Thyroid examination in highly radiation-exposed workers after the Chernobyl accident.

CONTEXT: Radioactive contamination from the Chernobyl nuclear accident that happened on the morning of 26th April 1986 had a major impact on thyroid health in the Belarus region. OBJECTIVE: Observational study of a cohort of 99 adults, most strongly exposed to ionizing radioactivity. DESIGN, SETTING AND PATIENTS: Observational study performed between 1998 and 2000. The cohort comprised 99 workers (92 male) of the Chernobyl nuclear power plant. Examination including physical examination, ultrasonography of the thyroid gland and measurement of serum free thyroxin (fT(4)), free triiodothyronine (fT(3)) and TSH. Anti-thyroperoxidase (anti-TPO), antithyroglobulin (anti-Tg) antibodies and thyroid stimulating immunoglobulin were also determined. MAIN OUTCOME MEASURES: The impact of exposure to high-dose radiation, including radioactive iodine, on the thyroid gland was examined. RESULTS: Levels of fT(4) in all probands were within the normal World Health Organization-defined range. Elevated levels of fT(3) were found in two workers (2%), high titres of anti-TPO and anti-Tg antibodies were present in four subjects (4%). Mild hypothyroidism was present in one patient. Enlargement of the thyroid gland was observed in 17 workers (17%). There was no evidence of clinically overt thyroid cancer. CONCLUSIONS: The Chernobyl accident showed surprisingly little impact on the thyroid in a cohort of workers strongly exposed to radiation. Our data suggest an age-dependent heterogeneity in response to the short-lived radioiodine isotopes and favours long-term follow-up analysis.

Bath PUVA and saltwater baths followed by UV-B phototherapy as treatments for psoriasis: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of psoralens dissolved in a warm-water bath followed by exposure to UV-A irradiation (bath PUVA) or saltwater phototherapy (SW UV-B) compared with tap-water phototherapy (TW UV-B) or UV-B irradiation alone in psoriasis. DESIGN: Multisite, prospective, randomized, controlled trial with 4 parallel groups. SETTING: Total of 102 dermatologic outpatient clinics. PATIENTS: Total of 1241 patients with stable psoriasis vulgaris and a Psoriasis Area and Severity Index score of 7 or greater. INTERVENTIONS: Four-times-weekly UV-B, TW UV-B, SW UV-B, or bath-PUVA with baths preceding UV irradiation over a maximum of 8 weeks. The UV dose was adapted to erythemal response. MAIN OUTCOME MEASURES: Incidence of therapeutic success, defined as a reduction of the Psoriasis Area and Severity Index or affected body surface area of 50% or more. RESULTS: Patients who received TW UV-B had a significantly higher incidence of therapeutic success than did patients treated with UV-B alone (60.7% vs 43.3%; P<.001; number needed to treat, 5.8; 95% confidence interval [CI], 3.9-10.9). Patients who received SW UV-B or bath PUVA had a significantly higher incidence of therapeutic success than did patients treated with TW UV-B (74.9% vs 60.7%; P<.001; number needed to treat, 7.0; 95% CI, 4.6-14.9; and 78.4% vs 60.7%; P<.001; number needed to treat, 5.7; 95% CI, 4.0-9.7, respectively). Bath PUVA was not superior to SW UV-B (78.4% vs 74.9%; P = .34). CONCLUSION: Bath PUVA and SW UV-B are comparably effective treatments in psoriasis and superior to UV-B and TW UV-B.

Radiation-induced late effects in two affected individuals of the Lilo radiation accident.

Radiation exposure leads to a risk for long-term deterministic and stochastic late effects. Two individuals exposed to protracted photon radiation in the radiological accident at the Lilo Military site in Georgia in 1997 received follow-up treatment and resection of several chronic radiation ulcers in the Bundeswehr Hospital Ulm, Germany, in 2003. Multi-parameter analysis revealed that spermatogenetic arrest and serum hormone levels in both patients had recovered compared to the status in 1997. However, we observed a persistence of altered T-cell ratios, increased ICAM1 and beta1-integrin expression, and aberrant bone marrow cells and lymphocytes with significantly increased translocations 6 years after the accident. This investigation thus identified altered end points still detectable years after the accident that suggest persistent genomic damage as well as epigenetic effects in these individuals, which may be associated with an elevated risk for the development of further late effects. Our observations further suggest the development of a chronic radiation syndrome and indicate follow-up parameters in radiation victims.

Expression of stromal cell markers in distinct compartments of human skin cancers.

BACKGROUND: The importance of changes in the supporting tumor stroma for cancer initiation and progression is well established. The characteristics of an activated tumor stroma, however, are not completely understood. In an effort to better characterize the desmoplastic response to human skin tumors, we evaluated the expression pattern of three stromal cell markers, fibroblast-activation protein (FAP), endoglyx-1, and endosialin, in a series of melanocytic and epithelial skin tumors. METHODS: Immunohistochemistry using antibodies against FAP, endoglyx-1, and endosialin was carried out in skin samples obtained from 43 patients. Furthermore, microarray data from an independent set of human skin cancers were analyzed. RESULTS: FAP-positive fibroblasts were detected in all tumor tissues tested, including cases of melanocytic nevi, melanoma metastases, basal cell carcinomas, and squamous cell carcinomas. In cutaneous melanoma metastases, we identified different compartments within the stromal response on the basis of the regions of FAP expression. Endoglyx-1 expression was confined to normal and tumor blood vessel endothelium including 'hot spots' of neoangiogenesis within the cutaneous melanoma metastases. Endosialin was selectively induced in subsets of small- and medium-sized tumor blood vessels in melanoma metastases and squamous cell carcinomas. CONCLUSIONS: These data describe novel aspects of stromal marker expression in distinct compartments of human skin tumors and may point to potential targets for novel therapeutic strategies aimed at the tumor stroma.

Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors.

Growth and metastasis of solid neoplasms require the recruitment of a supporting tumor stroma. A highly consistent trait of tumor stromal fibroblasts in most epithelial cancers is the induction of fibroblast activation protein (FAP), a member of the serine protease family. Recently it was demonstrated that FAP has both dipeptidyl peptidase and collagenolytic activity capable of degrading gelatin and type I collagen. In this study, we describe the expression and enzyme activity of FAP in benign and malignant melanocytic skin tumors. FAP-positive fibroblasts were detected immunohistochemically in the reactive stroma of all melanocytic nevi tested. In primary and metastatic melanomas an upregulation of FAP expression in the reactive mesenchyme could be observed. Whereas 30% of the nevi revealed additional FAP expression on subsets of melanocytic cells, melanoma cells from primary and metastatic melanomas were FAP negative. This may indicate a possible role for FAP in the control of tumor cell growth and proliferation during melanoma carcinogenesis. Consistent with this in vivo expression pattern FAP enzyme activity could be detected by a specific immunocapture assay in extracts of melanocytic nevi and melanoma metastases, whereas no significant activity was detectable in normal adult skin. Strong protein expression of FAP was observed in patterned structures restricted to a subset of the melanoma metastases. Our findings that these FAP-positive structures showed no overlap with endothelial cell surface markers, nor with various melanoma antigens, suggest that FAP is a marker for specific stromal-cell-derived patterns in cutaneous melanoma metastases.

The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice.

Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.