Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases of nephrogenic systemic fibrosis (n ‫؍‬ 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75 d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% confidence interval 1.9 to 549.2; P < 0.0001). Seven (54%) patients became severely disabled, and one died 21 mo after exposure. No other exposure/event than gadodiamide that was common to more than a minority of the patients could be identified. These findings indicate that gadodiamide plays a causative role in nephrogenic systemic fibrosis. , previously known as nephrogenic fibrosing dermopathy, have been reported worldwide (1,2). The appearance of this new and serious disease has triggered considerable interest as to possible causative factors, including newly introduced clinical practices. However, until now, the eliciting factor(s) has not been identified. Mendoza et al. (3) recently reviewed the clinical picture of NSF. The typical patient is middle-aged and has ESRD. Most but not all are on regular dialysis treatment. The typical course begins with subacute swelling of distal parts of the extremities and is followed in subsequent weeks by severe skin induration and sometimes anatomic extension to involve thighs, antebrachium, and lower abdomen. The skin induration may be aggressive and associated with constant pain, muscle restlessness, and loss of skin flexibility. In some cases, NSF leads to serious physical disability, including wheelchair requirement. NSF initially was observed in and thought to affect solely the skin (thus the initial term nephrogenic fibrosing dermopathy), but more recent patient reports have demonstrated that several organs may be involved. Organ involvement may explain the suspected increased mortality of patients with NSF (3). There is no established treatment for NSF, but some cases have been reported to improve after kidney transplantation, and others seem to have been treated successfully with extracorporeal photopheresis (4).At the department of nephrology, Copenhagen University Hospital at Herlev, we became aware of a formerly unknown skin disease among our patients with ESRD during 2002 through 2005. Skin biopsies supported the clinical suspicion of NSF. Some of the case stories strongly indicated that the skin changes were elicited by contrast-enhanced magnetic resonance imaging (MRI). Since late 2001, we have used this method frequently for patients with ESRD, in particular for description of iliac and lower limb arteries before kidney transplantation (5). During the past 5 to 10 yr,...

Melanoma is the most aggressive skin cancer. The specificity and sensitivity of clinical diagnosis varies from around 40% to 80%. Here, we investigated whether the chemical changes in the melanoma tissue detected by Raman spectroscopy and neural networks can be used for diagnostic purposes. Near-infrared Fourier transform Raman spectra were obtained from samples of melanoma (n=22) and other skin tumors that can be clinically confused with melanoma: pigmented nevi (n=41), basal cell carcinoma (n=48), seborrheic keratoses (n=23), and normal skin (n=89). A sensitivity analysis of spectral frequencies used by a neural network was performed to determine the importance of the individual components in the Raman spectra. Visual inspection of the Raman spectra suggested that melanoma could be differentiated from pigmented nevi, basal cell carcinoma, seborrheic keratoses, and normal skin due to the decrease in the intensity of the amide I protein band around 1660 cm-1. Moreover, melanoma and basal cell carcinoma showed an increase in the intensity of the lipid-specific band peaks around 1310 cm-1 and 1330 cm-1, respectively. Band alterations used in the visual inspection were also independently identified by a neural network for melanoma diagnosis. The sensitivity and specificity for diagnosis of melanoma achieved by neural network analysis of Raman spectra were 85% and 99%, respectively. We propose that neural network analysis of near-infrared Fourier transform Raman spectra could provide a novel method for rapid, automated skin cancer diagnosis on unstained skin samples.

Increasing cumulative gadodiamide exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.

FOXP3 is a unique marker for CD4 þ CD25 þ regulatory T cells (Tregs). In solid tumours, high numbers of Tregs are associated with a poor prognosis. Knowledge about the implications of Tregs for the behaviour of haematological malignancies is limited. In this study, skin biopsies from 86 patients with mycosis fungoides (MF) and cutaneous T-cell lymphoma (CTCL) unspecified were analysed for the expression of FOXP3 on tumour cells and tumour-infiltrating Tregs. Labelling of above 10% of the neoplastic cells was seen in one case classified as an aggressive epidermotropic CD8 þ cytotoxic CTCL. In the remaining 85 cases, the atypical neoplastic infiltrate was either FOXP3 negative (n ¼ 80) or contained only very occasional weakly positive cells (n ¼ 5). By contrast, all biopsies showed varying numbers of strongly FOXP3 þ tumour-infiltrating Tregs. MF with early or infiltrated plaques had significantly higher numbers of FOXP3 þ Tregs than CTCL unspecified or advanced MF with tumours or transformation to large cell lymphoma. An analysis of all patients demonstrated that increasing numbers of FOXP3 þ Tregs were associated with improved survival in both MF and CTCL unspecified. In conclusion, our data indicate that the presence of FOXP3 þ Tregs in CTCL is associated with disease stage and patient survival.

These findings demonstrate the in vivo release (through transmetallation) of the toxic free Gd3+ from gadodiamide, and its retention in apatite-like deposits. We suggest that Gd may be mobilized over time from bone stores, explaining variably delayed onset of NSF and increasing skin concentration over time in patients with NSF.

Background: The expression of vascular endothelial growth factors (VEGFs) in tumors including lung cancer is considered to be associated with tumor development via angiogenesis and lymphangiogenesis. Pleural dissemination and lymph node metastasis of lung cancer are major poor prognostic factors. We investigate how VEGF-A, VEGF-C, and VEGF-D expressed in the intrathoracic infiltrating lung cancer cells are involved in dissemination and metastasis. Methods: We established large cell lung cancer cell lines in which stably VEGF-A-, VEGF-C-, VEGF-D-, or VEGF-C and VEGF-D were stably expressed (TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, TKB5/VEGF-C/D, respectively). These transfectants were orthotopically inoculated into the right thoracic cavity (i.t.) of nude mice, and then we evaluated subsequent development of pleural effusion, pleural dissemination, and lymph node metastasis. Results: There were no significant differences in cell growth rate among the control lines (empty vector-transfected TKB5) and VEGFtransfectants in vitro. However, each i.t. model demonstrated significantly different biological properties. TKB5/empty showed no apparent pleural effusion, dissemination, or lymph node metastasis. In contrast, TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, and TKB5/VEGF-C/D promoted bloody pleural effusion and dissemination (4/4, 4/7, 4/4, and 5/10, respectively). TKB5/VEGF-D and TKB5/VEGF-C/D showed aggressive mediastinal invasion around the thoracic aorta and thoracic duct. Furthermore, TKB5/VEGF-C/D generated mediastinal lymph node metastasis (2/10). These findings suggested that VEGF-D could facilitate mediastinal spread of lung cancer cells. Immunohistochemical study revealed that the expression of both VEGF-A and VEGF-D in the disseminated tumor promoted intense blood vessel formation rather than lymph vessel formation. In contrast, TKB5/VEGF-C showed mild increase of lymph vessel density and significantly low blood vessel density in the disseminated tumor. Conclusions:The biological behavior of lung cancer cells within the thoracic cavity appears to be regulated by expression patterns of VEGFs. The regulation of the expression of VEGFs in intrathoracic lung cancer cells might be a useful therapeutic approach to inhibit tumor development and improve patient prognosis.

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