[Assurance-associated aspects of head and neck carcinomas: disposition, exposition, prognosis]. / Versicherungsrelevante Aspekte bei Karzinomen der Kopf-hals-Region: Disposition, Exposition, Prognose.

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.

Does sophisticated diagnostic workup on neuroectodermal tumors have an impact on the treatment of esthesioneuroblastoma?

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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 dilemma of follow-up in head and neck cancer patients.

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 < or = 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.

[Cytokine pattern in various forms of sinusitis]. / Zytokinmuster bei verschiedenen Formen der Nasennebenhöhlenentzündungen.

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.

Effectiveness of hyperbaric oxygen therapy in patients with acute and chronic cochlear disorders.

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.

Promoting effects of fibroblasts on growth and progression of head and neck carcinoma cells.

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.

Exposure of organ cultures from human tracheal epithelium to chemical carcinogens and subsequent long-term co-cultivation with autologous isotopic fibroblasts.

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.

[Hearing screening within the scope of pediatric U5 preventive examination: can diagnosis be improved by use of a parent questionnaire?]. / Hörscreening im Rahmen der Kinderärztlichen Vorsorgeuntersuchung U5: Kann die Diagnostik durch Einsatz eines Elternfragebogens verbessert werden?

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 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. 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.

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-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.

Immunohistochemical examination of 11 cell lines derived from human head and neck squamous cell carcinomas, their recurrences or metastases.

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, 10B), 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.

Dual role of fibroblasts in tumor cell growth.

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.

[The role of pro-inflammatory cytokines in recruiting inflammatory cells in the nose]. / Die Rolle der proinflammatorischen Zytokine bei der Rekrutierung von Entzündungszellen an der Nase.

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.

[References for after-care of tumor patients]. / Anmerkungen zur Nachsorge von Tumorpatienten.

Recent publications have questioned the benefit of extensive routine follow-up measures in all patients that have undergone treatment for head and neck cancer. Both the poor detection rate of asymptomatic early tumor lesions and the severe limitations that are encountered with regard to further treatment options require an individual follow-up protocol mainly depending on site, size, and treatment of the respective tumor. The objective is to increase the efficacy of the follow-up in head and neck cancer patients carried out in both clinics and private practice.