Cellular and molecular effects of pulsed dye laser and local narrow-band UVB therapy in psoriasis.

BACKGROUND AND OBJECTIVES: Pulsed dye laser (PDL) therapy is effective in clearing psoriasis plaques, but the mechanism of action is only partially understood. Local narrow-band ultraviolet B (NB-UVB), which has a better-defined mode of action, is an effective standard treatment for psoriasis. Our aim was to evaluate the cellular and molecular effects of PDL and to compare them with those of local NB-UVB in order to gain further insight into their mechanisms of action in psoriasis. STUDY DESIGN/PATIENTS AND METHODS: Nineteen patients with stable plaque-type psoriasis were treated either with PDL or NB-UVB. Lesional punch biopsies were obtained from all patients before treatment. Additional biopsies were obtained at 3 and 24 hours after PDL treatment in five of these patients. In 14 patients additional biopsies were taken after 7 and 13 weeks of treatment. Samples were histopathologically examined for the level of dermal T cell infiltrate, and the expression of epidermal beta-defensin 2, immune cell-derived tumor necrosis factor (TNF)-alpha, endothelial E-selectin, vascular endothelial growth factor receptor (VEGFR) 2 and 3, and the expression of interleukin (IL)-23 before and after treatment. RESULTS: The expression of VEGFR2, VEGFR3, and E-selectin was decreased in clinically high responders within 24 hours after PDL treatment. The expression of IL-23, TNF-alpha mRNA, and E-selectin protein were significantly reduced after two PDL treatments, whereas the expression of all epidermal markers and dermal T cell infiltrates had normalized after four treatments. The expression of epidermal activation markers and E-selectin were significantly reduced after 13 weeks of NB-UVB treatment. CONCLUSIONS: The expression of epidermal activation markers and the dermal T cell infiltrates were decreased after both treatments. The decreased expression of VEGFR2 and VEGFR3 followed by the down-regulation of TNF-alpha and IL-23p19 may be contributory factors in the efficacy of PDL in stable plaque-type psoriasis.

Optimizing ALA-PDT in the management of non-melanoma skin cancer by fractionated illumination.

The aim of this review was to describe briefly the mechanism and history of photodynamic therapy (PDT). The achieved preclinical and clinical results in Rotterdam are discussed in the light of a search to optimize aminolevulinic acid-photodynamic therapy (ALA-PDT). As the incidence of skin cancer is rising, an optimized treatment in non-melanoma skin cancer is needed.

A comparative study on the efficacy of treatment with 585 nm pulsed dye laser and ultraviolet B-TL01 in plaque type psoriasis.

BACKGROUND: Narrow-band ultraviolet-B and pulsed dye laser (PDL) affect psoriasis but via different pathways. OBJECTIVE: To compare the results of PDL with ultraviolet-B light therapy (UVB) and to look for synergism of both therapies in patients with plaque type psoriasis. METHODS: In each eligible individual, four similar target plaques were selected, and halves of these plaques were treated using PDL, UVB, or a combination of PDL and UVB or were not treated. Results were recorded single-blind using the Physician's Global Assessment score at study enrolment and Week 13. Nonparametric, paired statistical tests were used to test for differences within and between therapies.The results were also analyzed after dichotomization of the changes in the Physician's Global Assessment score into responsive and nonresponsive to treatment. RESULTS: A significant improvement of the psoriasis lesions was noted at Week 13 (P<.001) with each therapy. No significant differences were noted between the therapies. Synergism of PDL and UVB was not observed. CONCLUSIONS: PDL is safe for treating plaque type psoriasis, but its efficacy is limited to a subgroup of patients. Combining PDL with UVB has no additional benefit.

Diode laser hair removal around ileo-colo ostomys is safe, effective and beneficial: a pilot study.

BACKGROUND AND OBJECTIVE: Hair removal around an ileo-colo ostomy can cause a number of problems. We compared laser hair removal with mechanical shaving around the ostomy. METHOD: Eleven patients were selected with hairy skin around the ostomy for therapy with an AlGaAs diode laser at 800 nm. Three to four treatments were given with an interval of 6 weeks. RESULTS: Ten patients completed laser therapy. The average hair reduction was 60% based on visual inspection. Shaving frequency reduced from once a week to once every 6 weeks. CONCLUSIONS: Laser hair removal likely becomes the preferred method in ostomy patients.

The garlic-derived organosulfur component ajoene decreases basal cell carcinoma tumor size by inducing apoptosis.

Although the therapeutic role of ajoene, an organosulfur compound of garlic, in cardiovascular diseases and mycology has been established, its usefulness in cancer treatment has only recently been suggested. We applied ajoene topically to the tumors of 21 patients with either nodular or superficial basal cell carcinoma (BCC). A reduction in tumor size was seen in 17 patients. Immunohistochemical assays for Bcl-2 expression in a selection of these tumors before and after treatment showed a significant decrease in this apoptosis-suppressing protein. On average, the percentage of tumor cells expressing the proliferation marker Ki-67 was not decreased, which suggests that the action of ajoene is not explained by a cytostatic effect. To obtain further insight into the mode of action of ajoene, the BCC cell line TE354T and a short-term primary culture of BCC were analyzed for apoptosis induction after treatment with the drug. Apoptosis was detected by morphology of the cells and by flow cytometry. Ajoene induced apoptosis in a dose- and time-dependent manner in these cultures. Taking together the results of the in vivo and in vitro studies, we conclude that ajoene can reduce BCC tumor size, mainly by inducing the mitochondria-dependent route of apoptosis.

Adjuvant cytokeratin staining in Mohs micrographic surgery for basal cell carcinoma.

BACKGROUND: Mohs micrographic surgery (MMS) is a technique that offers excellent cure rates in the treatment of basal cell carcinoma (BCC). One of the reasons for its success is the 100% visualization of the resection margins. Still, recurrences do occur in 2% to 5% of the treated BCCs. It has been suggested that BCC cells in frozen sections stained with hematoxylin and eosin (H&E) may be missed. OBJECTIVE: To determine whether an additional immunohistochemical staining with a cytokeratin marker (MNF 116) indicates BCC cells in sections in which the H&E-stained frozen sections were negative. METHODS: The Mohs procedure was performed under standard conditions in which H&E-stained slides were judged by the Mohs surgeon and the pathologist. After the H&E slides where judged negative, an extra slide was stained using immunohistochemistry and a monoclonal antibody against cytokeratin (MNF 116). RESULTS: A total of 143 complete slides were stained and judged by two Mohs surgeons and a pathologist. One of the 143 slides stained with MNF 116 showed positive staining where the H&E slides were negative, which is 0.7% of the slides. However, this single slide represents a failure of nearly 2% of the treated patients. CONCLUSION: Frozen sections stained with H&E in MMS offer enough security in detecting BCC cells during surgery; however, adjuvant cytokeratin staining can be useful in very selected cases of aggressive growing BCC.

Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare skin disease, mostly seen on the legs and often occurring in patients with diabetes mellitus. The disease belongs to the idiopathic cutaneous palisading granulomatous dermatitides associated with a degeneration of collagen, thus leading to skin atrophy. Application of topical corticosteroids is the most widely used treatment but the results are not always satisfactory and may worsen skin atrophy. Preliminary studies in patients with NL have shown a clinical response with psoralen plus ultraviolet (UV) A (PUVA). Objectives To study the effect of topical PUVA on NL in a multicentre prospective study. METHODS: Thirty patients (27 women and three men) including 13 with insulin-dependent diabetes mellitus, with a diagnosis of NL proven by histopathology, were included. All patients had been unsuccessfully treated with topical and/or intralesional corticosteroids. Patients were treated twice weekly with an aqueous gel containing 0.005% psoralen followed by irradiation with UVA. Clinical photographs were taken for evaluation. In addition, 20-MHz high-frequency ultrasound analysis was performed in 10 patients to evaluate the thickness and density of the dermis during topical PUVA therapy. RESULTS: Five patients (17%) showed complete clearing (healing of ulceration and disappearance of erythema) after a mean of 22 exposures (range 15-30). Eleven patients (37%) showed improvement, defined as healing of ulceration and/or reduction of erythema, after a mean of 23 exposures (range 11-42). Ten patients (33%) showed no effect and four patients (13%) worsened during topical PUVA therapy. The treatment results of the patients who suffered from diabetes mellitus were not different from those who did not have diabetes mellitus. No difference was seen in mean dermal thickness (1666 vs. 1706 micro m) and density (17 vs. 16 units) before and after topical PUVA therapy. Side-effects were seen in 10 patients: hyperpigmentation (n = 4), blistering (n = 4) and bacterial infection (n = 2). CONCLUSIONS: Topical PUVA may be a useful treatment modality for NL in patients not responding to topical or intralesional corticosteroids.

Gene expression of Medicago sativa inoculated with Sinorhizobium meliloti as modulated by the xenobiotics cadmium and fluoranthene.

Alfalfa plants (Medicago sativa cv. Europe) inoculated with Sinorhizobium meliloti 2011 (formerly Rhizobium meliloti, de Lajudie et al., 1994) were cultivated for 14 days under standardized growth conditions in mineral medium with addition of the heavy metal cadmium or the polycyclic aromatic hydrocarbon fluoranthene. These xenobiotics significantly reduced the numbers of root nodules before any visible damage to the plant could be detected. EC10, EC50, and EC90 (effective concentrations reducing nodulation, shoot and root fresh weight by 10, 50, or 90% compared to the control without pollutant) were calculated. EC50 for cadmium ranged from 5.8 microM (nodulation) to more than 20 microM (root fresh weight). Testing fluoranthene resulted in an EC50 of 2.5 microg cm(-2) for nodulation, and EC50 values of more than 35 microg cm(-2) for shoot and root biomass production, indicating that the effect parameter nodulation is 10-fold more sensitive than shoot and root fresh weight. With mRNA differential display techniques the effects of both xenobiotics on gene expression in alfalfa root systems were studied. 37 differentially displayed transcripts were detected. Two of them, called DDMs1 and DDMs2, were confirmed by northern hybridization to be down-regulated in the presence of the xenobiotics. The expression of transcript DDMs1 was enhanced in alfalfa control plants inoculated with rhizobia, the transcript level was increased 2.5-3-fold compared to non-inoculated plants. This positive effect of nodulation was suppressed, partly by 35 microg cm(-2) fluoranthene and totally by 20 microM cadmium. The decrease in DDMs1 transcription was highly affected by the cadmium concentration with an EC50 of 5.9 microM. Compared to nodulation, almost identical EC10, EC50, and EC90 values were found for DDMs1 expression. Sequence analysis of DDMs1 revealed a significant overall homology (50% identity) to a hypothetical protein from Arabidopsis thaliana with high similarity to a copper transporting ATPase. High levels of transcript DDMs2 were observed in control plants with a 50% decrease in the xenobiotic-treated plants. DDMs2 gave a strong homology (82% identity) to the cytoplasmatic 60S ribosomal protein L18 from Arabidopsis thaliana.

Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma.

OBJECTIVE: Octreotide scintigraphy has been reported to visualize chromaffine tumours. This study in patients with malignant phaeochromocytoma was designed to assess octreotide in comparison with standard m-iodobenzylguanidine (MIBG) scintigraphy and to study functional activity of somatostatin receptors. Finally, two cases of octreotide treatment are reported. DESIGN: Open, prospective clinical trial. PATIENTS: In 12 patients with histologically proven malignant phaeochromocytoma, 111In-octreotide scintigraphy, 123I-MIBG scintigraphy and computed tomography were performed. In ten patients plasma catecholamine response to a single dose of octreotide (200 micrograms i.v.) was monitored up to 5 hours after injection. Two patients were treated with octreotide over several months. MEASUREMENTS: Plasma catecholamines were measured by high performance liquid chromatography (HPLC). Scintigraphy was performed using a large field gamma camera and SPECT technique where appropriate. RESULTS: At least one metastatic lesion was visualized by octreotide scintigraphy in eight patients while the remaining four patients had negative findings. In total, 43 out of 54 known metastases (79.6%) were detected by MIBG, 24 (44.4%) by octreotide. Nevertheless, octreotide scintigraphy detected six metastases that were negative by MIBG. There was no correlation between the results of octreotide scintigraphy and catecholamine suppression after i.v. octreotide. In two patients on octreotide treatment, symptomatic improvement, but not mass reduction, could be documented. CONCLUSIONS: Octreotide scintigraphy behaves in part complementary to MIBG, thus, increasing diagnostic sensitivity. Presence of somatostatin receptors, as demonstrated by octreotide scintigraphy, does not necessarily predict functional activity or therapeutic response.

Early postoperative enteral nutrition with arginine-omega-3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: an immunologic evaluation of Impact.

OBJECTIVE: To evaluate the effect of early postoperative feeding with a nutritionally complete enteral diet supplemented with the nutrients arginine, ribonucleic acid (RNA), and omega-3 fatty acids on the immune function in patients undergoing surgery for upper gastrointestinal (GI) malignancies. DESIGN: Prospective, randomized, placebo-controlled, double-blind study. SETTING: Surgical intensive care unit (ICU) in a German university hospital. PATIENTS: Forty-two consecutive patients receiving an enteral diet via needle catheter jejunostomy after GI surgery for cancer. INTERVENTIONS: Patients were randomized to receive either the arginine, RNA, and omega-3 fatty acids supplemented diet or an isocaloric and isonitrogenous placebo diet. Early enteral nutrition was started on postoperative day 1 in the surgical ICU with 20 mL/hr and progressed to the optimal goal of 80 mL/hr by postoperative day 5. MEASUREMENTS AND MAIN RESULTS: Clinical examination and adverse GI symptoms were recorded on a daily basis. Body weight was determined twice weekly. Immunoglobulin concentrations were determined by laser nephelometry. Interferon-gamma concentrations were measured with a modified enzyme-linked immunosorbent assay method. Fluorescence-activated cell scan flow cytometry was performed to analyze B cells, T lymphocytes and their subsets. Clinical patient characteristics and mean caloric intake were similar between the two groups and both formulas were well tolerated. The number of T lymphocytes and their subsets, helper T cells (CD4) and activated T cells (CD3, HLA-DR), were significantly higher in the supplemented diet group on postoperative days 10 and 16 (p < .05). Mean interferon-gamma concentration after phytohemagglutinin stimulation was higher in the supplemented diet group on postoperative day 16. In the supplemented diet group, mean immunoglobulin M concentrations were significantly higher on postoperative day 10 and mean immunoglobulin G concentrations were higher on postoperative day 16 (p < .05) compared with the results in the placebo group. B-lymphocyte indices were significantly higher in the supplemented vs. the placebo diet group on postoperative days 7 and 10 (p < .05). CONCLUSIONS: Supplementation of enteral diet with arginine, RNA, and omega-3 fatty acids in the early postoperative time period improves postoperative immunologic responses and helps to overcome more rapidly the immunologic depression after surgical trauma.

Treatment of disseminated malignant melanoma with cisplatin in combination with whole-body hyperthermia and doxorubicin.

Twenty-three patients with disseminated malignant melanoma were entered in a pilot study conducted from January 1983 to January 1988. There were 14 men and nine women. Fifteen patients were available for final evaluation. The criterion for evaluation was the completion of the two thermochemotherapy cycles. Patients received multiple-drug chemotherapy consisting of cisplatin (80 mg/m2, i.v., day 1) and doxorubicin (50 mg/m2, i.v., day 2); applications were repeated on days 22-29. Cisplatin was administered concurrently with whole-body hyperthermia (WBH) on day 1 (body core temperature 41 +/- 0.5 degrees C/h). The following response rates were achieved: complete remission (CR) 0/15; partial remission (PR) 3/15; minor response (MR) 4/15, no change (NC) 3/15; progressive disease (PD) 5/15. These findings are within the range known from the literature of the response to multiple-drug chemotherapy without hyperthermia. Toxicity, in particular renal toxicity, was not enhanced by the combined application of cisplatin and hyperthermia, with the exception of the bone marrow toxicity, which seemed to be slightly more pronounced than that known from normothermic application. Concurrent administration of thermochemotherapy with cisplatin and WBH (41 +/- 0.5 degrees C/h) is no more effective than the multiple-drug chemotherapy without hyperthermia as reported in the literature.

Predicting the sensitivity of human cancers to combined chemotherapy and hyperthermia.

In order to estimate its ability to predict the thermochemosensitivity of human cancers, a rapid in vitro assay based on morphological changes in the nucleus was performed on eight different human tumors (four malignant melanomas, two lung tumors, one renal carcinoma, and leukemia K-562). Nude mice, implanted with tumors, supplied the tumor material, with the exception of leukemia. Nimustine, melphalan, mitomycin C, vincristine and vinblastine were tested. Tumor cells developed karyorrhectic changes after incubation for 4 h with each of the aforementioned five drugs. An increase in the karyorrhectic changes was observed with hyperthermia at 43 degrees C. The individual tumors showed different sensitivities to 43 degrees C. Five of the eight tumors were significantly sensitive to 43 degrees C. However, in two thermosensitive tumors no drug enhancement was recognized at 43 degrees C. In four tumors several drugs were synergistically enhanced by hyperthermia at 43 degrees C. This study suggests that this simple method may be of clinical use in predicting response to thermochemotherapy.

Inhibition of human tumor colony formation by the new alkyl lysophospholipid ilmofosine.

The cytostatic-cytotoxic effect of the new thioether alkyl lysophospholipid analogue Ilmofosine (1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine, BM 41.440) on colony formation of 30 different spontaneous human tumors was investigated in vitro with the use of a methylcellulose monolayer assay. Twenty-five neoplasms were sensitive to Ilmofosine within the concentration range tested (0-16 micrograms/ml). The most susceptible tumors were 2 colon carcinomas, 2 squamous cell carcinomas and 1 small-cell carcinoma of the lungs, 2 myosarcomas, 2 ovarian carcinomas, 1 gallbladder carcinoma, and 1 pleural mesothelioma with 50% colony formation inhibition doses ranging from 1.5 to 4.0 micrograms/ml. Due to the sensitivity criteria of the U.S. National Cancer Institute (greater than or equal to 70% inhibition of colony formation at 10 micrograms/ml), 15 of 30 tumors tested have to be considered as susceptible to Ilmofosine.