[The innate immune system in oropharyngeal squamous cell carcinoma : Immune modulation by HPV]. / Das angeborene Immunsystem beim Oropharynxkarzinom : Immunmodulation durch HPV.

Based on clinical and experimental data, oropharyngeal squamous cell carcinomas (OPSCC) associated with human papillomavirus (HPV) have been recognized as a distinct entity of head and neck cancers. However, outside of clinical trials, HPV status currently has no impact on treatment. The natural replication cycle of HPV takes place in epithelial cells, and is thus spatially separated from cytotoxic immune cells in the epidermis. Dendritic cells (Langerhans cells, LC), however, are frequent in this upper dermal layer. The ability of LC to process antigens, migrate, and, ultimately activate T cells is inhibited by the activity of the viral oncoproteins (E5-E7). Downregulation of functional human leukocyte antigen I (HLA-I) epithelial cell surface expression contributes to LC inhibition. However, due to their absence in upper skin layers, corresponding activation of natural killer (NK) cells via missing-self recognition is not relevant. Genome-wide analyses have revealed specific expression signatures for HPV-associated OPSCC that are distinct from HPV-negative cancers. Interestingly, aberrations in HLA-I genes were common in HPV-associated OPSCC. Our own findings indicate more frequent infiltration of HPV-associated OPSCC by CD56-positive (CD56+) NK cells, which might be related to HLA-I downregulation during HPV-associated carcinogenesis. In patients with OPSCC, CD56 positivity correlates with improved prognosis after conventional therapy. This could be evidence for HPV-associated OPSCC being especially eligible for novel immune-based therapies and an indication that immunological data should be included in the design of clinical trials.

Direct Observation of Photoinduced Tautomerization in Single Molecules at a Metal Surface.

Molecular switches are of fundamental importance in nature, and light is an important stimulus to selectively drive the switching process. However, the local dynamics of a conformational change in these molecules remain far from being completely understood at the single-molecule level. Here, we report the direct observation of photoinduced tautomerization in single porphycene molecules on a Cu(111) surface by using a combination of low-temperature scanning tunneling microscopy and laser excitation in the near-infrared to ultraviolet regime. It is found that the thermodynamically stable trans configuration of porphycene can be converted to the metastable cis configuration in a unidirectional fashion by photoirradiation. The wavelength dependence of the tautomerization cross section exhibits a steep increase around 2 eV and demonstrates that excitation of the Cu d-band electrons and the resulting hot carriers play a dominant role in the photochemical process. Additionally, a pronounced isotope effect in the cross section (∼100) is observed when the transferred hydrogen atoms are substituted with deuterium, indicating a significant contribution of zero-point energy in the reaction. Combined with the study of inelastic tunneling electron-induced tautomerization with the STM, we propose that tautomerization occurs via excitation of molecular vibrations after photoexcitation. Interestingly, the observed cross section of ∼10(-19) cm(2) in the visible-ultraviolet region is much higher than that of previously studied molecular switches on a metal surface, for example, azobenzene derivatives (10(-23)-10(-22) cm(2)). Furthermore, we examined a local environmental impact on the photoinduced tautomerization by varying molecular density on the surface and find substantial changes in the cross section and quenching of the process due to the intermolecular interaction at high density.

Role of ondansetron plus dexamethasone in fractionated chemotherapy.

This randomised, double-blind, parallel-group study was carried out to compare the efficacy and safety profile of ondansetron plus dexamethasone and metoclopramide plus dexamethasone in patients receiving fractionated cisplatin (20-25 mg/m2/day) chemotherapy for the treatment of testicular cancer. An interim analysis of 95 patients showed that the ondansetron regimen was significantly superior compared to the metoclopramide regimen (p < 0.001). According to the study protocol the study was terminated at this stage. At the time the decision to stop the study was taken, a total of 113 patients had been enrolled and were evaluable on an 'intention to treat' basis. Fifty-six of these had received ondansetron (32 mg i.v. single dose/day) plus dexamethasone (20 mg i.v. single dose/day) and 57 were given metoclopramide (2 mg/kg or 1 mg/kg i.v. twice a day) plus dexamethasone (20 mg i.v. single dose/day). The ondansetron regimen was significantly superior in the control of emesis and nausea. Seventy-one percent of patients experienced 2 or fewer emetic episodes over the entire 5-day study period compared with 26% of patients given metoclopramide (p < 0.001). Seventy-nine percent of patients in the ondansetron group experienced 'none' or only 'mild' nausea compared with 39% of patients in the metoclopramide group (p < 0.001). The dose of metoclopramide had to be reduced during the study from 2 mg/kg i.v. twice daily to 1 mg/kg i.v. twice daily because 4 of the first 8 patients randomised to this treatment experienced extrapyramidal reactions. Ondansetron was well tolerated and it did not induce any extrapyramidal reactions. The results of this study show that ondansetron plus dexamethasone represents a very effective treatment option for patients receiving fractionated cisplatin chemotherapy for testicular cancer.

Long-term observation of endocrine ophthalmopathy and retrospective appraisal of therapeutic measures.

The course of endocrine ophthalmopathy was investigated on the basis of clinical and biochemical parameters and in relation to different therapeutic strategies. A retrospective appraisal was made of 297 patients (44 +/- 14 yr, 249 women) with inclusion of anamnestic and clinical data as well as the results of computer tomography. At the beginning of therapy, 253 patients were hyperthyroid, 36 were euthyroid and eight were hypothyroid. The HLA typing carried out in 89 patients showed the phenotypes B8 and DR3 in 32% and 42% of the cases, respectively. Raised microsomal antibodies were present in 56% of the patients and there were raised thyroglobulin antibodies in 19%. Sixty-three % of the patients received immunosuppressants in the course of therapy: glucocorticoids in all cases, nonsteroid immunosuppressants in 15%. Eight % of the patients were irradiated retrobulbarly. The inflammatory parameters could be favorably affected, whereas eye muscle involvement and bulbar protrusion proved to be more resistant to therapy. In patients with combined immunosuppressant therapy or steroids + retrobulbar radiation, there were unequivocal successes with regard to the proptosis, vision and intraocular pressure. None of the strategies applied constitutes an optimal treatment with regard to the long-term course. Following therapy, there is an improvement of endocrine ophthalmopathy, but not complete healing.

Investigation by scintigraphic methods of neutrophil kinetics under normal and septic shock conditions in the experimental baboon model.

The purpose of this study was the correlation of neutrophil kinetics with the pathogenic course of septic shock in the baboon model. Radioactively labelled neutrophils were traced in vivo in normal baboons (n = 6) and in Escherichia coli-infected baboons, which were reinjected with labelled autologous neutrophils either 2 h after the onset of the E. coli infusion (procedure A) (n = 3) or simultaneously with the infusion (procedure B) (n = 3). Cell isolation was done according to a method developed in this laboratory. The cells were labelled with tropolonate In 111, resuspended in 1-2 ml plasma and reinjected. One-minute images were taken every 5th min and then hourly for 4 h with a gamma camera and analysed with a data processor. Time-activity curves were obtained for neutrophil washout from the lungs and neutrophil accumulation in the liver and spleen. These curves were compared for normal baboons and for those treated according to procedures A and B. A significant retention of neutrophils in the lungs of baboons with E. coli-induced septic shock was noted as well as an abnormally slow rate of accumulation in the liver and spleen. It also seems that any lung injury which could be attributed to changes in neutrophil behaviour should be traced back to events during the early exposure of neutrophils to bacterial infection.

Correlation between the macromolecular effects of estradiol and catecholestradiols and the total prostatic catecholestrogen concentration.

Various authors have demonstrated that estrogens stimulate both protein and DNA synthesis, as well as cell proliferation. This study was therefore undertaken to investigate the correlation between these physiological effects of estrogens and the total prostatic catecholestrogens. Either 17 beta-estradiol (5 ng), 2-hydroxyestradiol (40 ng), 4-hydroxyestradiol (17 ng), propane-1,2-diol or a saline solution was injected intraperitoneally to 22-day-old Sprague-Dawley rats daily. Regardless of the treatment, the prostate mass, the rate of DNA or protein synthesis correlates positively with the total prostatic catecholestrogen concentration. We therefore conclude that the effect of each estrogen per se should be regarded in terms of the total prostatic catecholestrogen concentration.

[Long-term study of endocrine ophthalmopathy and retrospective assessment of therapeutic measures]. / Langzeitbeobachtung der endokrinen Ophthalmopathie und retrospektive Beurteilung therapeutischer Massnahmen.

The follow-up of Graves' ophthalmopathy was analysed regarding to clinical and chemical data on the one hand and to dependence on different therapeutic alternatives on the other. 297 patients (44 +/- 14 years, 249 female, 48 men) were observed with inclusion of data from the history and clinical data as well (computer tomography and orbital sonography). At the onset of therapy 253 patients were hyperthyroid, 36 euthyroid and eight showed hypothyroidism. The staging was: I 13, II 54, III 113, IV 95, V five, VI eight patients. The HLA-typing in 89 patients showed the following results: B8 in 32%, DR3 in 42%, B8 as well as DR3 in 24% of the patients. In about 50% of the cases there were raised microsomal and in about 18% there were raised thyroglobuline antibodies. 63% of the patients received immunosuppressive medication: corticosteroids in 100% (more than one time in 43%), cyclosporine A in 11%, ciamexone in 10%, other non-steroid immunosuppressants in 5% of the cases. The retrobulbar irradiation was performed in 9%, and total thyroidectomy in 7%. During therapy the inflammatory process was clearly ameliorated, however exophthalmos and diplopia were more resistant to treatment. In the group of patients with combined cyclosporine and prednisone therapy and in the group of patients with total thyroidectomy and partly retrobulbar radiotherapy, significant differences were observed regarding to visual acuity and Hertel values. None of the therapies applied constitutes an optimal treatment with the regard to the long-term course. Under therapy an improvement can be reached, but no complete healing.