Case report of multiple pustules of the bilateral lower limbs caused by a granulocyte colony-stimulating factor-producing solid pseudopapillary tumour of the pancreas.

Here we report a rare case of neutrophilic dermatoses related to a granulocyte colony-stimulating factor (G-CSF)-producing solid pseudopapillary tumour (SPT). The patient was a 39-year-old woman presenting with scattered pustules and crusts of the palms, heels and thighs and plaques of the bilateral lower legs. The skin biopsy revealed dense neutrophil infiltration in the epidermis to the dermis. A pancreatic head tumour was detected using computed tomography. A pathological examination of the resected specimen suggested an SPT. As the skin eruption promptly disappeared after SPT resection, we hypothesized that SPT secretes growth factors including epidermal growth factor (EGF) and G-CSF. The SPT cells stained positive for both EGF and G-CSF tumour cells. The serum levels of interleukin (IL)-6 and IL-10 and tumour necrosis factor-α were within normal limits before and after the SPT resection. In contrast, the serum IL-8, EGF and G-CSF levels decreased after the SPT resection. This is a rare case of neutrophilic dermatoses related to a G-CSF-producing SPT. The present case suggests that physicians should be aware that a G-CSF-producing tumour is a differential diagnosis to consider in patients with unusual aseptic pustulosis.

Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells.

BACKGROUND: Polymorphisms of the Plant homeodomain finger protein 11 (PHF11) are strongly associated with high serum IgE levels and clinical severity of atopic patients. However, the precise mechanism has not been fully elucidated. We investigated the role of Phf11 in class switch recombination (CSR) to IgE by activated B cells. METHODS: We generated Phf11 transgenic (Lckd-Phf11-Tg) mice that express the exogenous murine Phf11 in lymphocytes under the control of distal Lck promoter. We examined IL-4-induced CSR to IgE in activated Lckd-Phf11-Tg B cells in vitro. We analyzed production of ovalbumin (OVA)-specific IgE and nose-scratching symptoms in Lckd-Phf11-Tg mice using an OVA-induced allergic rhinitis model. RESULTS: The exogenous Phf11 promoted CSR to IgG1 and IgE in activated B cells with an increase in germ line transcript (GLT) γ1 and GLT ε expression. The exogenous Phf11 augmented transcriptional activity of the GLT γ1 and GLT ε promoters through permissive histone modifications and binding of NF-κB and STAT6. Furthermore, the exogenous Phf11 bound to the GLT ε promoter with increased binding of NF-κB. Silencing of the endogenous Phf11 reduced the frequency of CSR to IgE and GLT ε expression, but not to IgG1 or GLT γ1 expression, in activated B cells. In an allergic rhinitis model, Lckd-Phf11-Tg mice showed a significant increase in the production of OVA-specific IgE and the frequency of nose scratching. CONCLUSION: Phf11 accelerates CSR to IgE in activated B cells by increasing the transcriptional activity of GLT ε promoter and contributes to the exacerbation of allergic responses. These findings provide a novel therapeutic target for allergic diseases.

[Lymph node metastasis in superficial squamous carcinoma of the esophagus]. / Lymphknotenmetastasen bei Plattenepithelfrühkarzinomen des Ösophagus.

The definition of early carcinoma of the esophagus has changed with time on the basis of new data. As from 2007 an early carcinoma is defined as an intramucosal carcinoma with or without metastasis. In the subclassification based on invasion depth, m1 and m2 squamous cell carcinomas have no metastasis and are considered curable by endoscopic resection alone, whereas less than 10% of m3 carcinomas and some 20% of sm1 squamous cell carcinomas have lymph node metastasis. In this article the relationship between various histopathological findings and the incidence of lymph node metastasis is reviewed. The m3 and sm1 superficial squamous cell carcinomas showing 0-I and 0-III types, large tumors over 50 mm in size or those showing vessel permeation have higher incidences of lymph node metastasis. In the field of gastrointestinal surgical pathology pathologists are now expected to not only diagnose the presence or absence of malignancy but also to investigate in detail many of the histological factors related to the prevalence of lymph node metastasis.

Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget's disease.

BACKGROUND: Paget's disease is an intraepidermal adenocarcinoma that is difficult to diagnose clinically as it mimics inflammatory or infectious diseases. As a consequence, it may be clinically misdiagnosed resulting in a delay in appropriate management. Reflectance confocal microscopy allows the visualization of the upper layers of the skin and mucosa at cellular resolution. Paget's disease is characterized histologically by the presence of neoplastic cells scattered throughout all layers of the epidermis in a pattern similar to that also observed in melanoma (and termed Pagetoid spread). OBJECTIVE: In vivo confocal microscopy is an excellent diagnostic tool for detecting Pagetoid spread and for diagnosing melanoma. We therefore hypothesized that it may also assist in the diagnosis of Paget's disease. METHODS: In this study, we describe the confocal features of nine cases of extramammary Paget's disease and one case of mammary one. RESULTS: Large atypical Pagetoid cells were present singly and in clusters in all 10 cases and were readily visualized on ex vivo and in vivo confocal microscopy. The presence of Pagetoid spread and other confocal features, in the appropriate clinical context, is suggestive Paget's disease and should allow distinction from other inflammatory diseases that may appear similar clinically. CONCLUSION: The use of confocal microscopy is likely to facilitate earlier diagnosis of Paget's disease and the instigation of appropriate management with concomitant improvement in clinical outcomes.

Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation.

BACKGROUND: There is synteny in the CC-type chemokine gene clusters between humans (CCL2/MCP-1, CCL7MCP-3, CCL11/eotaxin, CCL8/MCP-2, CCL13/MCP-4, and CCL1/I-309) and mice (CCL2, CCL7, CCL11, CCL12/MCP-5, CCL8, and CCL1). OBJECTIVE: As many putative Bcl6/STAT-binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium. METHODS: We generated transgenic (Tg) mice carrying the Bcl6 or the dominant-negative (DN)-Bcl6 gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. For in vitro studies, A549, alveolar type II-like epithelial cell line transfected with the SPC-DN-Bcl6 gene were stimulated with IL-4+TNF-α, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT-PCR. RESULTS: The amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL-4 and TNF-α, whereas STAT6 binding increased in association with regional histone H3-K9/14 acetylation and H3-K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with the DN-Bcl6 gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs. CONCLUSION AND CLINICAL RELEVANCE: Expression of the pulmonary epithelium-derived CC-type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.

Over-expression of the LTC4 synthase gene in mice reproduces human aspirin-induced asthma.

BACKGROUND: The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated. OBJECTIVE: The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA. METHODS: To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed. RESULTS: The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine. CONCLUSION AND CLINICAL RELEVANCE: The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.

Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa. PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method. RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively. CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.

Early squamous cell carcinoma of the oesophagus: the Japanese viewpoint.

In Japan, more than 90% of oesophageal malignancies are squamous cell carcinomas, and superficial and early carcinomas now account for about 40% and 20%, respectively, of all oesophageal carcinomas. Definition of early carcinoma has changed on the basis of new data. As of 2007, early carcinoma is defined as intramucosal carcinoma with or without metastasis. In the subclassification based on depth of cancer invasion, m1 and m2 carcinomas have no metastasis and are considered curable by endoscopic mucosal resection alone, whereas < 10% of m3 carcinomas and about 20% of sm1 carcinomas have lymph node metastasis. The relationship between various pathological findings and the incidence of lymph node metastasis has been reviewed. High-grade squamous dysplasia (squamous cell carcinoma in situ in Japan) requires surgical or endoscopic removal. Very minute carcinomas have recently been detected by magnifying endoscopy and/or narrowband imaging. Endocytoscopy could replace biopsy histopathological examination for diagnosis of oesophageal squamous cell carcinoma, and endocytoscopic diagnosis and endoscopic therapy may be performed simultaneously. As a result of advances in the development of endoscopes, pathologists are now expected to diagnose very minute lesions, < 1 mm in size, in the oesophagus.

Reticulocyte hemoglobin content as a marker of iron status in patients receiving maintenance hemodialysis.

Background. Patients with renal anemia who show a poor response to erythropoietin might have iron insufficiency. Reticulocyte hemoglobin content (CHr) was measured in hemodialysis patients, and its potential as a marker for iron status was assessed by comparing CHr with ordinary markers. Methods. Ninety-one patients receiving maintenance hemodialysis were enrolled. Venous sampling was performed twice, at a 3-month interval. During the interval, none of the patients received any iron agent and there was no alteration in their erythropoietin doses. CHr was measured with an automated blood cell counter. Simultaneously, ordinary markers for iron status, such as hematocrit (Ht), mean hemoglobin content (CH), serum iron (Fe), ferritin (Fr), and transferrin saturation (TSAT), were measured. CHr was compared with these markers. Results. CHr randed from 24.1 to 34.7 pg, with a mean of 31.0 pg. CHr correlated with CH (P < 0.001), Fr (P < 0.01), Fe (P < 0.001), and TSAT (P < 0.001), but not with Ht. When patients were divided into two groups according to the CHr : CH ratio (CHr : CH ≧ 1 and CHr : CH < 1), there was no difference in any parameter between the two groups in the first measurement. In the second measurement, done after a 3-month interval, patients with CHr : CH ≧ 1 showed significantly higher values for CHr (P < 0.001), CH (P < 0.01), Fe (P < 0.05), and TSAT (P < 0.05) than patients with CHr : CH < 1. Conclusions. It was suggested that the CHr : CH ratio would predict changes in the state of iron supply. CHr might be a potential marker for monitoring renal anemia.

A549 cells can express interleukin-16 and stimulate eosinophil chemotaxis.

Alveolar epithelial cells produce many types of chemokines such as regulated on activation, normal T cells expressed and secreted (RANTES), eotaxin induced by interleukin (IL)-1 beta, or tumor necrosis factor (TNF)-alpha and may contribute to allergic disease by recruiting eosinophils. However, identification of the eosinophil chemotacic activity (ECA) release from A549 cells, an alveolar type II cell line, has not yet been completed. Recently, IL-16 was also reported to be a potent chemotactic stimulus for CD4(+) T lymphocytes and eosinophils in asthma and other pulmonary diseases. To test the possibility that alveolar epithelial cells produce IL-16, we analyzed RNA and culture supernatant from A549 cells by reverse transcription/ polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The release of ECA from A549 cells was assessed using a blind-well chemotactic chamber. IL-16 release was increased in a concentration-dependent manner by stimulation with IL-1 beta or TNF-alpha. A549 cells also expressed IL-16 messenger RNA. The combination of IL-4 and IL-1 beta or TNF-alpha had an additive effect on IL-16 production. The release of ECA was induced by IL-1 beta or TNF-alpha in a dose-dependent manner. The combination of these cytokines had a greater effect than one alone. The blockade of eotaxin and IL-16 caused 70% inhibition of ECA, but anti-RANTES antibodies only caused 30% inhibition and anti-IL-8 antibodies failed to affect inhibition. These findings suggest a role for chemokines released by alveolar epithelial cells in the recruitment of eosinophils into the lung in pulmonary disorders such as asthma and interstitial lung diseases, and suggested that eotaxin and IL-16 are potent and effective eosinophil chemoattractants.

Binding of BAZF and Bc16 to STAT6-binding DNA sequences.

BAZF, a family member of Bcl6, can function as a sequence-specific transcriptional repressor. We determined BAZF-binding DNA sequence. The consensus binding sequence (CBS) of BAZF is almost the same as those of Bcl6 previously described. Three nucleotides of T, G and A at position 6, 8, and 9 in the CBS (5'-ATTCCTAGAAAG-3') are important nucleotides for binding of both BAZF and Bcl6. Since a part (5'-TTC-CTA-GAA-3') of the CBS resembled the sequence motif (5'-TTC-(N3-4)-GAA-3') bound by STAT factors, BAZF and Bcl6 can bind to the CD23b-STAT6-binding sequence (5'-TTTC-TTA-GAAAT-3'), the immunoglobulin germline epsilon-STAT6-binding sequence (5'-CTTC-CCAA-GAAC-3'), and the IL4-STAT6-binding sequence (5'-TTTC-CCA-GAAAA-3') with weak affinity. However, a mutation of C nucleotide to T nucleotide in the IL4-STAT6-binding sequence (5'-TTTC-CTA-GAAAA-3') strongly increased the binding activity of BAZF and Bcl6. These results suggest that BAZF and Bcl6 can repress some of STAT-induced transcription by binding to DNA sequences recognized by STAT factors.

Recurrence of myocarditis presenting as pacing and sensing failure after implantation of a permanent pacemaker at first onset.

A 31-year-old woman was admitted to hospital with loss of consciousness and generalized convulsions. Electrocardiography (ECG) showed complete atrioventricular block (AV block) with a pulse rate of 30 beats/min. Endomyocardial biopsy from the right ventricle showed massive necrosis and degeneration of myocardial cells with extensive infiltration of lymphocytes into the interstitial space. These pathological findings suggested fulminant myocarditis. Following glucocorticoid therapy, the patient became asymptomatic, but the AV block did not resolve completely and a bifocal pacemaker was implanted. However, similar symptoms recurred 7 years later. An ECG showed pacing and sensing failure linked to an increase in the pacing threshold and a decrease in the sensing threshold. Endomyocardial biopsy from the right ventricle again showed interstitial infiltration with lymphocytes and eosinophils. After glucocorticoid therapy, she became asymptomatic once more, and the improvement in the pacing and sensing failure, and cardiomegaly, was satisfactory. This patient represents a very rare case of recurrence of acute myocarditis without progression, as much as 7 years after its first occurrence. Glucocorticoid therapy was still effective in treating the recurrent myocarditis presenting with pacing and sensing failure.

Interleukin (IL)-4/IL-9 and exogenous IL-16 induce IL-16 production by BEAS-2B cells, a bronchial epithelial cell line.

Previous studies have suggested that bronchial epithelial cells may perpetuate airway inflammation. We have reported that the bronchial epithelial cell line BEAS-2B can produce interleukin (IL)-16, a potent chemoattractant for CD4+ T cells. IL-16 is thought to regulate airway inflammation in asthmatics. Recent studies showed that IL-4 induces inflammatory cytokines in bronchial epithelial cells and that IL-9 is a candidate gene for development of asthma. The present study demonstrated that BEAS-2B cells produced specifically IL-16 by synergistic effects of IL-4 + IL-16, or IL-9 + IL-16, and that the synthesized IL-16 induced migration of CD4+ T cells. This study is a first report indicating that IL-16 production may be maintained by an autocrine machinery by epithelial cell-derived IL-16 with IL-4 and IL-9 in asthma.

Clinical benefits of steroid therapy on surgical stress in patients with esophageal cancer.

BACKGROUND: Despite improvements in surgical techniques and perioperative care, severe complications lead to long hospital stays for some esophageal cancer patients. The purpose of this study was to evaluate the safety and effectiveness of perioperative steroid therapy on the postoperative clinical course. METHODS: Fifty-seven patients operated for esophageal cancer in 1997 and 1998 were treated with perioperative steroid therapy. Fifty consecutive patients operated in 1995 and 1996 served as a control group. In the steroid group, each patient was given 250 mg of methylprednisolone intravenously before operation followed by 125 mg on postoperative days 1 and 2. Serum interleukin-6, polymorphonuclear cell elastase, and C-reactive protein levels, and the postoperative clinical course were compared between the groups. RESULTS: Morbidity rates including hyperbilirubinemia, anastomotic leakage, and liver dysfunction were significantly lower in the steroid group than in the control group. Days until extubation and hospital stay were significantly shorter for the steroid group. Inflammatory mediators, body temperature, heart rate, and respiratory index after the surgical procedure were significantly lower in the steroid group. Adverse effects possibly caused by steroid therapy were not observed. CONCLUSIONS: Perioperative steroid therapy was safe and effective for the inhibition of inflammatory mediators and the improvement of the postoperative clinical course of patients with esophageal cancer.