Increasing Heme Oxygenase-1-Expressing Macrophages Indicates a Tendency of Poor Prognosis in Advanced Colorectal Cancer.

BACKGROUND: Many cancers express heme oxygenase-1 -(HO-1) at a higher frequency than healthy tissues, and this elevated expression is associated with cancer prognosis. Here, we aim to clarify the correlation between HO-1-expressing macrophage numbers and clinicopathological parameters of advanced colorectal cancer. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded tissues of patients with advanced colorectal cancer were used. To detect HO-1 expression in macrophages, immunohistochemistry was performed. The number of positive cells was measured. Furthermore, HO-1 mRNA in colorectal cancer was examined by reverse transcription polymerase chain reaction. RESULTS: Among the HO-1-negative and HO-1-positive groups, 58.02 and 85.00% of cases, respectively, were positive for lymph node metastasis. The disease-free survival (DFS) time was significantly shorter (p < 0.05) in the -HO-1-positive group (2.44 years) than in the HO-1-negative group (4.09 years). However, according to the Cox proportional-hazards regression model, the HO-1-positive group could not be a risk factor of poor prognosis. HO-1 mRNA expression was confirmed in colorectal normal and cancer tissues. CONCLUSION: In this study, the correlation between HO-1-expressing macrophages and clinicopathological parameters in the tumor microenvironment of colorectal cancer was studied for the first time, and the expression was associated with lymph node metastasis and shortening of DFS.

Differential expression of estrogen receptor-α on follicular dendritic cells from patients with grade 1-2 and grade 3 follicular lymphoma.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (rs  = 0.81, P < 0.01) and the CD21-positive (rs  = 0.69, P < 0.01) and CD23-positive (rs  = 0.83, P < 0.01) FDC meshwork. The axillary lymph nodes had fewer ERα-positive cells, smaller GCs, and a looser CD21- and CD23-positive FDC meshwork with hormone therapy than without hormone therapy (P < 0.01). Neoplastic follicles of G1-2 FL had more ERα-positive cells and a larger CD23+ FDC meshwork than those of G3 FL (P < 0.01). ERα mRNA was detected in both G1-2 FL and G3 FL by reverse transcription-polymerase chain reaction. In conclusion, these results suggested that antiestrogen hormone therapy may decrease the number of ERα-positive FDCs and that the responses mediated by the estrogen-ERα interaction on FDCs may differ between G1-2 FL and G3 FL.

Expression of acetylated and dimethylated histone H3 in colorectal cancer.

AIM: The expression of acetylated and dimethylated histone H3 in colorectal cancer was examined by immunohistochemistry and chromatin immunoprecipitation (ChIP)/Western blot (WB) assay. The correlation between the expression of histone H3 and clinicopathological findings was analyzed. METHODS: Formalin-fixed and paraffin-embedded sections obtained from 80 operated cases of colorectal cancer were immunostained with anti-acetylated histone H3 (H3Ac) antibody and anti-dimethylated histone H3 lysine 4 (H3K4) antibody. Positive immunoreactivity was evaluated using the Allred scoring system. Furthermore, the expression was confirmed by ChIP/WB assay using formalin-fixed and paraffin-embedded sections. RESULTS: There was good correlation between immunostaining and expression on ChIP/WB assay (p = 0.0005). There was a significant difference between the Allred score of H3K4 and the depth of tumor invasion (p = 0.0003) and the pathological stages (p = 0.0065). In overall survival classified by Allred scores of H3Ac (p = 0.0072) and H3K4 (p = 0.0187), the highest scores represented significantly worse prognoses than the other scores. Specifically, in stages II and III, the highest scores represented significantly worse prognoses than the other scores (p < 0.0001 and p = 0.0173, respectively). CONCLUSION: The expression of H3Ac and H3K4 may estimate patient prognosis.

[A case of relapsed colon cancer successfully treated by capecitabine].

We report a case of advanced relapsed colon cancer, which had multiple liver and spleen metastasis, controlled for about two years by capecitabine therapy. A 60-year-old female had been diagnosed with ileus due to sigmoid colon cancer in August, 2005. She received sigmoidectomy and adjuvant chemotherapy (Leucovorin/5-fluorouracil therapy). In postoperative observation, multiple liver and spleen metastasis were detected by computed tomography in February, 2008. Therefore, she was administered twenty courses of FOLFOX therapy. However, a peripheral nerve disturbance appeared. There fore chemotherapy was changed from FOLFOX therapy to FOLFIRI therapy. After 2 courses of FOLFIRI therapy, she had severe nausea, vomiting, appetite loss and diarrhea. Therefore, chemotherapy was changed from FOLFIRI therapy to capecitabine therapy. After capecitabine therapy, her multiple liver and spleen metastasis disappeared, and complete response has continued for about 2 years. She has remained on capecitabine therapy and has a good quality of life.

Investigation of the Effect of Canagliflozin on the Disposition Index, a Marker of Pancreatic Beta Cell Function, in Patients with Type 2 Diabetes.

AIM: Our aim was to investigate the effects of add-on canagliflozin with glimepiride dose adjustment or glimepiride dose adjustment on pancreatic beta cell function in patients with type 2 diabetes mellitus and inadequate glycemic control despite stable triple therapy (metformin, teneligliptin, and glimepiride) plus diet/exercise therapy. METHODS: Forty patients on stable triple therapy were randomized to glimepiride dose adjustment without (glimepiride group) or with add-on canagliflozin 100 mg (canagliflozin group) for 24 weeks. The glimepiride dose was adjusted every 4 weeks based on continuous glucose monitoring over the previous 2 weeks according to a prespecified algorithm. After the 24-week treatment period, the patients returned to the pre-intervention regimen for 1 week (wash-out period). Patients underwent 75 g OGTTs at the start of the run-in period and at the end of the wash-out period. The primary endpoint was the change in disposition index (DI). RESULTS: Thirty-nine patients completed the study (canagliflozin, n = 19; glimepiride, n = 20). The change in DI was +5.1% and -11.0% in the canagliflozin and glimepiride groups, respectively, with a between-group difference ratio of 18.0% (P = 0.330). HbA1c, fasting plasma glucose, body weight, and daily-life continuous glucose monitoring-derived parameters improved in the canagliflozin group. Hypoglycemia occurred in 60% (44 episodes) and 70% (79 episodes) of patients in the canagliflozin and glimepiride groups, respectively. The change in DI was significantly correlated with the changes in glycemic control and variability in overall cohort. CONCLUSION: Adding canagliflozin to the triple therapy improved beta cell function by 18%, but it did not reach statistical significance. This study also demonstrated a correlation between the change in DI and glycemic control. As canagliflozin improved both glucose level and variability with relatively lower risk of hypoglycemia compared with glimepiride dose adjustment, adding canagliflozin to the triple therapy may be clinically beneficial. TRIAL REGISTRATION: UMIN000030208/jRCTs051180036.

A population-based study of gefitinib in patients with non-small cell lung cancer.

Survival data for non-small cell lung cancer is typically reported from clinical trials that include patients fit enough to meet treatment criteria. The denominator of all patients from which the gefitinib-treated population is derived has rarely been reported and the impact of gefitinib on population-based outcomes is difficult to measure. We have retrospectively reviewed data of 626 patients who received gefitinib in Ibaraki Prefecture (with a population of 3 million) in Japan from July 2002 until September 2007. Overall response rate was found to 30.8%, and the median survival time was 8.0 months (95% confidence interval: 7.0-9.0 months). Female gender, good PS, and adenocarcinoma were significantly associated with prolonged survival. Adverse events were generally mild and were mostly skin reactions and diarrhea. Our population-based study has generated similar results to those previously reported in published clinical trials, which had restrictive criteria for eligible patients.

Effect of Canagliflozin on Urinary Albumin Excretion in Japanese Patients with Type 2 Diabetes Mellitus and Microalbuminuria: A Pilot Study.

BACKGROUND: Albuminuria characterizes the progression of kidney injury. The effect of canagliflozin on the excretion of microalbumin was assessed for investigating its renoprotective potential in Japanese patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: Twenty Japanese patients with T2DM and microalbuminuria were enrolled and administered with 100 mg of canagliflozin once a day for 12 weeks. These subjects were admitted to the clinic at the start and end of the treatment period for 24-h urine collection. The primary endpoint was the percentage change in geometric mean 24-h urinary albumin excretion from baseline to week 12. RESULTS: The urinary albumin level decreased by 42.0% (95% confidence interval: 21.9-57.0; P = 0.0011) after 12 weeks of canagliflozin treatment. A number of blood and urinary parameters also significantly decreased, including hemoglobin A1c, fasting plasma glucose, estimated glomerular filtration rate, and creatinine clearance, while hematocrit was elevated. Among the biomarkers associated with kidney injury and inflammation, the urinary level of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine was also decreased. There were no meaningful correlations noted between changes in urinary albumin excretion and other parameters/biomarkers. No severe adverse events were reported over the 12-week treatment period. CONCLUSIONS: The results of this study indicate that canagliflozin decreases microalbuminuria in Japanese patients with T2DM. Albuminuria could be reduced as a result of changes in various physiological pathways; therefore, it is imperative that future, large-scale, studies attempt to determine the detailed mechanisms involved. Canagliflozin may offer a novel therapeutic option for Japanese patients with T2DM and incipient nephropathy.

Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials.

BACKGROUND: We aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L). METHODS: This post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated. RESULTS: The mean ALT change at 12 weeks was -10.3 ± 11.7 and -3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was -16.0 ± 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2). CONCLUSIONS: In T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated.

Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1-3 fibrosis.

AIM: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. METHODS: T2DM patients with NASH (hepatic fibrosis stage 1-3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. RESULTS: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI -48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. CONCLUSION: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH.

Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients. METHODS: Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors. RESULTS: Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast. CONCLUSION: Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and increased plasma renin activity, which may be a compensatory mechanism for sodium retention, leading to subsequent urine output recovery. CLINICAL TRIAL REGISTRATION: UMIN000019462. FUNDING: Mitsubishi Tanabe Pharma Corporation.

[Postoperative intensive care of a patient with Cushing's syndrome accompanied with retroperitoneal abscess and massive subcutaneous emphysema].

A 60-year-old woman with Cushing's syndrome due to right adreno-cortical adenoma was referred to us because retroperitoneal abscess was found during surgical removal of the right adrenal gland. The diagnosis of Cushing's syndrome was made on the basis of elevated serum levels of cortisol. The abscess was accompanied with massive subcutaneous emphysema and pneumomediastinum. After operation the patient was admitted to ICU in the Medical Center for Emergency and Critical Care. PMX-DHP, continuous hemodiafiltration, and drainage were performed, and antibiotics were given. Nine days after the admission the patient recovered generally, and was transfferd to the Department of Urology. It was demonstrated that an opportunistic infection must be always considered in the condition like the present case.

Levels of MCP-1 and GM-CSF mRNA correlated with inflammatory cytokines mRNA levels in experimental autoimmune myocarditis in rats.

Infiltration of monocytes and T cells is known to be an essential trigger for the progression of experimental autoimmune myocarditis (EAM) in rats. Monocyte chemotactic protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were shown to mediate the migration of monocytes and T cells into inflammatory sites and to proliferate monocytes. Thus, we evaluated levels of MCP-1 and GM-CSF mRNA in the myocardium of EAM in rats using a real time quantitative PCR method. We also examined the correlation of MCP-1 or GM-CSF mRNA levels with those of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in the same lesion. Levels of MCP-1, GM-CSF, TNF-alpha, IL-1beta and IL-6 mRNA increased with the progression of myocarditis which was accompanied by the accumulation of ED-1 positive cells. The MCP-1 and GM-CSF mRNA levels were positively correlated with TNF-alpha, IL-1beta and IL-6 mRNA levels in the same lesion of EAM. We also demonstrated that serum MCP-1 concentrations were increased during the active stage of EAM, and were correlated with MCP-1 mRNA levels in the myocardium of each rat. These findings suggest that elevated MCP-1 and GM-CSF may associate with the migration and proliferation of monocytes/macrophages in EAM. Thus, MCP-1 and GM-CSF may play an important role in the progression of EAM.

Insulin secretion and sensitivity in non-obese and obese Japanese patients with coronary artery disease.

In a cross-sectional study of 240 patients with angiographically documented coronary artery disease (CAD), we investigated whether obese and non-obese subjects differed as to the influence of insulin deficiency and insulin resistance on glucose intolerance and cardiovascular risk. Patients were classified according to a 75-g oral glucose tolerance test as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or diabetes mellitus (DM). We defined obesity as a body mass index (BMI) exceeding 25 kg/m(2). Early phase insulin secretion (insulinogenic index) declined with worsening glucose intolerance in non-obese (tau = -.216, P <.001; Kendall's correlation coefficient) and obese subjects (tau = -.392, P <.001). Total insulin secretion was higher in obese subjects with NGT or IGT than in controls and decreased in association with worsening glucose intolerance in obese subjects (tau = -.239, P <.001). Insulin sensitivity was calculated by 3 proposed indices. The first of these decreased in association with worsening in glucose tolerance in non-obese subjects (tau = -.137, P <.01). The second showed such a pattern in both groups (non-obese, tau = -.407, P <.001; obese, tau = -.311, P <.001), as did the third (non-obese, tau = -.512, P <.001; obese, tau = -.488, P < 0.001). Because even prediabetic Japanese subjects with CAD showed a latent insulin secretion defect in response to a glucose load, as well as impaired insulin sensitivity, compensatory hyperinsulinemia is not a sensitive indicator of coronary risk.

Vascular remodeling of the carotid artery in patients with untreated essential hypertension increases with age.

We examined whether hypertrophy of the carotid artery in patients with untreated essential hypertension is associated with compensatory carotid artery enlargement as these patients age. Carotid ultrasonography was evaluated in 163 patients with untreated essential hypertension (74 males and 89 females) and in 76 normotensive subjects. Intima-media end-diastolic thickness (IMT) and outer vessel diameter (VD) were measured, and relative wall thickness (IMT/R, R=VD/2) and vascular mass (VM) were calculated. Determinants of vascular hypertrophy in patients with untreated essential hypertension were also investigated. VD, VM, and IMT were significantly correlated with age in both the normotensive and hypertensive groups. Additionally, IMT was significantly correlated with VD in both groups. There was no correlation between increasing age and IMT/R in either group. IMT, VD and VM were significantly higher in the hypertensive group >50 years than in age-matched normotensive controls. However, IMT/R was significantly higher in the 50-59 years hypertensive group than in normotensive controls of the same age group. In addition to age, VM was related to systolic blood pressure, pulse pressure, fasting blood sugar, IMT, VD, and IMT/R in the hypertensive group. Multivariate regression analysis in the hypertensive group indicated that IMT/R was the strongest predictor of carotid vascular mass. Age and pulse pressure were also independently related to vascular mass. These results indicate that, as patients with untreated hypertension age, carotid arteries undergo remodeling. This should add further impetus to the implementation of appropriate hypertension treatment for such patients.

Metabolic syndrome and new category 'pre-hypertension' in a Japanese population.

OBJECTIVE: To examine whether insulin resistance and metabolic syndrome are associated with pre-hypertension, a new stage developed by the Joint National Committee on Prevention, Detection, Education and Treatment of High Blood Pressure (JNC-7). PATIENTS AND METHODS: Subjects included 506 Japanese taking no anti-hypertensive medication. Subjects were divided into three groups according to blood pressure status using the JNC-7 criteria. Normotension (NTN) was defined as a Systolic Blood Pressure (SBP) < 120 mmHg and a Diastolic Blood Pressure (DBP) < 80 mmHg, pre-hypertension (PHT) as a SBP 120-139 mmHg or a DBP 80-89 mmHg and hypertension (HTN) as a SBP > or = 140 mmHg or a DBP > or = 90 mmHg. The metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III as modified for waist circumference criteria by the Regional Office for the Western Pacific Region of WHO. Insulin sensitivity was assessed by plasma glucose and insulin concentrations obtained at fasting or during a 75 g oral glucose tolerance test. RESULTS: There were no differences with respect to age, gender or glucose intolerance status among the three groups. The mean values of body mass index were similar between NTN and PHT, but were significantly higher in HTN than in other groups. The prevalence of the metabolic syndrome was 9.9% in NTN, 19.2% in PHT and 35.5% in HTN, respectively. The prevalence increased linearly with worsening of blood pressure status (p < 0.0001). An increase in the number of metabolic syndrome components (MS score) was also associated with a progress in blood pressure status. Even in the non-obese persons, the prevalence of the metabolic syndrome and the MS score increased linearly with worsening in blood pressure status. The homeostasis model assessment of insulin resistance (HOMA-R) was significantly higher in PHT and HTN than in NTN and increased significantly with worsening in blood pressure status. Furthermore, the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index proposed by Stumvoll et al. decreased significantly with worsening in blood pressure status. CONCLUSIONS: The metabolic syndrome is prevalent even in the pre-hypertensive stage in a Japanese population and insulin resistance contributes to the underlying mechanisms of these abnormalities.

Validation of simple indices to assess insulin sensitivity based on the oral glucose tolerance test in the Japanese population.

The homeostasis model assessment (HOMA) represents a simple index for evaluating insulin sensitivity, but clinical use is limited. Insulin sensitivity indices calculated from plasma glucose and plasma insulin concentrations after an oral glucose tolerant test (OGTT) have been proposed, but have not been validated in the Japanese population. We compared these indices with the euglycemic hyperinsulinemic clamp technique to evaluate the predicting insulin sensitivities in 77 Japanese subjects with varying degrees of glucose tolerance (normal glucose tolerance, n=40; impaired glucose tolerance, n=22; and type 2 diabetes mellitus, n=15). Insulin sensitivity was measured by the euglycemic hyperinsulinemic glucose clamp technique using an artificial pancreas, and expressed as the M-value. Weak inverse correlations existed between the HOMA index and M-values (r=-0.227, P=0.0468). An alternative index calculated by Matsuda's formula correlated with the M-value (r=0.450, P=0.0001). A second index calculated by Stumvoll's formula also correlated with the M-value (r=0.641, P=0.0001). Finally, a third index calculated by Gutt's formula also significantly correlated with the M-value (r=0.526, P=0.0001). All three indices are applicable for clinical use. The second index is the most sensitive measure of insulin sensitivity in the Japanese population.

Transcardiac gradient of soluble adhesion molecules predicts progression of coronary artery disease.

BACKGROUND: During the development of atherosclerotic lesion, several types of cellular adhesion molecules (CAMs) are overexpressed on the surface of vascular endothelium. Some parts of these membrane proteins are proteolysed and are detected in blood as soluble forms. AIMS: The purpose of this study is to investigate the relationship between the transcardiac gradient of soluble cellular adhesion molecules (sCAMs) and the clinical characteristics of coronary artery disease (CAD). METHODS: We studied 46 patients with clinically stable CAD. Serum sCAM levels in both aortic sinus and coronary sinus were measured using enzyme-linked immunosorbent assay, and the transcardiac gradient of sCAMs was calculated. We also evaluated the angiographic severity of CAD, response of coronary artery to acetylcholine (Ach), as well as progression of coronary atherosclerosis over a 6-month period. RESULTS: The transcardiac gradient of sCAMs did not correlate to the angiographic severity of coronary atherosclerosis. The transcardiac gradient of sVCAM-1 was significantly higher in patients with vasoconstrictive response to Ach than patients without vasoconstrictive response to Ach (191.5+/-98.2 vs. -9.2+/-14.1 ng/ml, P<0.05). Furthermore, patients who exhibited progression of coronary atherosclerosis had a higher transcardiac gradient of sVCAM-1 at the initial study than patients without progression (47.8+/-24.5 vs. -6.4+/-12.3 ng/ml, P<0.05). CONCLUSIONS: An elevated transcardiac gradient of sVCAM-1 may represent the persistent activation of coronary artery that is accompanied by endothelial dysfunction, and may be a predictive index of progression of coronary atherosclerosis. Measurement of coronary circulating sVCAM-1 could provide important functional and predictive information about atherosclerosis.

Contribution of Velocity Profiles at the Left Ventricular Outflow Tract to Calculations of Stroke Volume: A Magnetic Resonance Imaging Study.

OBJECTIVE: The goal of the study was to determine whether the central velocity of the left ventricular outflow tract represents the mean velocity of the total outflow area. METHODS: Thirteen healthy men (mean age, 30 +/- 6 years) and nine patients with aortic valve disease (seven with aortic regurgitation and two with aortic valve stenosis) were examined. Cine gradient echo images were obtained in the left ventricular outflow long axis. Cine images with velocity mapping were obtained in the short axis of the outflow tract. Values for peak velocity were obtained on the right-left axis and on the anteroposterior axis. Distances were measured along the axes from the right and anterior edges of the outflow tract at the point of peak velocity. Percentages of the distances for outflow diameter were calculated. Peak velocity at the left ventricular outflow tract using pulsed-Doppler method were also measured. RESULTS: In normal subjects and in patients, on the right-left axis, the peak velocity was 87 +/- 16 and 72 +/- 11 cm/sec, respectively, and the distance from the right edge of outflow tract corresponded to 19% +/- 8% and 21% +/- 7%, respectively. On the anteroposterior axis, the peak velocity was 86 +/- 16 and 60 +/- 9 cm/sec, and the corresponding distance from the anterior edge was 30% +/- 13% and 41% +/- 12% for normal subjects and patients, respectively. The central velocity of the outflow tract was 74 +/- 15 cm/sec, whereas the mean of the total outflow tract was 74 +/- 13 cm/sec. Central and mean velocities of the outflow tracts as revealed by magnetic resonance imaging showed a close and highly significant correlation in both groups. Velocity obtained by pulsed-Doppler method and mean velocity of the outflow tract by magnetic resonance imaging also showed significant correlation in both groups. CONCLUSIONS: Central velocity at the left ventricular outflow tract represented the mean of the total outflow tract both in normal subjects and in patients with aortic valve disease. The stroke volume measured by pulsed Doppler is therefore considered reliable if the sampling point is placed exactly at the center of the outflow.

Subacute cor pulmonale due to tumor embolism.

We describe a patient wih subacute cor pulmonale caused by tumor emboli in the lungs. A 64-year-old female suffering from a subacute progressive cough and shortness of breathing died of severe pulmonary hypertension seven days after admission. Neither chest CT scans nor lung perfusion scintigraphy showed any abnormal findings. Microscopic examination after an autopsy revealed diffuse intravascular tumor emboli occluding not only the small pulmonary arteries and arterioles, but also the lymphatic vessels, which were suggested to be metastases of a breast carcinoma resected five years previously. Thus, pulmonary tumor embolism should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with a past history of cancers.

Primary seminoma in the middle mediastinum.

Primary mediastinal seminoma is a relatively rare tumor usually located in the anterior mediastinum. We report here an extremely rare case of a 66-year-old man with primary seminoma in the middle mediastinum. A physical examination showed lymphadenopathy in the right supraclavicular area. A chest CT confirmed the presence of a tumor occupying the retrotracheal space. A histological examination demonstrated metastatic seminoma from the open biopsy of the lymph node. Abdominal, pelvis, and cerebral CT scan and testicular ultrasound were negative. Thus, primary mediastinal seminoma in the middle mediastinum with supraclavicular lymph node metastasis was diagnosed.