Endoscopic placement of covered versus uncovered self-expandable metal stents for palliation of malignant gastric outlet obstruction.

OBJECTIVE: Stenting is an established endoscopic therapy for malignant gastric outlet obstruction (mGOO). The choice of stent (covered vs uncovered) has been examined in prior randomised studies without clear results. DESIGN: In a multicentre randomised prospective study, we compared covered (CSEMS) with uncovered self-expandable metal stents (UCSEMS) in patients with mGOO; main outcomes were stent dysfunction and patient survival, with subgroup analyses of patients with extrinsic and intrinsic tumours. RESULTS: Overall survival was poor with no difference between groups (probability at 3 months 49.7% for covered vs 48.4% for uncovered stents; log-rank for overall survival p=0.26). Within that setting of short survival, the proportion of stent dysfunction was significantly higher for uncovered stents (35.2% vs 23.4%, p=0.01) with significantly shorter time to stent dysfunction. This was mainly relevant for patients with extrinsic tumours (stent dysfunction rates for uncovered stents 35.6% vs 17.5%, p<0.01). Subgrouping was also relevant with respect to tumour ingrowth (lower with covered stents for intrinsic tumours; 1.6% vs 27.7%, p<0.01) and stent migration (higher with covered stents for extrinsic tumours: 15.3% vs 2.5%, p<0.01). CONCLUSIONS: Due to poor patient survival, minor differences between covered and uncovered stents may be less relevant even if statistically significant; however, subgroup analysis would suggest to use covered stents for intrinsic and uncovered stents for extrinsic malignancies.

Radiation-induced skin ulcer and rib fractures following percutaneous coronary intervention (PCI): A case of right back skin ulcer and adjacent rib fractures after single PCI.

We experienced a 75-year-old male patient with a refractory and severely painful skin ulcer on the right back. He had suffered from ischemic heart disease and undergone percutaneous coronary intervention 5 months prior to the consultation with us. The characteristic clinical appearance, location of the lesion and his past medical history led us to the diagnosis of radiation-induced skin ulcer. Magnetic resonance imaging, computed tomography as well as bone scintigraphy showed fractures of the right back rib adjacent to the ulcer, which was thought to be attributable to bone damage due to X-ray radiation and/or persistent secondary inflammation of the chronic ulcer. In the published work, there are no other reports of bone fractures associated with radiation dermatitis after coronary interventional radiology.

[Combined therapy of lapatinib and capecitabine effective against local recurrence of breast cancer].

A 67-year-old woman after mastectomy was afflicted with local recurrence of left breast cancer during adjuvant trastuzumab therapy. Oral administration of lapatinib and capecitabine served to distinguish the recurrent tumor and also reduce the patient's distressing symptoms. This combined anti-cancer therapy may be available for patients with breast cancer for whom trastuzumab therapy was not adequately effective.

[Fungal immunology in the skin; immune response to dermatophytes].

Infections with dermatophytes are generally confined to the keratinized stratum corneum. This superficial site of infection may protect the infecting dermatophytes from direct contact with some of the effector cells of the immune system; therefore, the immune system has developed a special subsystem in the skin to eliminate them.The innate immunity and acquired immunity (delayed-type hypersensitivity response) are both required for cutaneous immune surveillance against dermatophytes in the skin.Epidermal keratinocytes not only have an important structural role in forming a physical barrier to dermatophytes but also are important functionally in mediating cutaneous immune reactions. These cells can secrete proinflammatory cytokines, chemokines, and anti-microbial peptides in response to dermatophytes. The T cell-mediated delayed-type hypersensitivity response to dermatophyte antigens may play a central role in both pathogenesis of the typical skin lesions and an acquired, relative resistance that affords partial immunity to the host. However, the exact form of effector T cell immunity and the cellular and molecular mechanisms which eliminate dermatophytes from the skin are poorly understood. The literature on the immunology against dermatophyte infection is reviewed in this paper.

Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

Differential induction of Th1-prone immunity by human dendritic cells activated with Sporothrix schenckii of cutaneous and visceral origins to determine their different virulence.

Sporotrichosis is caused by a thermo-dependent dimorphic fungus, Sporothrix schenckii. The major clinical manifestations occur in the skin; however, cases of visceral manifestations have also been increasingly reported with some being observed in immune compromised patients. Different virulence of individual S. schenckii strain as well as immune status of the host could contribute to form such different clinical manifestations. Thus, the purpose of the study was to investigate whether different virulence of individual S. schenckii could be a factor for such clinical difference. We investigated the interactions between human monocyte-derived dendritic cells (MoDCs) and S. schenckii, assessed by (i) morphological features, (ii) surface marker expressions, cytokine productions, (iii) signaling pathways and (iv) allostimulatory activity of the activated MoDCs. Immature MoDCs, obtained from peripheral blood monocytes supplemented with granulocyte macrophage colony-stimulating factor and IL-4, were stimulated with S. schenckii strains of both yeasts and conidia forms of different origins (cutaneous isolates: KMU4649, IFM5906 and IFM46010; visceral isolates: KMU4648, IFM41598 and ATCC26331) to be used for various assays. Through the analysis, we found that the cutaneous S. shenckii of cutaneous origins were more potent to activate MoDCs to induce strong T(h)1 response, as evidenced by abundant IFN-gamma production, while the S. shenckii of visceral origins induced only minimal dendritic cell activation and T(h)1 induction. The p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signaling pathways appeared to be associated with the differential activation of the MoDCs by S. schenckii of cutaneous and the visceral origins. Overall, we concluded that the differential activation of MoDCs by S. schenckii of cutaneous and visceral origins to induce T(h)1 response, other than immune status or the host, may be a factor for their different clinical manifestations.

Expression of p16 and hTERT protein is associated with the presence of high-risk human papillomavirus in Bowenoid papulosis.

BACKGROUND: High-risk human papillomavirus (hrHPV) type E6 and E7 oncoproteins contribute to oncogenesis in multiple ways by modulating the activities of host components in cell-cycle regulation including the expression of p16 protein (p16) and human telomerase reverse transcriptase (hTERT). The expression of p16 and hTERT protein in Bowenoid papulosis (BP) has not been studied. METHODS: Biopsy samples of BP from 26 patients were subjected to in situ hybridization for various HPV strains and immunohistochemical staining for p16 and hTERT. RESULTS: Among the 26 biopsy specimens, in situ hybridization using DNA probes for HPV 16/18 revealed positivity in 18 specimens (69.2%), one of which also showed positivity with the probes for HPV 6/11. HPV 31/33/35 was found in three specimens (11.5%). Two specimens (7.7%) were positive for unclassified HPV. Twenty-one BP specimens that were infected with hrHPV were positive for p16 and/or hTERT. Moderate or strong and diffuse immunostaining was observed for p16 in 15 hrHPV-infected specimens and for hTERT in 16 hrHPV-infected specimens. The expression of p16 or hTERT was each significantly associated with the presence of hrHPV. CONCLUSIONS: hrHPVs were involved in inducing p16 and hTERT overexpression in BP. Moreover, our results suggested that immunohistochemical p16 and hTERT expression might be a useful marker of hrHPV infection in BP.

beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas.

BACKGROUND: beta-Catenin has been shown to play an important role in the formation of hair follicle-related tumors, including pilomatricomas. Several investigators have shown that beta-catenin gene mutation is observed in pilomatricomas. However, the relationship between the pattern of beta-catenin localization in the cell and beta-catenin gene mutation is still controversial. OBJECTIVES: This work was performed to determine the frequency of beta-catenin nuclear localization in pilomatricoma, the relationship between the pattern of beta-catenin localization and beta-catenin mutation, and the involvement of APC mutation. METHODS: Typical 32 pilomatricomas were examined for beta-catenin expression by immunostaining. Genomic DNA was extracted, amplified and sequenced from 23 pilomaticomas with nuclear beta-catenin staining and 4 pilomaticomas without nuclear beta-catenin staining. Mutations of beta-catenin gene were confirmed by subcloning assay and restriction endonuclease assay. RESULTS: Using immunostaining, we found that 81% (26/32) of pilomatricomas displayed nuclear beta-catenin staining in basophilic cells. Sequence analysis revealed that 61% (14/23) contained mutations in exon 3 of beta-catenin. However, no mutations were detected in 4 pilomaticomas without beta-catenin nuclear staining. Detected mutations were adjacent to or abolished well-known regulatory phosphorylation sites of beta-catenin. APC gene mutations were not detected in 27 pilomatricomas with/without beta-catenin nuclear staining. CONCLUSIONS: These results confirmed that beta-catenin mutation and its nuclear localization are frequent causes of Wnt signaling pathway activation and suggested that beta-catenin activation mutations contribute to tumorigenesis of pilomatricomas.

Cicatricial pemphigoid with autoantibodies against the laminin 5 gamma 2 subunit.

Cicatricial pemphigoid (CP) is an autoimmune bullous disease accompanied by mucosal lesions. The majority of patients with CP have autoantibodies against BP180. Anti-laminin 5 (epiligrin) CP is relatively rare. It is known that, in most cases, circulating autoantibodies against laminin 5 in these patients recognize the alpha3 and/or beta3 subunits of this molecule. Here we report a case of anti-laminin 5 CP, which showed IgG autoantibodies against the gamma2 subunit of laminin 5 alone. A 50-year-old woman suffered from skin blistering on the trunk and extremities and severe mucosal lesions in the eyes, oral cavities and laryngopharynx. Despite potent systemic steroids, the mucosal lesions and some parts of the skin lesions persisted. Salazosulfapyridine was of value in controlling the laryngopharyngeal lesions and persistent cutaneous blistering, and cyclophosphamide had definite effects especially on ocular lesions. Anti-laminin 5 autoantibodies became undetectable in serum from the patient after the disease was controlled.

Cutaneous Scedosporium apiospermum infection in an immunocompromised patient and a review of the literature.

Scedosporium apiospermum (also known as Pseudallescheria boydii) is a ubiquitous filamentous fungus. This fungus is known as a cause of mycetoma, which may occur in a normally immune host following trauma. However, in an immunocompromised host, S. apiospermum may cause a life-threatening infection. We describe a case of S. apiospermum infection of the right hand in a patient who was receiving long-term immunosuppressants for adult Still's disease. We also review the cases of S. apiospermum infection with cutaneous manifestations reported between 1998 and 2003.

Migration of keratinocytes is impaired on glycated collagen I.

Advanced glycation end products are the chemical modification of proteins induced by sugars in a hyperglycemic condition. Extracellular matrix proteins are prominent targets of nonenzymatic glycation because of their slow turnover rates. The aim of this study was to investigate the influence of nonenzymatic glycation of type I collagen on the migration of keratinocytes. The migration of keratinocytes was dramatically promoted on native type I collagen-coated dishes compared with that on uncoated dishes. When type I collagen was glycated with glycolaldehyde, large amounts of advanced glycation end products were produced; the glycated collagen I-coated dishes did not promote the migration of keratinocytes. Glycated collagen I did not affect the proliferative capacity of keratinocytes. However, the adhesion of keratinocytes to glycated collagen I was profoundly diminished in a glycation intensity-dependent manner. alpha2beta1 integrin is responsible for the migration and adhesion of keratinocytes to type I collagen. Pretreatment with glycated collagen I did not affect the expression level or functional activity of alpha2beta1 integrin on keratinocytes. These findings suggest that in the presence of glycated collagen I, keratinocytes lose their adhesive and migratory abilities. As the glycation did not modify the alpha2beta1 integrin on keratinocytes, it is suggested that glycation may diminish the binding capacity of type I collagen.

Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Intermittent dosing with potent topical steroids and/or combination therapy with steroid and tacrolimus have been frequently used in the daily management of AD to overcome the problems accompanying the long term use of steroids. We compared the clinical effects of topical steroid/tacrolimus and steroid/emollient combination treatments in 17 patients with AD. An intermittent topical betamethasone butyrate propionate/tacrolimus sequential therapy improved lichenification and chronic papules of patients with AD more efficiently than an intermittent topical betamethasone butyrate propionate/emollient sequential therapy after four weeks of treatment. Only one out of 17 patients complained of a mild, but temporary, burning sensation after tacrolimus application. The intermittent topical steroid/tacrolimus sequential therapy may be a useful adjunctive treatment for AD.

Dosage and adverse effects of topical tacrolimus and steroids in daily management of atopic dermatitis.

Since 1999, combination therapy with tacrolimus and topical steroids has been widely used for the treatment of adolescent/adult-type atopic dermatitis. In order to determine the clinical doses of topical tacrolimus and steroids for daily treatment of atopic dermatitis and to elucidate their beneficial and adverse effects, we analyzed the clinical data from 215 patients with atopic dermatitis who were more than 16 years old. Less than 70 g of tacrolimus and less than 15 g of steroids were applied to 90% of the patients on the face and neck, and less than 75.8 g of tacrolimus and less than 322 g of steroids were applied to 90% of the patients on the trunk and extremities during the six-month treatment period. Topical tacrolimus is much more frequently used on face and neck lesions (99.1%); in only 39.5% of cases was it used on the trunk and extremities. The majority of patients improved after six months of the combination topical therapy; however, atopic dermatitis was not controlled in 6% of the patients. The combination therapy did not seem to increase the risk of cutaneous infections; however, the incidence of herpes simplex infection on the face and neck was 2.8% at pre-treatment and slightly increased to 4.7% during the therapy. The incidence of all steroid-induced adverse effects was reduced both in frequency and intensity with a decrease in the dose of topical steroids through simultaneous tacrolimus application. Combination therapy with topical tacrolimus and steroids is useful for treating atopic dermatitis, but a small percentage of the patients still cannot be satisfactorily treated. For such patients, adjustments of the dose and rank of topical steroids and tacrolimus and other therapeutic adjuncts are necessary.

A case of multifocal lupus vulgaris that preceded pulmonary tuberculosis in an immune compromised patient.

We describe the rare case of a Japanese male with multifocal lupus vulgaris that preceded asymptomatic pulmonary tuberculosis and adult T-cell leukemia/lymphoma (ATL). He visited our hospital with multiple reddish plaques and erythema of 4-12 months duration. A skin biopsy revealed non-caseating epithelioid granulomas. Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR)-hybridization from a skin biopsy specimen and was also isolated from a culture of the skin biopsy sample. The result of chest roentogenography was compatible with pulmonary tuberculosis. In addition, the diagnosis of ATL was based upon the presence of atypical lymphocytes with convoluted nuclei in his peripheral blood and a positive anti-ATL antibody reaction. Cases of cutaneous tuberculosis presenting with unusual clinical features may be on the increase, accompanying the spread of tuberculosis in immunosuppressed patients, including those with ATL and acquired immunodeficiency syndrome (AIDS).

Reciprocal regulation of thymus and activation-regulated chemokine/macrophage-derived chemokine production by interleukin (IL)-4/IL-13 and interferon-gamma in HaCaT keratinocytes is mediated by alternations in E-cadherin distribution.

Keratinocytes produce many cytochemokines that are involved in the pathogenesis of skin disorders. In particular, the CC chemokines thymus and activation-regulated chemokine (TARC)/macrophage-derived chemokine (MDC) play an important role in the infiltration of Th2 cells. This study was undertaken to examine the regulatory effects of interleukin (IL)-4, IL-13, and interferon (IFN)-gamma on TARC/MDC production in the human keratinocyte cell line HaCaT. HaCaT cells spontaneously secrete TARC and MDC. The production of TARC/MDC was downregulated by IL-4/IL-13, whereas it was upregulated by IFN-gamma. To explore these regulatory mechanisms, we investigated the capacity of cytokines to regulate expression of several adhesion molecules that may affect TARC/MDC production. Of the adhesion molecules examined, the constitutive surface expression of E-cadherin was downregulated by IL-4/IL-13, but was upregulated by IFN-gamma. Moreover, disruption of the homophilic adherence of E-cadherin by anti-E-cadherin antibody or calcium chelation abolished the production of TARC/MDC. We further examined the distribution of the adherens junction complex composed of E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin. IL-4/IL-13 decreased the levels of membrane staining for adherens junction proteins, whereas IFN-gamma increased membrane staining. Taken together, these results suggest that IL-4/IL-13 and IFN-gamma induce alternations in the distribution of adherens junctions in a different fashion and thereby contribute to the reciprocal regulation of TARC/MDC production.

[Immune response in dermatophytosis].

A delayed-type hypersensitivity (DTH) response to a dermatophyte antigen is one of the host defense mechanisms. Peripheral blood mononuclear cells from patients with dermatophytosis produce a high level of IFN-gamma in response to stimulation with trichophytin. The presence of IFN-gamma mRNA in skin lesions of dermatophytosis was detected using reverse transcription-polymerase chain reaction. IFN-gamma-positive cells were observed immunohistochemically in the upper dermis of the skin lesions. These findings support the hypothesis that the skin lesions of dermatophytosis are associated with a Th1 response. The Th1 response, which is characterized by IFN-gamma release, is thought to be involved in the host defense against dermatophytes and to reflect cutaneous reaction in dermatophytosis. The stimulation of trichophytin significantly enhanced the release of IL-8 from keratinocytes. These findings account for the accumulation of neutrophils beneath the stratum corneum. The capacity of trichophytin-stimulated keratinocytes to release an enhanced level of IL-8 thus suggests that these cells can indeed help to induce the acute inflammatory response seen in dermatophyte infection. It therefore appears that keratinocytes not only play an important structural role in the formation of a physical barrier to dermatophytes but may also play an important functional role in initiating cutaneous inflammatory reactions, which might be involved in the host defense against dermatophytes. The production of IFN-gamma by peripheral blood mononuclear cells from patients with tinea unguium in response to stimulation with trichophytin was not impaired in contrast to that from patients without tinea unguium. Comparable lymphocyte proliferation with trichophytin was observed in both groups. No deficiency in Th1 response to dermatophyte antigen was shown in patients with tinea unguium by measuring the release of IFN-gamma, which plays a role in the effector phase of the DTH reaction. A deficiency of Th1 response to dermatophyte antigen, therefore, does not appear to play an important role in the establishment of tinea unguium.

Interleukin-8 expressed in the granulocytes of the eye in a patient with Behçet's disease complicated by lens-induced endophthalmitis.

BACKGROUND: Interleukin-8 (IL-8) is believed to be involved in the progression of intraocular inflammation. We sought the source of IL-8 in the enucleated eye of the present patient. CASE: A 40-year-old Japanese man was diagnosed as having Behçet's disease. His vision deteriorated due to persistent uveitis and secondary glaucoma. His left eye had lens-induced endophthalmitis. OBSERVATIONS: The left eye had to be enucleated, and it was investigated by an immunohistochemical analysis using antibodies for CD 1a (dendritic cells), CD 3 (T cells), CD 68 (monocytes/macrophages), interferon-gamma, or IL-8. Fibrovascular tissue had formed on and beneath the lens where inflammatory cells had infiltrated. Most of the mononuclear inflammatory cells were T cells. A large number of macrophages were observed especially around the lens. Interferon-gamma-positive cells were scattered, while IL-8 was observed only in the accumulated granulocytes, but not in either mononuclear cells or macrophages. CONCLUSION: IL-8 is thus considered to play a role in the progression of intraocular inflammation, and granulocytes are thought to be a possible source of IL-8 in endophthalmitis.