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.

[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.

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.

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.

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.

CX-659S, a diaminouracil derivative, indirectly inhibits the function of Langerhans cells by blocking the MEK1/2-Erk1/2 pathway in keratinocytes.

Keratinocytes are an important component of the skin immune system, and keratinocyte-derived cytokines control the function of Langerhans cells. We previously showed that CX-659S, a novel diaminouracil derivative, had an inhibitory effect on hapten-induced contact hypersensitivity reaction in mice. In this study, we investigated the mechanism by which CX-659S elicits its inhibitory effect. CX-659S inhibited the expressions of CD80 and CD86, but not that of CD54, on Langerhans cells in epidermal cell suspensions. Exogenous granulocyte-macrophage colony-stimulating factor restored the CX-659S-induced inhibition of CD80 and CD86 expressions of Langerhans cells. The production of interleukin-2 from allogeneic T cells was also inhibited when the cells were stimulated with CX-659S-treated epidermal cells, and this inhibition was suppressed by the addition of granulocyte-macrophage colony-stimulating factor during CX-659S treatment. As CX-659S significantly inhibited production of granulocyte-macrophage colony-stimulating factor from keratinocytes, CX-659S was thought to indirectly affect Langerhans cells by inhibiting the function of keratinocytes. These effects of CX-659S were preceded by blockade of the phosphorylation of extracellular-signal-regulated kinase 1/2 and their direct activators, mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2 (MEK1/2), but not p38 mitogen-activated protein kinase or inhibitory nuclear factor kappaBalpha, in keratinocytes. Furthermore, a specific MEK1/2 inhibitor, U0126, mimicked the effect of CX-659S. CX-659S, a keratinocyte-response modifier, would be an effective therapeutic compound to inhibit contact hypersensitivity reaction, its action mechanism being different from those of other immunosuppressive agents such as glucocorticosteroids or cyclosporine A.

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.

Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes.

It is known that large amounts of histamine are stored in mast cells located in the superficial dermis of the skin and can be released upon appropriate stimulation. However, the effects of histamine on keratinocyte function have not been well characterized. We therefore examined the capacity of histamine to modulate the production of interleukin (IL)-6 and IL-8 by keratinocytes. We found that histamine significantly augmented the production of IL-6 and IL-8 in a dose- and time-dependent manner. The enhancing effects of histamine were completely inhibited by a potent H1 receptor (H1R) antagonist, emedastine difumarate. Pyrilamine (a much weaker H1R antagonist) and cimetidine (an H2R antagonist) only partially inhibited the enhancing effects of histamine. The histamine-induced up-regulation of IL-6 and IL-8 production, however, was completely abrogated by a combination of pyrilamine and cimetidine. The IL-6 production was significantly enhanced by interferon (IFN)-gamma. Interestingly, IFN-gamma and IL-4 both significantly augmented the histamine-induced IL-6 production. On the other hand, the production of IL-8 was inhibited by IFN-gamma, and IFN-gamma and IL-4 both completely abrogated the histamine-induced IL-8 production. These results suggest that the histamine-induced IL-6 production and IL-8 production are differentially regulated by IFN-gamma and IL-4. Histamine may be an important modulator of cytokine production in epidermal milieu.

Propionibacterium acnes-induced IL-8 production may be mediated by NF-kappaB activation in human monocytes.

Propionibacterium acnes (P. acnes) causes an inflammatory acne that is characterized by massive neutrophilic infiltration. IL-8 is thought to play an important role in the pathophysiology of P. acnes, although the mechanisms by which P. acnes up-regulates the release of IL-8, a neutrophilic chemokine, from target cells is not well understood. In this study, we investigated the mechanisms through which heat-killed P. acnes induces IL-8 production in THP-1 cells (a human monocytic cell line). We found that P. acnes is able to directly induce IL-8 production and IL-8 mRNA expression in human monocytic cells in a dose- and time-dependent manner through a mechanism requiring transcription factor NF-kappaB activation. Additionally, P. acnes-induced IL-8 secretion was inhibited by roxithromycin, a macrolide antibiotic, and its inhibitory effect seemed to be partially associated with the inhibition of P. acnes-induced NF-kappaB activation. This is the first study to show that NF-kappaB activation is involved in the IL-8 production of monocytic cells stimulated by P. acnes.

Differential regulation of thymus- and activation-regulated chemokine induced by IL-4, IL-13, TNF-alpha and IFN-gamma in human keratinocyte and fibroblast.

The CC chemokine thymus- and activation-regulated chemokine (TARC/CCL17) acts on CC chemokine receptor 4 (CCR4), which is known to be selectively expressed in Th2 cells. In order to compare the regulatory profiles of TARC production by tumor necrosis factor-alpha (TNF-alpha), IFN-gamma, interleukin-4 (IL-4) and IL-13 in keratinocytes and fibroblasts, HaCaT cells, a human keratinocyte cell line, and NG1RGB cells, a human skin fibroblast cell line, were used. The expression of TARC protein was measured using enzyme-linked immunosorbent assay (ELISA), and the mRNA level was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The spontaneous expression of TARC protein and mRNA levels were augmented by TNF-alpha and IFN-gamma and were inhibited by IL-4 and IL-13 in the keratinocytes. The fibroblasts expressed the TARC protein and mRNA only in the presence of IL-4+TNF-alpha or IL-13+TNF-alpha stimulation. IFN-gamma further enhanced the IL-4+TNF-alpha or IL-13+TNF-alpha-induced TARC production in the fibroblasts. Thus, TNF-alpha and IFN-gamma -induced TARC production was differentially regulated by IL-4 and IL-13 in human keratinocytes and fibroblasts.

Classification of cell lineage and anatomical site, and prognosis of extranodal T-cell lymphoma -- natural killer cell, cytotoxic T lymphocyte, and non-NK/CTL types.

Due to their minority among the non-Hodgkin lymphomas, classification of extranodal T-cell lymphomas, including those of the natural killer (NK) cell type, has long been controversial and unclear, and the clinical outcome is not well clarified. Recently, new well-defined disease entities have been described based on tumor cell biology combined with anatomical site, clinical features, Epstein-Barr virus (EBV) status, and cell lineage as determined by immunophenotype and genotype. Cytological features are usually not specific, and there are no morphologic correlates with the classification of extranodal T/NK-cell lymphomas. From a human T-cell lymphotropic virus type 1 (HTLV-1) endemic area in Japan, we report here the analysis of 144 cases of extranodal T-cell lymphoma, from which fresh tissues were available. As the clinicopathological features were known, we simply reclassified the cases according to cell lineage and anatomical site. The extranodal T-cell lymphomas were classified into three types on the basis of cell lineage: (1) natural killer cell (NK) type [sCD3-, CD56+, T-cell receptor gene (TCR) germline], (2) cytotoxic T lymphocyte (CTL) type [sCD3+, TIA-1+, TCR rearranged, CD8+/-, CD4-/+], and (3) non-NK/CTL type [sCD3+, TIA-1-, TCR rearranged, CD4+/-, CD8-/+]. In addition to cell lineage, the anatomical site and clinical features were added for subclassification. NK type tumors (35 cases) included the lymphoblastic type, nasal/nasal-type NK lymphoma, and NK leukemia. The CTL type (46 cases) included anaplastic large cell lymphoma (ALCL), cutaneous type, intestinal, gamma delta T-cell type, and an unspecified type. The non-NK/CTL type (63 cases) included adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and an unspecified type. With the exception of ATLL and MF, most extranodal T-cell lymphomas had a cytotoxic phenotype of NK type or CTL type and were often associated with EBV infection. MF and the unspecified type within the non-NK/CTL tumors, with the exception of ATLL, had a favorable prognosis. However, NK and CTL types, with the exception of ALCL, were associated with a poor prognosis. Our results indicate that anatomical site and cell lineage are useful predictors of clinical outcomes of extranodal T-cell lymphomas.

Therapeutic approaches to subcutaneous mycoses.

Subcutaneous mycoses, which are much less common than superficial fungal infections, are characterized by a heterogeneous group of infections that often result from direct penetration of the fungus into the dermis and subcutaneous tissue through traumatic injury. The fungus spreads by local deep tissue invasion from the inoculation site. The disease usually remains localized and then slowly spreads to adjacent tissue and eventually to the lymphatics. More rarely, hematogenous dissemination is observed. There are usually various clinical features and thus a broad range of differential diagnoses. The common subcutaneous mycoses are sporotrichosis, chromoblastomycosis, phaeohyphomycosis, eumycotic mycetoma, and hyalohyphomycosis. Many subcutaneous mycoses are confined to the tropical and subtropical regions, but some, such as sporotrichosis, are also prevalent in temperate regions. Subcutaneous mycoses can occur in healthy individuals. In immunocompromised individuals, these infections can disseminate widely. Treatment usually involves use of antifungal agents and/or surgical excision. Treatment of some serious subcutaneous mycoses remains unresolved, and there have been reports of relapses or progression during therapy and problems with lack of tolerability of antifungal drugs. Identification of the etiologic agent by culture is essential for prognostic and management considerations, since some fungi are more frequently associated with dissemination. Results of antifungal susceptibility tests may provide valuable information for deciding the appropriate method of treatment. Development of new antifungal agents and combination therapies may result in improvement in the management of subcutaneous mycoses in the future.

In situ localization of IFN-gamma-positive cells in psoriatic lesional epidermis.

Interferon-gamma (IFN-gamma) is believed to be an important mediator in the cytokine cascade of psoriasis. Lesional T cells in the epidermis may play a role in psoriasis. We examined whether IFN-gamma-producing T cells were present in the epidermis of psoriasis in situ by immunohistochemical techniques. Mixtures of CD4+ T cells and CD8+ T cells were found to be present in the papillary dermis and the epidermis of the psoriatic lesions. CD8+ T cells seemed to be dominant in the epidermis. Considerable amounts of IFN-gamma-positive cells were detected in infiltrates of the papillary dermis. IFN-gamma-positive cells were found to be present in the epidermis. The pattern of IFN-gamma staining appeared to be a combination of intracellular staining in mononuclear lymphoid cells and extracellular deposition in the surrounding areas. The staining was considered to be highly specific because it could be completely blocked by preabsorption with recombinant IFN-gamma. Our data suggest that psoriatic epidermal T cells produce and secrete IFN-gamma within the lesion and that these T cells are involved in the pathogenesis of psoriasis.

Cutaneous and lingual papules as a sign of beta 2 microglobulin-derived amyloidosis in a long-term hemodialysis patient.

Although hemodialysis has permitted long-term survival of patients with renal failure, beta 2 microglobulin-derived amyloidosis is a serious complication occurring most commonly in long-term hemodialysis patients. Orthopedic manifestations are quite common, but cutaneous and lingual manifestations are relatively uncommon. We report a 56-year-old patient with lichenoid plaque type of skin eruptions and lingual papules caused by beta 2 microglobulin-derived amyloidosis. Immunohistochemical study showed that amyloid deposits were positive for anti-beta 2 microglobulin antibody, but negative for anti-advanced glycation end products antibody (anti-CML and CLE antibody). We discuss the histological and the clinical features of skin manifestations of beta 2 microglobulin-derived amyloidosis.

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.

A case of nodular cutaneous lupus mucinosis.

The patient was a 44-year-old female. She was diagnosed as having systemic lupus erythematosus at the age of 21 years and had been receiving systemic steroid treatment (5 mg prednisolone/day). Nodules began to appear on her neck, chest and back from June in 2000, and she was referred to our clinic for examination and treatment. Examination of a biopsy sample of an eruption on the neck revealed mucin deposition in the dermis. Based on the clinical and histopathological findings, she was diagnosed as having typical nodular cutaneous lupus mucinosis. The dose of steroid was increased, and the eruptions gradually disappeared.

Rapid effects of olopatadine hydrochloride on the histamine-induced skin responses.

Olopatadine hydrochloride is one of the second-generation nonsedating antihistamines that are used for treating allergic disorders such as urticaria, rhinitis, and atopic dermatitis. We examined the inhibitory effects of this drug on the flare and wheal responses induced by histamine iontophoresis at 30, 60, and 90 min after oral administration in a double-blind, cross-over, and placebo-controlled study. Olopatadine hydrochloride significantly inhibited the histamine-induced flare and wheal responses as early as 60 min after oral administration when compared with placebo. Significant inihibitory effects of olopatadine hydrochloride on the itch responses were seen at 90 min after administration. Thus, olopatadine hydrochloride exhibited a very rapid and potent antihistamine effect on the histamine-induced skin responses.

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).