protein level in chronic sinusitis.These findings suggest that IL-8 plays a pivotal role in neutrophil-dominated and IL-5 in eosinophil-dominated sinusitis. IL-3 seems to sustain chronic inflammation.

Over the course of 18 months 359 patients with defined acute and chronic inner ear disorders who had not responded to treatment with medication were given hyperbaric oxygen (HBO) therapy. The inner ear diseases of the patients were divided, based on the duration of their conditions, into four symptomatic groups. Of the patients who had had hearing loss for less than 3 months, noticeable improvement or complete recovery was seen in 13% (20 dB in at least three test frequencies); 25.2% showed an improvement between 10 and 20 dB. Changes up to 10 dB or less were not considered to be positive. Patients with a pretreated hearing loss for more than 3 months had markedly less benefit from HBO therapy. Two percent regained normal hearing function. In 30% an improvement of more than 10 dB was achieved. For patients who had suffered from tinnitus for less than 3 months excellent improvement was seen in 6.7% and noticeable improvement in 44.3% expressed by means of a visual analog scale. In 44.3% the tinnitus was described as unchanged. Patients who had had tinnitus for more than 3 months before HBO therapy showed a less favorable response to HBO. In none of the patients did the tinnitus disappear; 34.4% of the patients described a noticeable improvement in their complaints.

As a continuation of previous experiments introducing an extracorporeal model for transformation of human respiratory epithelium that might be able to mimic a spontaneously occurring malignant tumor, we prepared organ cultures from tracheal specimens and exposed them repeatedly to chemical carcinogens, using benzo(a)pyrene and methylnitronitrosoguanine for 6 weeks. We then tried to select possibly initiated cells by subsequent co-cultivation with autologous isotopic fibroblasts for 2 years. Nontreated controls were maintained from the same specimens and cultured in the same manner. By this technique we selected from specimen La24 three long-living cell lines with varying morphology and an antigenic pattern indicating dedifferentiation. The cells expressed simultaneously a panel of cytokeratins, vimentin and neuroectodermal antigens. Transplantation of these cell lines under the subrenal capsule of athymic mice resulted in tumorlike nodules of limited size. Success rate was dependent on time of previous in vitro culture and carcinogen treatment. None of the lines produced invasive or metastasizing tumors.

Assessment of a) the efficacy of hearing loss screening in baby check-ups at the age of 6 to 8 months b) the efficiency and efficacy using parent questionnaires about hearing loss risk factors and parents' concern about the child's hearing as part of baby check-up.The analyses are based on 7282 baby check-ups carried out in 47 pediatricians' offices in the Düsseldorf area from July 1991 to March 1993: 3385 of these check-ups were performed in the traditional manner (period A; July 1, 1991, to January 1, 1992; 3897 check-ups involved parent questionnaires (period B June 1, 1992, to March 31, 1993). All children who failed the tests and a random sample of those who had passed the test when tested in the traditional manner, were offered extensive hearing assessment.In period A, 4.3% of the children failed the test as compared to 21.7% with the first version of the questionnaire and 14.3% with a revised questionnaire in period B. Compliance to the offer of extensive hearing assessment was unsatisfactory (53% in period A and 63% in period B). The first extensive hearing examination failed to distinguish healthy children from children with probable sensorineural hearing loss in about 30% of the patients, mainly because of glue ear. One child with sensorineural hearing loss was identified by the screening in period A as compared to six children in period B.1) The systematic use of parent questionnaires in baby check-ups at ages 6 to 8 months is likely to increase the efficacy of the screening. 2) The efficiency of the questionnaires currently in use, however, needs to be improved and can be improved with the data from the study. 3) The compliance with extensive hearing testing in children who have failed the screening test must be improved. 4) Due to the high prevalence of conductive hearing loss in this age group, treatment of potential glue ear problems is mandatory before referral for extensive testing for sensorineural hearing loss.

Vast experience with cultivating biopsies from human tumors indicates that in most cases the admixture of fibroblasts has a negative effect on growth of tumor cells. Only rarely is observed help provided by the fibroblasts. It has also long been known that fibroblasts can inhibit by contact themselves and also produce growth factor(s) promoting cell proliferation. We have used three permanent squamous cell carcinoma lines and fibroblasts derived from biopsies of trachea to study this paradox. The inhibitory activity of fibroblasts is contact-dependent in a cell membrane-bound factor, which is trypsin sensitive. We prepared microsomal fractions (MF) from aged (more than 40 passages) fibroblasts and followed their effect on proliferation of the tumor cell lines in MTT assay. MF from all three fibroblast lines inhibited the tumor cells. Most regularly was this phenomenon observed with line UM-SCC 22B. Not all tumor cells are immortal. On the contrary, a large portion of them undergoes terminal differentiation. With the line UM-SCC 22B we tested the possibility that MF from fibroblasts can increase the portion of tumor cells which will senescence after few mitoses. The immortal cells were defined as cells capable in 8 or 13 days of forming colonies of more than 50 or 200 cells. The senescent cells were defined as cells not capable of producing within the same period of time colonies of more than 12 or 30 cells. The MF was able to increase the number of small colonies, i.e. the number of senescent tumor cells. The fibroblasts of the same passage level were releasing soluble growth factor(s) promoting growth of cells. Fibroblasts can apparently simultaneously inhibit growth by contact and release factor(s) promoting growth of cells. The final outcome is a result of the balance between these two forces. This balance is regulated by many intrinsic and extrinsic forces.

Since in vitro derived tumor cell lines usually correspond to their tumors of origin, a potential biological difference between a primary tumor and its derivative metastases and recurrent tumors should be reflected in established tumor cell lines. The aim of this study was to determine useful cellular markers in permanent tumor cell lines of head and neck squamous cell carcinomas (SCC) and to evaluate a possible relationship between these markers and the origin of selected cell lines. The cell lines, established in the laboratory of T. Carey at the University of Michigan (UM) (Ann Arbor, Mich., USA), were derived from primary tumor and its metastases (UM-SCC 10A, IOB), primary tumor and its recurrent tumors (UM-SCC 14A, 14B, 14C) and single tumors (UM-SCC 11B, 17A, 22B). An additional tumor cell line (HLac 79) was isolated by H.-P. Zenner (Tubingen, Germany) and a clone (8029 NA) with its cisplatin-resistant subline (8029 DDP4) was established in our laboratory. As markers we chose three groups known to be related to growth behavior and/or tumor differentiation: cytoskeletal proteins, oncogene products and membrane-associated antigens. These markers were detected by immunohistochemical methods using commercially available monoclonal antibodies. The “metastatic” and “recurrent” cell lines showed changes in comparison to the corresponding “parental” lines, which could be associated with a higher degree of de-differentiation, such as the occurrence of vimentin and neuroectodermal proteins, loss of HLA-ABC or HLA-DR and increased expression of epidermal growth factor receptor. The expression of cytokeratins was more stable and dissociation of the classical cytokeratin pairs was observed only in a few cases. Oncogene products were practically identical in cell lines from parental and recurrent or metastatic tumors. These data serve not only as a basis for further experiments with these cell lines but also provide information about the biological significance of various markers in newly established cell lines from primary tumors.

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-alpha (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-1 beta, TNF-alpha 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-1ra) 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.

Die bosartige Transformation entsteht nach mehreren konsekutiven genetischen Veranderungen der betroffenen Zellpopulation. Bosartig transformierte Zellen sind durch die voneinander unabhangigen Eigenschaften Unsterblichkeit und invasives Wachstum charakterisiert. Experimentelle und epidemiologische Daten beweisen, das Tumoren der Atemwege nach Einwirkung von chemischen Karzinogenen entstehen. In vitro sind menschliche Zellen gegen chemische Karzinogene sehr resistent. Epithelzellen der Atemwege konnten bisher mit Karzinogenen nicht transformiert werden. Bosartige Transformation wurde nur an Bronchialzellen erreicht, die vorher mit Hilfe SV40 immortalisiert wurden. Differenzierung sowie Dedifferenzierung vieler Epithelzellen, das Atemwegepithel eingeschlossen, lauft nur unter Kontakt mit dem lokalen mesenchymalen Gewebe ab.

In der Behandlung der allergischen Rhinitis ist der positive Effekt der spezifischen Immuntherapie (IT) durch zahlreiche klinische Studien nachgewiesen. Trotzdem bestehen aufgrund des nach wie vor unbekannten Wirkprinzips weiterhin Vorbehalte gegenuber dieser Therapieform. Einen erfolgsversprechenden Ansatz liefern die Arbeiten von Durham et al. Sie beschrieben eine Umkehr des beim Allergiker pathologischen Verhaltnisses von TH1-zu TH2-Zellen nach einer IT. Mittels In-situ-Hybridisierung wurde intrazellulare messenger-RNA nachgewiesen, um die beiden TH-Subpopulationen anhand ihres unterschiedlichen Zytokinmusters zu differenzieren. Da das Vorhandensein von intrazellularer messenger-RNA keinen definitiven Ruckschlus auf die tatsachliche Synthese eines Proteins zulast, beschaftigten wir uns mit der Frage, ob eine IT auch den Gehalt von Zytokinen im Nasensekret, als Ausdruck ihrer Freisetzung, beeinflussen kann. Unser Interesse richtete sich hierbei auf die Interleukine Il-4, Il-6 und Il-8. Il-4 ist als typischerweise von TH2-Zellen synthetisiertes Lymphokin v.a. fur die Stimulation der IgE-Produktion verantwortlich.

Inzwischen gilt es als gesichert, das auch die allergische Rhinitis als duale allergische Reaktion aufgefast werden kann. Wahrend die Sofortphase vor allem durch die Freisetzung von Mediatorsubstanzen der Mastzelle gekennzeichnet ist, ist fur die Spatphase ein Einstrom von Entzundungszellen in die Nasenschleimhaut charakteristisch. Hierbei spielen vor allem die eosinophilen Granulozyten eine zentrale Rolle. Deren Mediatorsubstanzen — es handelt sich um eine Reihe basischer Proteine wie ECP, MBP, EDN und andere — sind stark zytotoxisch und schadigen das respiratorische Epithel. Dies wiederum fuhrt zu der in der Spatphase auftretenden, unspezifischen Schleimhauthyperreagibilitat.

Entzundungsprozesse gehen charakteristischerweise mit der Einwanderung von Zellen einher, deren Aufgabe in der immunologischen Abwehr besteht. Proinflammatorische Zytokine — Interleukin 1, Tumornekrosefaktor Alpha und Interleukin 6 — spielen bei der Chemotaxis von Entzundungsherden eine Schlusselrolle, da sie in der Lage sind, die Expression von Adhasionsrezeptoren auf Endothelzellen zu induzieren. Die Adhasionsrezeptoren lassen sich aufgrund ihres molekularen Aufbaus in verschiedene Gruppen unterteilen, deren Lokalisation und Stimulus tabellarisch aufgefuhrt sind (Tabelle 1).

Die im Zuge des industriellen Fortschritts entstandene ubiquitare Verbreitung von Blei bedeutet eine Gesundheitsgefahrdung der Gesamtbevolkerung. Die Bleiaufnahme erfolgt inhalativ, durch gastrointestinale Absorption und diaplazentar. 90% des resorbierten Bleis sind an das Hamoglobin gebunden. Der Normwert des Blutbleispiegels betragt 10–20 mm/dl. Hauptangriffspunkt im Organismus sind die Hamoglobinsynthese und das Nervensystem. Die charakteristische Bleineuropathie geht mit einer, bei der Ableitung somatosensorisch evozierter Potentiale nachweisbaren, verminderten Nervenleitgeschwindigkeit einher.

Die proinflammatorischen Zytokine Interleukin-1β (I1-1β, Interleukin-6 (Il-6), Interleukin-8 (I1-8) und Tumornekrosefaktor-α (TNF-α) spielen eine wichtige Rolle bei der Initiierung von Entzundungsvorgangen, indem sie uber die Expression von Adhasionsmolekulen zur Zellmigration in das Zielorgan fuhren und dort Entzundungszellen in ein hoheres Aktivierungsstadium versetzen. Wir konnten in vorangehenden Studien einen Anstieg von Il-1β, Il-6, Il-8 und TNF-α im Nasensekret etwa 4–6 h nach Allergenprovokation beobachten. Entzundliche Veranderungen in der Nasenschleimhaut sind aber auch noch nach einem Tag zu beobachten. Um zu untersuchen, ob die genannten Zytokine hier eine Rolle spielen, fuhrten wir eine Studie durch, bei der wir deren Ausschuttung in das Nasensekret 24 h nach Allergenprovokation untersuchten.

Fur die In-vitro-Transformation der Epithelzellen aus Atemwegen stellen Organkulturen die Methode der Wahl dar, weil hier Epithelzellen in verschiedenen Differenzierungsstadien vorliegen und auch fibroblastisches Stroma vorhanden ist. Wir haben Organkulturen aus der Trachea fur 6 Wochen chemischen Karzinogenen [Benzo(a)pyrene, MNNG] ausgesetzt. Danach wurden die Zellen dieser Organkulturen mit Fibroblasten aus derselben Biopsie kokultiviert. Dabei sollten eine Selektion und eventuelle weitere Transformationen der initiierten Zellen stattfinden. Nach 15 Monaten wuchsen Zellen mit Merkmalen einer Transformation (z.B. 3dimensionales Wachstum, Produkte des mutierten p53 Onkogenes). Nach weiteren 10 Monaten verlangsamte sich das Wachstum dieser Zellen sehr. Es ist moglich, das Fibroblasten bei der Transformation und Progression eine Doppelrolle spielen: unter bestimmten Bedingungen aktivieren sie, bei anderen inhibieren sie das Wachstum. Die inhibierenden Eigenschaften werden hauptsachlich den alten (d.h. in hohen Passagen befindenden) Fibroblasten zugeschrieben.

Unter proinflammatorischen Markern versteht man Zytokine und Zelloberflachenmolekule, die von immunkompetenten Zellen in einem Entzundungsprozes synthetisiert und exprimiert werden. Die Einwanderung von Entzundungszellen wird durch Adhasionsmolekule bewirkt, die sich in Form von Eiweismolekulen auf den Blutzellen befinden und einen entsprechenden Rezeptor auf dem Gefasendothel erkennen. Die Lokalisation der Adhasionsmolekule bietet Aufschlus uber Migrations- und Adhasionsprozesse in einem entzundlichen Geschehen.

Cytokines and cell adhesion receptors play a pivotal role in the recruitment of cells from the peripheral blood into inflamed tissue. Allergic rhinitis has previously been described as an inflammatory reaction characterised by the migration of granulocytes into the nasal mucosa. Using this model, we investigated the release of proinflammatory cytokines (interleukin IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha TNF-alpha) and the expression of cell adhesion molecules (ELAM-1, ICAM-1 and LFA-1) in two studies involving biopsies as well as lavage and brush techniques. IL-1 beta and TNF-alpha can be found rapidly after allergen exposure and seem to initiate the cellular infiltration. The release of the chemokine IL-8 correlates with the continuously increasing number of granulocytes on the mucosal surface. Allergic rhinitis subjects showed significantly increased secretion levels of the proinflammatory cytokines IL-1 beta and IL-6 and of the chemokine IL-8. These findings correspond to a higher expression of the adhesion receptors ELAM-1, ICAM-1 and LFA-1 in allergic mucosa. We conclude that proinflammatory cytokines regulate the cell infiltration by the induction of adhesion receptor expression.

The goal of this study was to determine the lee-side flow of a delta wing experimentally and to compare this data with results of currently available theoretical models. Velocity measurements using a Laser-2-focus velocimeter had to be carried out in addition to flow visualization using Schlieren, Oil-film and Laser-light-sheet techniques. Three-dimensional flow-velocity vectors had to be determined using two angels at a perticular position.