Association of CD4-positive cell infiltration with response to vedolizumab in patients with ulcerative colitis.

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4ß7) integrin, suppresses immune cell migration by blocking the interaction between α4ß7 integrin and mucosal addressin cell adhesion molecule 1. Reports about histological features that predict vedolizumab efficacy are scarce. So, we examined the association between histological features and vedolizumab efficacy. This was a multicenter, retrospective study of patients with UC treated with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified. We enrolled 42 patients. Patients with a high CD4+ infiltration showed a better response to vedolizumab [odds ratio (OR) = 1.44, P = 0.014]. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR = 0.11, P = 0.008 and OR = 0.50, P = 0.009, respectively). Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

Primary Presacral Neuroendocrine Tumor Presenting as Multiple Liver Metastasis: A Case Report.

BACKGROUND Various neoplasms, including neuroendocrine neoplasms (NENs), can arise from the presacral space. Most presacral lesions are detected due to symptoms arising from tumor growth. However, diagnosing small, asymptomatic presacral tumors is challenging because of their unique location. CASE REPORT A 63-year-old woman with chronic hepatitis C underwent follow-up after achieving a sustained virological response. Abdominal ultrasonography revealed multiple new hyperechoic masses in the liver. Physical and laboratory examinations, including tumor marker analysis, yielded unremarkable results. Computed tomography (CT) and magnetic resonance imaging (MRI) indicated metastatic liver tumors but failed to identify the primary site of these lesions. The hepatic mass was biopsied, leading to a diagnosis of grade 2 neuroendocrine tumor. 111In-pentetreotide somatostatin receptor scintigraphy revealed significant radiotracer accumulation in multiple hepatic masses, several bones, and a small presacral space lesion. Pathological examination of the presacral lesion confirmed a grade 2 neuroendocrine tumor, similar to the hepatic mass. Review of a CT scan performed 4 years earlier indicated a small cyst-like lesion in the presacral space suspected of being a developmental cyst; however, the presence of cystic components was not confirmed pathologically. The patient was diagnosed with a primary presacral neuroendocrine tumor, which might have originated from a developmental cyst, with multiple liver metastases. Chemotherapy with everolimus was initiated, and the clinical course has been uneventful. CONCLUSIONS We report a rare neuroendocrine tumor arising from the presacral space with multiple liver metastases. The presacral space should be examined when a NEN with an unknown primary site is found.

Adenocarcinoma Arising From a Gastric Duplication Cyst With Lymph Node Metastasis.

Gastric duplication cysts (GDCs) are a relatively rare congenital anomalies and are mostly diagnosed in the early years of life. Herein, we report a very rare surgical case of adenocarcinoma arising from a GDC with lymph node metastasis. A 78-year-old woman was referred to our hospital because of elevated serum levels of cancer antigen (CA) 19-9. Endoscopic ultrasound, contrast fistulography, and computed tomography showed a cystic lesion communicating with the lesser curvature of the stomach. The serum levels of CA 19-9 were high, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging demonstrated a slightly enlarged lymph node with high FDG uptake after four months. The size of the cyst was unchanged. It was diagnosed as a GDC. The enlarged lymph node was highly likely to be malignant. Hence, we performed a distal gastrectomy involving the origin of entry and whole body of the GDC with en bloc regional lymphadenectomy. The postoperative pathology was consistent with GDC with moderately differentiated adenocarcinoma and lymph node metastasis. Adjuvant chemotherapy with tegafur-gimeracil-oteracil potassium (S-1) was administered for 12 months. At present, the patient is alive, with no recurrence of the lesion even four years after the operation. GDCs in adults are rare and may predispose to malignancy. Early diagnosis and prompt surgical intervention are important for favorable outcomes.

Eosinophil transendothelial migration induced by the bronchoalveolar lavage fluid of acute eosinophilic pneumonia.

BACKGROUND AND OBJECTIVE: Acute eosinophilic pneumonia (AEP) is characterized by a massive pulmonary infiltration of eosinophils. Mechanisms regulating the selective accumulation of eosinophils in AEP have not been fully established. The objective of this study was to evaluate the mechanisms of eosinophil accumulation in alveolar spaces through examination of bronchoalveolar lavage fluid (BALF) from AEP patients (AEP-BALF). METHODS: Eosinophils were isolated from the blood of healthy subjects and were placed on a human pulmonary microvascular endothelial cell monolayer cultured on Transwell filters (Coster, Cambridge, MA, USA). A saline control solution or BALF from patients with AEP, sarcoidosis or hypersensitivity pneumonitis was applied to the lower compartment, and the transendothelial migration of the eosinophils was evaluated. The concentrations of cytokines and chemokines in BALF were also measured. RESULTS: Transmigration of eosinophils across endothelial cells was only induced by the AEP-BALF. This transmigration was blocked by anti-ß2 integrin mAb. The concentrations of eotaxin-2 and monocyte chemotactic protein (MCP)-4, which are CC chemokine receptor (CCR) 3 ligands, were elevated in the AEP-BALF, and anti-CCR3 mAb or anti-MCP-4 mAb inhibited the AEP-BALF-induced transmigration of eosinophils. Furthermore, the concentration of leukotriene (LT) B4 was increased in the AEP-BALF, and an LTB4 receptor antagonist partially suppressed the AEP-BALF-induced transmigration of eosinophils. CONCLUSION: These findings suggest that CCR3 ligands including eotaxin-2 and MCP-4, and LTB4 play a role in the accumulation of eosinophils in AEP.

Nonspecific elevation of serum Aspergillus galactomannan antigen levels in patients with rheumatoid arthritis.

BACKGROUND: Infections are an important cause of morbidity and mortality in patients with rheumatoid arthritis. Patients receiving immunosuppressive or anti-tumor necrosis factor (TNF) agents are vulnerable to fungal infections, including those derived from Aspergillus species. Detection of the Aspergillus galactomannan antigen in serum is useful for the early diagnosis of invasive aspergillosis in patients with hematological malignancies. However, its usefulness for detecting early invasive aspergillosis in rheumatoid arthritis patients remains unestablished. METHODS: Galactomannan antigen levels were measured in 340 patients (311 female patients). For patients who exhibited galactomannan antigen levels ≥0.5 during the initial examination, a second examination was performed 3-6 months later. Conventional blood tests and chest radiography were also performed. RESULTS: Elevated galactomannan antigen levels (≥0.5) were observed in 62 (18.2%) of 340 patients during the initial examination. A second examination was performed in 56 of 62 patients, 50 of whom exhibited elevated antigen levels. Elevated antigen levels were not associated with the use of any drug including anti-TNF agents. Serum galactomannan antigen levels were correlated with the albumin/globulin ratio (r=-0.19, p<0.001), γ-globulin (%; r=0.17, p=0.001), and hemoglobin concentration (r=-0.15, p=0.005). No patient was clinically diagnosed with invasive aspergillosis during the study period. CONCLUSIONS: Serum galactomannan antigen levels are frequently elevated in a nonspecific manner in patients with rheumatoid arthritis.

Relationships among smoking habits, airflow limitations, and metabolic abnormalities in school workers.

BACKGROUND: Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality. OBJECTIVE: We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities. METHODS: Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥ 30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history. RESULTS: Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012-1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010-1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975-0.994; p = 0.007). CONCLUSIONS: Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities.

Diagnostic and prognostic value of procalcitonin in community-acquired pneumonia.

INTRODUCTION: The value of measuring procalcitonin (PCT) in patients with community-acquired pneumonia (CAP) is unclear. The aim of this study was to determine the value of PCT as a marker for microbial etiology and a predictor of outcome in CAP patients. METHODS: A single-center observational study was conducted with CAP patients. On admission, their leukocyte count, serum C-reactive protein level, and serum PCT level were determined, and microbiological tests were performed. Patients were classified into 4 groups according to the A-DROP scoring system, which assesses the severity of CAP. RESULTS: A total of 102 patients were enrolled. The pathogen was identified in 60 patients, and 31 patients had streptococcal pneumonia. The PCT levels were significantly higher in those patients with pneumococcal pneumonia than in those patients with other bacterial pneumonias (P < 0.0001). Multivariate regression analysis revealed that high PCT levels were associated with a pneumococcal etiology [odds ratio, 1.68; 95% confidence interval (CI): 1.02-2.81; P = 0.04] after adjustment for disease severity and demographic factors. The PCT levels were correlated with the A-DROP score (r = 0.49; P < 0.0001). The area under the curve for predicting mortality was highest for the A-DROP score (0.97; 95% CI: 0.92-0.99), followed by the area under the curve for PCT (0.82; 95% CI: 0.74-0.89) and C-reactive protein (0.77; 95% CI: 0.67-0.84). CONCLUSIONS: High PCT levels indicate that pneumococcal pneumonia and PCT levels depend on the severity of pneumonia. PCT measurements may provide important diagnostic and prognostic information for patients with CAP.

[Kartagener syndrome with lung cancer and mediastinal tumor].

A 71-year-old man was admitted to Kanto Central Hospital with hemoptysis. He had had chronic sinusitis and deafness since childhood. Situs inversus, bronchiectasia, and diffuse panbronchiolitis had been also diagnosed at the age of 59. Chest computed tomography demonstrated a 5-cm mass in the anterior mediastinum as well as a 4-cm mass in the upper lobe of the right lung. A transbronchial lung biopsy of the right lung tumor revealed squamous cell carcinoma. Electron microscopic examination of the bronchial epithelial cilia revealed a total defect of both inner and outer dynein arms, leading to a diagnosis of primary ciliary dyskinesia. Biopsy of the mediastinal tumor was not performed. After concurrent chemoradiation therapy, the lung cancer decreased in size partial remission (PR) and the mediastinal tumor disappeared complete remission (CR). Later, a cavity formed in the tumor, where a Pseudomonas aeruginosa infection occurred. He died 1 year after the diagnosis of lung cancer was established. There have been 5 reported cases of Kartagener syndrome complicated with lung cancer, but to the best of our knowledge there have been no reports of Kartagener syndrome with mediastinal tumor.

[Case of sarcoidosis with myelodysplastic syndrome in an elderly woman].

An 85-year-old woman, who had been given a diagnosis of myelodysplastic syndrome with refractory anemia 2 years previously and required blood transfusion once a month, was admitted with complaints of fever, general fatigue, and dry cough. A chest X-ray film showed multiple small nodules in bilateral lung fields which were not observed 1 month previously. Although smear and culture tests for acid-fast bacilli in her bronchoalveolar lavage fluid, urine, and bone marrow aspiration fluid were all negative, miliary tuberculosis was strongly suspected. Antituberculosis drugs were administered, but neither her symptoms nor chest X-ray findings improved. Five months later, right oculomotor nerve palsy, followed by left abducens nerve paralysis occurred. Lumber puncture examination revealed lymphocytosis, and increased protein and ACE levels, suggesting neurosarcoidosis. A transbronchial lung biopsy specimen demonstrated non-caseating epithelioid granulomas. Oral administration of 30 mg/day prednisolone improved her symptoms as well as the chest X-ray findings.

Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization.

BACKGROUND: Recent studies suggested that administration of corticosteroids may improve clinical outcomes in patients with severe pneumonia. OBJECTIVES: The aim of this study was to assess the effectiveness of corticosteroids as an adjunctive therapy in community-acquired pneumonia (CAP) requiring hospitalization. DESIGN AND SETTING: An open label, prospective, randomized control study was conducted from September 2003 to February 2004 in a community general hospital in Japan. PATIENTS: Thirty-one adult CAP patients who required hospitalization were enrolled. MEASUREMENTS AND RESULTS: Fifteen patients received 40 mg of prednisolone intravenously for 3 days (steroid group). Sixteen patients did not receive prednisolone (control group). Both groups were also evaluated for their adrenal function. The primary endpoint was length of hospital stay. Secondary endpoints were duration of intravenous (IV) antibiotics and time required to stabilize vital signs. Both groups demonstrated similar baseline characteristics and length of hospital stay, and yet a shorter duration of IV antibiotics was observed in the steroid group (p < 0.05). In addition, vital signs were stabilized earlier in the steroid group (p < 0.05). These differences were more prominent in the moderate-severe subgroup but not as significant in the mild-moderate subgroup. The prevalence of relative adrenal insufficiency (RAI) in both groups was high (43%), yet there was no difference in baseline characteristics between patients, with or without RAI. In multiple regression models, RAI seemed to have no influence on clinical courses. CONCLUSIONS: In moderate-severe CAP, administration of corticosteroids promotes resolution of clinical symptoms and reduces the duration of intravenous antibiotic therapy.

[A case of steroid-resistant acute hypersensitivity pneumonitis successfully treated with an immunosuppressive drug].

A 28-year-old man complaining of cough and fever was hospitalized because of bilateral diffuse granular lung shadows. Hypersensitivity pneumonitis was diagnosed based on bronchoalveolar lavage fluid (BALF) and transbronchial lung biopsy (TBLB). Since antigen avoidance alone was not effective, steroid pulse therapy was started, and his symptoms and chest X-ray findings improved. After discharge, he moved to another residence. A few weeks later, fever and dyspnea recurred, then he was hospitalized on the suspicion of acute exacerbation of hypersensitivity pneumonitis. Steroid therapy resulted in no improvement on this occasion. Lung biopsy under video-assisted thoracoscopy was performed, and acute hypersensitivity pneumonitis was diagnosed pathologically. Although steroid therapy was continued, hypoxia still remained and a KL-6 level markedly increased. Combined therapy with steroid and cyclosporin A was started, and his symptoms, physical findings, laboratory data, and chest X-ray findings gradually improved. There has been no report in which cyclosporin A was used for acute hypersensitivity pneumonitis but this case indicates that cyclosporin A is efficacious for its treatment.

Eosinophil trans-basement membrane migration induced by interleukin-8 and neutrophils.

Neutrophilic inflammation observed with severe asthma is often associated with interleukin-8 (IL-8). Neutrophils can secrete a variety of mediators that may augment the migration of eosinophils. We have reported a positive correlation between the concentrations of neutrophils and eosinophils in sputum from subjects with severe asthma, suggesting a possible role of neutrophils in regulating eosinophilic inflammation. The aim of this study was to investigate whether neutrophils stimulated with IL-8 modify the trans-basement membrane migration (TBM) of eosinophils. Eosinophils and neutrophils were isolated from peripheral blood drawn from healthy donors or subjects with mild asthma. The TBM of eosinophils in response to IL-8 was evaluated in the presence or absence of neutrophils using the chambers with a Matrigel-coated transwell insert. Neither IL-8 alone nor the presence of neutrophils alone induced the TBM of eosinophils. However, when eosinophils were coincubated with neutrophils and stimulated with IL-8, the TBM of eosinophils was significantly augmented. This augmented TBM of eosinophils was inhibited by a matrix metalloproteinase-9 inhibitor, a leukotriene B4 receptor antagonist, platelet-activating factor antagonists, or an anti-TNF-alpha monoclonal antibodies. These results suggest that neutrophils migrated in response to IL-8 may lead eosinophils to accumulate in the airways of asthma and possibly aggravate this disease.

CC chemokines and transmigration of eosinophils in the presence of vascular cell adhesion molecule 1.

BACKGROUND: Interaction between eosinophil alpha4 integrin and vascular cell adhesion molecule 1 (VCAM-1) expressed on activated endothelial cells may be a key step in the selective recruitment of eosinophils from the circulation to sites of inflammation. OBJECTIVE: To investigate the factor(s) that induces transmigration of eosinophils after firm adhesion via the alpha4 integrin/VCAM-1 pathway. METHODS: We examined the effects of a variety of inflammatory mediators on the migration of eosinophils across recombinant human (rh) intracellular adhesion molecule 1- or rhVCAM-1-coated Transwell filters or VCAM-1-expressing human pulmonary microvascular endothelial cells (HPMECs) that had been stimulated with interleukin 4 (IL-4) and tumor necrosis factor alpha. The number of eosinophils that had transmigrated was evaluated by measuring eosinophil peroxidase activity. RESULTS: The CC chemokines RANTES (regulated on activation, normal T-cell expressed, and secreted), eotaxin, eotaxin 2, monocyte chemotactic protein 3 (MCP-3), and MCP-4 each increased eosinophil transmigration across rhVCAM-1-coated filters compared with fetal calf serum-blocked or rh intracellular adhesion molecule 1-coated filters (P < .01). On the other hand, platelet-activating factor, C5a, formyl-methionyl-leucil-phenylalanine, granulocyte-macrophage colony-stimulating factor, IL-5, and IL-8 did not enhance migration across rhVCAM-1. The enhancement of migration by RANTES in the presence of rhVCAM-1 was blocked by an anti-alpha4 integrin monoclonal antibody. CC chemokines augmented eosinophil transmigration across VCAM-1-expressing HPMECs compared with resting HPMECs (P < .01). Conversely, the transmigration induced by platelet-activating factor, C5a, formyl-methionyl-leucil-phenylalanine, or IL-8 was not modified by the expression of VCAM-1 on HPMECs. CONCLUSIONS: CC chemokines induce transendothelial migration of eosinophils after interaction between eosinophil alpha4 integrin and endothelial VCAM-1.

Identification of an enhancer that controls up-regulation of fibronectin during differentiation of embryonic stem cells into extraembryonic endoderm.

The extraembryonic endoderm is derived from inner cell mass cells of the blastocyst during early mouse embryogenesis. Formation of the extraembryonic endoderm, which later contributes to the yolk sac, appears to be a prerequisite for subsequent differentiation of the inner cell mass. While embryonic stem cells can be induced to differentiate into extraembryonic endoderm cells in vitro, the molecular mechanisms underlying this process are poorly understood. We used a promoter trap approach to search for genes that are expressed in embryonic stem cells and are highly up-regulated during differentiation to the extraembryonic endoderm fate. We showed that fibronectin fits this expression profile. Moreover we identified an enhancer in the 12th intron of the fibronectin locus that recapitulated the endogenous pattern of fibronectin expression. This enhancer carries Sox protein-binding sequences, and our analysis demonstrated that Sox7 and Sox17, which are highly expressed in the extraembryonic endoderm, were involved in enhancer activity.

Leukotriene D4 and eosinophil transendothelial migration, superoxide generation, and degranulation via beta2 integrin.

BACKGROUND: Evidence indicates that cysteinyl leukotriene (cysLT) 1 receptor antagonists possess anti-inflammatory properties in asthmatic patients in vivo. Although the exact mechanisms of these actions remain unknown, cysLTs regulate the locomotion and functions of eosinophils. We previously reported that leukotriene D4 augments the expression of eosinophil beta2 integrin and the adhesion of eosinophils to rh intercellular adhesion molecule 1 via beta2 integrin. OBJECTIVE: To examine whether leukotriene D4 modifies the transendothelial migration (TEM) and effector functions of eosinophils. METHODS: We evaluated the effects of leukotriene D4 on (1) eosinophil TEM across human umbilical vein endothelial cells, (2) superoxide anion (O2-) generation, and (3) eosinophil-derived neurotoxin release in eosinophils isolated from the blood of healthy individuals. RESULTS: Leukotriene D4 (0.1-1 microM) significantly induced eosinophil TEM, O2- generation, and eosinophil-derived neurotoxin release. Pranlukast, a cysLT1 receptor antagonist, significantly inhibited all of these parameters, although the inhibitory effect on O2- generation was partial. All of these responses were significantly inhibited by anti-beta2 integrin but not by anti-alpha4 integrin antibodies. CONCLUSIONS: Leukotriene D4 directly up-regulates the TEM and effector functions of eosinophils mainly via the cysLT1 receptor and beta2 integrin. These effects of leukotriene D4 probably contribute to the manifestation of eosinophil inflammation in asthmatic airways.

[Treatment of pulmonary amyloidosis with dimethyl sulfoxide--a case report].

Metastatic lung tumor was suspected in a 52-year-old woman who showed multiple nodules on her chest radiographs. Conventional examinations did not define the diagnosis, and so a biopsy was performed using video-assisted thoracoscopic surgery. Pathological examination demonstrated deposits of amorphous materials which were stained red by Congo red staining, even after potassium permanganate treatment. Green birefringence was also observed in the deposits under a polarized light microscope. A diagnosis of localized pulmonary amyloidosis with AL type amyloid protein was made, and therapy with dimethyl sulfoxide (10 ml/day) was started. During the two-year therapy, little exacerbation on pulmonary nodules was observed. It was suggested that dimethyl sulfoxide inhibited the progression of the disease.

Immunotherapy attenuates eosinophil transendothelial migration induced by the supernatants of antigen-stimulated mononuclear cells from atopic asthmatics.

BACKGROUND: Eosinophil transendothelilal migration across vascular endothelial cells is an initial step of eosinophil accumulation in allergic inflammation. There is increasing evidence that specific immunotherapy (SIT) modulates the production of inflammatory molecules from mononuclear cells. OBJECTIVE: The present study was undertaken to examine whether SIT modifies eosinophil transendothelial migration induced by the supernatants of antigen-stimulated mononuclear cells from atopic asthmatics. METHODS: Dermatophagoides farinae (Df)-sensitive mild persistent asthmatics were divided into a SIT-treated group and a control group. Peripheral blood mononuclear cells (PBMC) were isolated before and after SIT using the rush protocol, and cultured for 96 h at 37 degrees C in the presence or absence of Df antigen. Eosinophils were isolated from the blood of healthy subjects, and put on transwell filters coated with pulmonary microvascular endothelial cell monolayers stimulated with IL-4 plus TNF-alpha. The supernatants of PBMC were applied to the lower compartment and the transmigration of eosinophils was examined. RESULTS: Df stimulation of PBMC resulted in an augmentation of eosinophil transendothelial migration. This enhancement was abrogated following SIT. In the control group, the antigen-induced effect on eosinophil transmigration did not show an interval change. CONCLUSION: SIT attenuates eosinophil transendothelial migration induced by antigen-stimulated mononuclear cells.