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Vol 349 • May 17, 1997 1477 is characteristic of non-healing, chronic localised leishmaniasis. Third, the source of paromomycin sulphate was Synopharm (USP quality 23). Paromomycin was added by the pharmacy to unguentum cordes. The 10% suspension did not contain preservatives or solvents. This ointment was applied to the lesion, covered with a plastic foil, and then fixed by a normal dressing. The dressing was changed thrice weekly. Thus, in view of the typical histological picture, it is most likely that occlusive paromomycin application was responsible for the therapeutic effect. We think that at least one of the objectives of a research letter is to draw attention to new ideas. Thus, our previous report of phototherapy for localised scleroderma profoundly changed the therapeutic approach to this disease. After publication of this letter, phototherapy of scleroderma was established in several countries and studies have confirmed our initial report. Initiated by our letter, phototherapy became the first-line therapy of localised scleroderma within 2 years. We hope that our latest report will be similarly helpful for all patients who need a topical treatment for cutaneous leishmaniasis and are refractory to other conventional treatments.

REPORT OF A CASE A 42-year-old woman who suffered for more than 2 years from disseminated localized scleroderma (LS) (Figure 1) markedly improved during treatment with psoralen with UV-A (PUVA) bath photochemotherapy with 8-methoxy-psoralen (8-MOP).1The 8-MOP was applied to the skin during a warm water bath, which was immediately followed by UV-A exposure. Clinical, histological, and ultrasound indications of LS (Figure 2) regressed almost completely during PUVA bath photochemotherapy in this and 2 other patients, 1 with disseminated LS and 1 with contractures caused by linear LS of the dorsal aspects of the left thigh and entire left leg.1 THERAPEUTIC CHALLENGE No single therapy produces uniform disease remission in LS.2-6A safe and effective therapy associated with the least potential complications is required. SOLUTION Since clinical regression of sclerosis was confirmed by ultrasound and histological evaluations, we considered PUVA bath photochemotherapy a promising novel therapeutic approach

Lichen planus (LP) is a common inflammatory skin disease, accounting for approximately 1% of all diagnoses seen in patients seeking dermatologic care. In some patients, therapy remains difficult, and systemic application of glucocorticosteroids, cyclosporine, systemic photochemotherapy with psoralen plus UV-A (PUVA), and acitretin have been used with limited success.1To circumvent the problems of oral PUVA therapy, methoxsalen (8-methoxypsoralen) in a dilute bathwater solution may be applied to the skin before UV-A.2A PUVA-bath photochemotherapy regimen has been shown to be an elegant alternative in the treatment of psoria- sis.2,3We describe our first four patients with LP who received PUVA-bath photochemotherapy. Patients and Methods. Four patients (age range, 42 to 76 years) with histopathologically proven LP received PUVA-bath photochemotherapy (Table). All had a history of LP for 14 to 24 months and had received topical or systemic glucocorticosteroids, oral PUVA (one patient), and acitretin (one patient)

Lymphomatoid papulosis (LyP) is a recurrent papulonodular skin disease affecting the trunk and extremities. 1,2 In some patients, LyP may resolve spontaneously. However, in some patients skin lesions persist and, in approximately 10% of patients, may even progress into malignant lymphoma. In rare cases, LyP may occur in young adults or children. These young patients pose a most difficult therapeutic challenge, as therapies applied to patients with LyP, such as systemic administration of steroids or oral psoralens plus UVA (PUVA) 3 are given to children very reluctantly. Report of a Case. A 6-year-old boy presented in May 1994 with multiple, large, erythematous, partially ulcerated nodules and nodes involving the trunk and extremities. Histopathologic assessment revealed a dense infiltrate that extended deeply into the reticular dermis that consisted of numerous atypical bizarre-shaped cells of different size. Immunophenotypic analysis demonstrated the presence of CD30 + cells. There were no signs of systemic involvement

Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.

Inflammatory diseases at epithelial borders develop from aberrant interactions between resident cells of the tissue and invading immunocytes. Here, we unraveled basic functions of epithelial cells and immune cells and the sequence of their interactions in an inflammatory skin disease. Ubiquitous deficiency of the IkappaBalpha protein (Ikba(Delta)(/Delta)) as well as concomitant deletion of Ikba specifically in keratinocytes and T cells (Ikba(K5Delta/K5Delta lckDelta/lckDelta)) resulted in an inflammatory skin phenotype that involved the epithelial compartment and depended on the presence of lymphocytes as well as tumor necrosis factor and lymphotoxin signaling. In contrast, mice with selective ablation of Ikba in keratinocytes or lymphocytes showed inflammation limited to the dermal compartment or a normal skin phenotype, respectively. Targeted deletion of RelA from epidermal keratinocytes completely rescued the inflammatory skin phenotype of Ikba(Delta)(/Delta) mice. This finding emphasizes the important role of aberrant NF-kappaB activation in both keratinocytes and lymphocytes in the development of the observed inflammatory skin changes.

Mitochondrial (mt) contribution to carcinogenesis has been critically discussed with circumstantial evidence against as well as for a causal role. Proliferating cancer cells are dependent on sufficient energy supply that would argue against defective mitochondria in tumor cells. On the other hand, mitochondria are the main endogenous source of reactive oxygen species as highly mutagenic side products of oxidative phosphorylation (Fridovich, 2004) and increased amounts of mtDNA mutations have been detected in a variety of tumors (reviewed by Berneburg et al., 2006).

The inflammasome is a protein complex cleaving the pro-inflammatory cytokines IL-1 β and IL-18 into their active forms by caspase-1 activation. The cytosolic protein complex can be activated by danger signals, such as bacterial and viral components, ATP, or uric acid crystals, and reacts as a sensor of innate immunity. In the skin, sensitizing agents promote induction of specific T-cell-mediated contact hypersensitivity. They induce dendritic cell migration, a precondition for the priming of specific T cells. They are a prerequisite for the recruitment of cells into the skin that demand pro-inflammatory stimuli, such as IL-1 β and IL-18. Watanabe et al. (2007, this issue) demonstrate the presence of the inflammasome complex in keratinocytes and report that this complex can be activated by contact sensitizers, such as trinitrocholorobenzene (TNCB), both in vitro and in vivo . The study documents a regulatory effect of innate immunity in a T-cell-mediated delayed-type hypersensitivity reaction.

Background [18F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [18F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [18F]FAZA uptake. Methods We injected subcutaneous CT26 colon carcinoma or polyomavirus middle-T (PyV-mT) mammary carcinoma-bearing mice intravenously with18F-FAZA and performed PET scans 1-3 h post injection (p.i.). To analyze the impact of oxygen supply in CT26 carcinomas we used three different breathing protocols: (P0) air; (P1) 100% oxygen 1 h prior injection until 3 h p.i.; (P2) 100% oxygen breathing starting 2 min prior tracer injection until 1 h p.i. and during the PET scans; mice were breathing air between the 2 h and 3 h 10 min static scans. Normalized PET images were analyzed by using defined regions of interest. Finally, some mice were dissected for pimonidazole immunohistochemistry. Results There was no difference in18F-FAZA uptake 1-3 h p.i. between the two carcinoma types (CT26: 1.58 ± 0.45%ID/cc; PyV-mT: 1.47 ± 0.89%ID/cc, 1 h p.i., tumor size < 0.5 cm3). We measured a significant tracer clearance, which was more pronounced in muscle tissue (P0). The [18F]FAZA tumor-to-muscle-ratios in CT26 colon carcinoma-bearing mice 2 h and 3 h, but not 1 h p.i. were significantly higher when the mice breathed air (P0: 3.56 ± 0.55, 3 h) compared to the oxygen breathing protocols (P1: 2.45 ± 0.58; P2: 2.77 ± 0.42, 3 h). Surprisingly, the breathing protocols P1 and P2 showed no significant differences in T/M ratios, thus indicating that the crucial [18F]FAZA uptake phase is during the first hour after [18F]FAZA injection. Importantly, the muscle clearance was not affected by the different oxygen breathing conditions while the tumor clearance was lower when mice were breathing air. Conclusion Exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas showed no differences in [18F]FAZA uptake 1-3 h p.i. Our analysis using various breathing protocols with air (P0) and with pure oxygen (P1, P2) clearly indicate that [18F]FAZA is an appropriate PET biomarker for in vivo analysis of hypoxia revealing an enhanced tracer uptake in tumors with reduced oxygen supply. [18F]FAZA uptake was independent of tumor-type.