Frequent c-Kit gene mutations not only in gastrointestinal stromal tumors but also in interstitial cells of Cajal in surrounding normal mucosa

Gastrointestinal stromal tumors (GISTs) are thought to originate from mesenchymal stem cells that differentiate toward the interstitial cells of Cajal (ICCs). The frequent occurrence of activating mutations involving exon 11 of c-Kit gene in sporadic GISTs indicates an important role in genesis of this tumor type. In the present study we examined c-Kit gene mutations in a series of GISTs and also in ICCs of surrounding normal tissues. Samples from 18 patients were monitored immunohistochemically for c-Kit expression and microdissected for sequencing analysis of exons 9, 11, 13, and 17 of the c-Kit gene. It was revealed to be mutated in exon 11 or adjacent introns in 9 out of the total of 18 (50.0%) GISTs. In 6 (33.3%) cases, mutations in ICCs were also detected in the same exon. With stomach GISTs, 8 of 16 (50.0%) cases harbored mutations and 4 had mutations in background ICCs (25.0%). In contrast counterpart ICCs in gastric cancer cases harbored no c-Kit gene mutations (0 out of 24=0%) (P<0.02). ICCs undergoing c-Kit mutation as a possible early initiation step in GIST tumorigenesis may thus have pre-neoplastic potential.     

A case of tuberculous aneurysm of subclavian artery occurred in the course of treatment for miliary tuberculosis

This case is a 56-year old woman. Steroids were being administered perorally after a thymectomy for myasthenia gravis. A fever of 38-39 degrees Celsius appeared during night, an abnormal shadow showed up on a chest X-ray and the patient was hospitalized. Gaffky No. 2 acid-fast bacilli were detected in the patient's sputum and the chest CT showed diffuse granular-like shadow, the patient was diagnosed as miliary tuberculosis and treatment with combined use of INH, RFP, EB, and PZA was started. Subsequently, fever started to subside and the miliary shadow on chest X-ray improved, however, six weeks after the start of treatment, hoarseness and dysphagia appeared. From the cervical CT and cervical angiography findings, the diagnosis of right subclavian artery impending ruptured aneurysm was made. Because the patient's sputum was acid-fast bacilli positive and because the patient had undergone thymectomy, it was decided that it would be difficult to treat her by a thoracotomy again. Therefore, a right subclavian artery stent insertion, right subclavian artery-right common carotid artery bypass creation operation was carried out with the objective of blocking the flow of blood to the aneurysm. The hoarseness and dysphagia improved post-operatively and the patient's progress is being monitored. Tuberculous aneurysms are a rare affection and they are mostly discovered when the autopsy is done, however, this case was diagnosed due to the manifestation of subjective symptoms. While this case was not diagnosed histopathologically, it is envisaged from the clinical progress that this was a tuberculous subclavian aneurysm complicated during the treatment for miliary tuberculosis.     

Perfectionism underlying psychological background correlated with the symptoms of functional dyspepsia

BACKGROUNDS: Early satiety, bloating, and postprandial distress are common symptoms in patients with functional dyspepsia (FD) and anorexia nervosa (AN). Perfectionism is known to be associated with AN, accompanied by abnormal eating behavior. We analyzed perfectionism in FD as compared with that in AN, and investigated the correlation of perfectionism with abdominal symptoms. METHODS: The study group comprised 168 patients with FD according to the Rome II criteria (65% females, mean age 47.7 years) and 101 with AN according to the DSM-IV criteria (100% females, mean age 23 years). As control, 130 healthy subjects (81% females, mean age 26.2 years) were studied. Frost's Multidimensional Perfectionism Scale (FMPS) was used to evaluate perfectionism. Abdominal symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale (GSRS). RESULTS: All subscale scores except for organization were significantly higher in patients with AN than in controls. The parental criticism (PC) score in patients with FD was also significantly higher than that in controls, but lower than that in patients with AN. PC was significantly correlated with the total GSRS, particularly indigestion scores of FD patients (P = 0.0476 and P = 0.0294). CONCLUSIONS: Perfectionism such as PC underlying the psychological background of FD patients may be correlated with their abdominal symptoms.     

Adoptive T-cell therapy for B-cell malignancies

The success of allogeneic hematopoietic cell transplantation (HCT) for B-cell malignancies is evidence that these tumors can be eliminated by T lymphocytes. This has encouraged the development of specific adoptive T-cell therapy, both for augmenting the anti-tumor effect of HCT and for patients not undergoing HCT. T cells that are capable of recognizing antigens expressed on malignant B cells may be recruited from the endogenous repertoire or engineered to express tumor-targeting receptors. Critical insights into the qualities of T cells that enable their persistence and function in vivo have been derived, and obstacles to effective T-cell-mediated tumor eradication are being elucidated. These advances provide the tools to translate adoptive T-cell transfer into reliable clinical therapies.     

Aortic arch calcification evaluated on chest X-ray is a strong independent predictor of cardiovascular events in chronic hemodialysis patients

Vascular calcification is associated with cardiovascular disease in hemodialysis (HD) patients. Some reports have previously shown that simple assessment of aortic calcification using plain radiography is associated with cardiovascular (CV) events; however, these studies simply assessed whether aortic calcification was present or absent only, without considering its extent. Here, we evaluated the validity of grading aortic arch calcification (AoAC) to predict new CV events. We retrospectively reviewed chest X-rays in 212 asymptomatic HD patients who underwent measurement of pulse wave velocity (PWV) in 2006 without a past history of CV events. The extent of AoAC was divided into four grades (0–3). Among these subjects, the follow-up of CV events in 197 patients was completed. At baseline, AoAC grade was positively associated with age, dialysis vintage, PWV and parathyroid hormone levels, and negatively correlated with body weight and body mass index. Arterial stiffness, as determined by PWV, was also correlated with increasing AoAC grade. Eighty-nine CV events in total occurred during a mean follow-up period of 69 ± 45 months. With multivariate adjustment, Kaplan–Meier analysis showed that the incidence was significantly higher in patients with higher AoAC grade (grades 2 and 3) than in those with grade 0 or 1 (p = 0.013, log-rank test). Multivariate Cox proportional hazards analyses showed the predictive values of AoAC grade were significant (hazard ratio 1.512; p = 0.0351). AoAC detectable on chest X-ray is a strong independent predictor of CV events in accordance with PWV. Risk stratification by assessment of AoAC may provide important information for management of atherosclerotic disease in HD patients.     

Association of serum bilirubin levels with development and progression of albuminuria,and decline in estimated glomerular filtration rate in patients with type 2 diabetes mellitus

Aims/Introduction

Recent observational studies suggest elevated levels of bilirubin, an endogenous anti‐oxidant, might protect against kidney disease. We carried out an observational cohort study to assess whether higher baseline levels of bilirubin, within normal range, could predict the rate of development and progression of diabetic nephropathy in patients with type 2 diabetes.

Materials and Methods

Japanese type 2 diabetic patients with normo‐ or microalbuminuria and normal serum bilirubin (<1.2 mg/dL) were recruited from a single center, and categorized according to baseline serum bilirubin levels. Two independent end‐points were specified: development or progression of diabetic nephropathy, based on transition to a more advanced stage of albuminuria (albuminuria cohort), and the rate of change in estimated glomerular filtration rate (eGFR cohort).

Results

Albuminuria and eGFR cohorts were constructed consisting of 1,915 patients and 1,898 patients, respectively, with 1,738 patients overlapping. Mean follow up was 4.4 and 5.4 years for the two cohorts, respectively. Within the albuminuria cohort, 132 (9%) of 1,418 patients with normoalbuminuria developed microalbuminuria, and 56 (11%) of 497 patients with microalbuminuria developed macroalbuminuria. Higher baseline bilirubin levels were associated with significantly lower risk of progression from microalbuminuria to macroalbuminuria in both the univariate and multivariate analyses. In normoalbuminuric patients, an inverse association was found when restricted to a subgroup with elevated hemoglobin A1c levels. There was no relationship between bilirubin levels and the rate of change in eGFR.

Conclusions

Higher serum bilirubin levels, within normal range, might be predictive of a lower risk of progression of nephropathy in type 2 diabetic patients.     

Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis

Tumor necrosis factor-α (TNF-α) has an essential role in the pathogenesis of rheumatoid arthritis (RA) and has been known to induce the production of several inflammatory molecules in vivo. To analyze in vivo the active mechanism of the TNF-α blocking agent, etanercept, the serum levels of the cytokine interleukin-15 (IL-15) and the chemokines growth-regulated protein-α (Gro-α), and interferon-γ inducible protein-10 (IP-10) in RA patients were measured. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months. The clinical and laboratory parameters were measured and serum levels of IL-15, Gro-α, and IP-10 were determined using enzyme-linked immunosorbent assay (ELISA) kits at the baseline and at 3 and 6 months after the initial treatment. Additionally, the production of IL-15 and IP-10 by cultured synovial cells stimulated with TNF-α from RA patients was determined by ELISA. A significant decrease in serum levels of IL-15 and IP-10 was observed at 3 and 6 months after initial treatment with etanercept, but not in those of Gro-α. TNF-α induced production of IP-10, but not IL-15 in cultured synovial cells from RA patients. This study demonstrated for the first time the reduction of IP-10 and IL-15 production in RA patients as active mechanisms of etanercept.     

Cardiac sarcoidosis mimicking right ventricular dysplasia.

A 59-year-old woman with skin sarcoidosis was admitted to hospital for assessment of complete atrioventricular block. Cross-sectional echocardiography showed that the apical free wall of the right ventricle was thin and dyskinetic with dilation of the right ventricle. Thallium-201 myocardial imaging revealed a normal distribution. Both gallium-67 and technetium-99m pyrophosphate scintigraphy revealed no abnormal uptake in the myocardium. Right ventriculography showed chamber dilation and dyskinesis of the apical free wall, whereas left ventriculography showed normokinesis, mimicking right ventricular dysplasia. Cardiac sarcoidosis was diagnosed on examination of an endomyocardial biopsy specimen from the right ventricle. A permanent pacemaker was implanted to manage the complete atrioventricular block. After steroid treatment, electrocardiography showed first-degree atrioventricular block and echocardiography revealed an improvement in the right ventricular chamber dilation. Reports of cardiac sarcoidosis mimicking right ventricular dysplasia are extremely rare and as this case shows, right ventricular involvement may be one of its manifestations.     

Cruciferous vegetables, mushrooms, and gastrointestinal cancer risks in a multicenter, hospital-based case-control study in Japan

We assessed the possible association of gastrointestinal cancers with cruciferous vegetables and mushrooms in a multicenter, hospital-based case-control study in an agricultural area of Japan. One hundred forty-nine cases and 287 controls for stomach cancer and 115 cases and 230 controls for colorectal cancer were matched by age, sex, and residential area. In stomach cancer, the protective effect of vegetables (consumption of total vegetable) was obscure, but it became clearer when we examined specific kinds of vegetables. Marginal associations were observed in the group of the highest consumption of Chinese cabbage (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.35-1.07), broccoli (OR = 0.60; 95% CI = 0.34-1.08), Hypsizigus marmoreus (Bunashimeji) (OR = 0.57; 95% CI = 0.31-1.04) and Pholita nameko (Nameko) (OR = 0.56; 95% CI = 0.30-1.06). In colorectal cancer, we observed decreased risks from the highest tertile of total vegetables (OR = 0.22; 95% CI = 0.08-0.66) and low-carotene-containing vegetables (OR = 0.28; 95% CI = 0.08-0.77), and inverse associations were observed in the group of the highest consumption of broccoli (OR = 0.18; 95% CI = 0.06-0.58). Although the sample size was limited, subgroup analyses showed that the associations differed with the histopathological subtype. These findings suggest that cruciferous vegetables decrease the risk of both stomach and colorectal cancer, and that mushrooms are associated with a decreased risk of stomach cancer.     

Direct detection of rifampicin resistant Mycobacterium tuberculosis in sputum by line probe assay (LiPA)

OBJECTIVES: To examine the direct detection of rifampicin (RFP)-resistant Mycobacterium tuberculosis in sputum by Line Probe Assay (LiPA). MATERIALS AND METHODS: We collected 130 sputa and analyzed both by LiPA and the Amplicor M.tuberculosis assay. For culture-positive samples, RFP resistance testing was performed and compared with the results by LiPA. RESULTS: Eighty two out of 84 M. tuberculosis samples were detected by LiPA and all of 10 Mycobacteria other than M. tuberculosis (MOTT) samples and 36 negative samples were negative by LiPA. The detection rate is same as Amplicor. For culture-positive samples, LiPA showed mutation pattern for all of 22 RFP-resistant strains and wild type pattern for 19 of 20 RFP-sensitive strains. The one remaining showed mixed pattern of wild type and mutation pattern. CONCLUSION: The use of LiPA for sputum coould enable early detection of RFP-resistant tuberculosis and seems to be useful for the control of tuberculosis.