Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT.

A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

Effect of the Pt buffer layer on perpendicular exchange bias based on collinear/non-collinear coupling in a Cr2O3/Co3Pt interface.

In this study, we fabricated a Cr2O3 (0001) film without and with a Pt buffer layer and investigated its effect on perpendicular exchange coupling in a Cr2O3/Co3Pt interface. The results showed that the exchange bias field (µ0Hex) and blocking temperature (TB) of a Cr2O3 film without and with Pt were very different. The Cr2O3 film without Pt had a lower µ0Hex of 176 Oe and a lower TB of 75 K, whereas that with Pt had a higher µ0Hex of 436 Oe and a higher TB of 150 K. We discussed this difference in µ0Hex and TB values based on collinear/non-collinear coupling in a ferromagnetic and antiferromagnetic interface using Meiklejohn and Bean's exchange anisotropy model.

Disease stage stratified effects of cell dose in unrelated BMT for hematological malignancies: a report from Japan Marrow Donor Program.

Cell dose is one of the major factors that can be manipulated in unrelated BMT. However, regarding disease-stage-stratified effects of cell dose, data are limited. We analyzed the registry data from 3559 patients with acute leukemia, CML and myelodysplastic syndrome who received T-cell replete unrelated BMT through the Japan Marrow Donor Program. Adjusted effects of cell dose were evaluated for various outcomes separately according to disease stages and children or adults. Acute GVHD and nonrelapse mortality were not affected by cell dose. Among children, a cell dose lower than 3.0 × 10(8)/kg was associated with lower engraftment rates in advanced-stage diseases. Among adults, a cell dose of 3.4 × 10(8)/kg or higher was associated with lower relapse rates and better survival rates only in early-stage diseases, whereas cell dose below 2.3 × 10(8)/kg was associated with lower engraftment rates in advanced-stage diseases. In conclusion, effects of cell dose may differ among disease stages. A cell dose of 3.4 × 10(8)/kg or higher is recommended only for adults with early-stage diseases. With the number of patients available for analysis in this study, we could not show any significant benefits associated with 4.6 × 10(8)/kg or higher in children.

K-ras mutations and cell kinetics in Helicobacter pylori associated gastric intestinal metaplasia: a comparison before and after eradication in patients with chronic gastritis and gastric cancer.

BACKGROUND: Helicobacter pylori related gastric intestinal metaplasia (IM) is considered to be a precancerous lesion. AIMS: To identify the effects of H pylori eradication on K-ras mutations, cell kinetics in IM and histological changes in patients with and without gastric cancers in a one-year prospective study. METHODS: Patients included group A (n = 39), chronic gastritis, and group B (n = 53), intestinal-type early gastric cancer patients who had all undergone endoscopic mucosal resection (n = 25) or surgical resection (n = 28). K-ras codon 12 mutations in IM were examined, followed by DNA sequencing analysis. Proliferating and apoptotic cells were detected with anti-Ki-67 antibody and using the TUNEL method, respectively. RESULTS: The incidence of K-ras mutations in the cancer was only 3.8%. The mutant K-ras in IM was observed more frequently in group A (46.2%) than in group B patients (1.9%) (p<0.005). After eradication, the K-ras mutations significantly declined to 12.8% in group A (p<0.005). The mutation pattern of K-ras codon 12 before eradication was that GGT was mainly changed to AGT (50%) in group A. AGT transformation was not affected by treatment. Apoptosis in IM showed an increase after H pylori eradication in both groups (p<0.05 in group A) although no histological improvement in IM was observed. The monocyte score was significantly higher in group A than in group B (p<0.05); the score improved significantly after eradication. CONCLUSIONS: K-ras mutations in IM do not always play a role in gastric carcinogenesis but cell kinetics, especially apoptosis, in IM may contribute to it. There are early events in K-ras mutations which are influenced by H pylori infection; some mutations may also be selected by eradication. These unstable K-ras mutations in IM may be related to lymphocyte infiltration caused by H pylori infection.

Phase II study of irinotecan, leucovorin, 5-fluorouracil and tegafur/uracil for metastatic colorectal cancer.

Irinotecan combined with continuous-infusion 5-fluorouracil (5FU) has been shown to be an effective and tolerable regimen in the treatment of metastatic colorectal cancer (MCRC). Tegafur/uracil (UFT) during 5FU infusion enhances plasma 5FU concentration, mimics continuous 5FU infusion and delivers the drug to target tumor cells. We conducted a phase II trial of four-agent combined therapy for MCRC, giving patients (pts) intravenous irinotecan (30 mg/m2 on day 1), leucovorin (LV, 200 mg/m2 on day 1 and 2), 5FU (300 mg/m2 on day 1 and 2), and UFT (400 mg/day for 14 days). The main endpoint was the objective tumor response rate. Sixteen pts with a good performance status were enrolled from February 2001 to May 2002. The response rate was 19% (3 partial responses), and 13 pts had stable disease. The median time to progression was 5.2 months, and the median survival time was 20.2 months. Considering the low toxicity and reasonable cost, this regimen deserves further investigation.

Expression and activation of MAP kinases, ERK1/2, in the human villous trophoblasts.

Mitogen-activated protein kinase (MAP kinase) plays a central role in the signal transduction for diverse cellular responses, such as proliferation, differentiation, stress response and cell death, via activation after binding of growth factors to the respective receptors on the cell membrane. In the human placental tissues, however, little is known about the expression and activation of the classical MAP kinases, extracellular signal-regulated kinase1/2 (ERK1/2). We therefore examined the expression of ERK1/2 in the human chorionic and placental tissues between 5 and 41 weeks of gestation, using Western blotting, immunohistochemistry and in situ hybridization. To explore the activation of ERK1/2 protein, we used an antibody that reacts with both phosphorylated and non-phosphorylated ERK1/2 (total ERK1/2), as well as antibodies that react only with phosphorylated ERK1/2. The expression pattern of phosphorylated ERK1/2 in the trophoblasts was compared with that of various growth factor receptors, such as c-met, IGF-1R, flt-1, EGFR, PDGFR, Bek, and flg. Total ERK1/2 was immunolocalized in the villous cytotrophoblasts (CTs), but not in the syncytiotrophoblasts (STs), throughout pregnancy. In situ hybridization also showed the localization of ERK1 mRNA in the villous CTs. Interestingly, however, phosphorylated ERK1/2 was immunolocalized in the villous CTs only up to 12 weeks of gestation. Western blot also showed the stronger bands of phosphorylated ERK1/2 in the tissues of the first trimester. Among the growth factor receptors, c-met was strongly expressed in the villous CTs during the first trimester, and resembled the expression pattern of phosphorylated ERK1/2. These findings suggest that the MAP kinase pathway is activated in the villous CTs during the first trimester in the human placenta.

Clinical pilot studies on pre-operative hyperthermic tumour ablation for advanced breast carcinoma using an 8 MHz radiofrequency heating device.

The multimodality treatment approach for advanced breast cancer provides survival advantages with decreased locoregional and distant recurrences, but these intensive anti-tumour treatments cause severe myelosuppression. Thus, in this study, the usefulness of pre-operative anti-tumour treatment without myelosuppression was investigated. Nine patients with advanced breast carcinoma underwent pre-operative hyperthermic tumour ablation (HTA) using an 8 MHz radiofrequency (RF) heating device (Thermotron RF-8) combined with a grounded needle electrode. The patients had a mean age of 58.3+/-13.9 years and included four patients with stage IIIA, two with stage IIIB and three with stage IV cancer. The target temperature was over 50 degrees C. They tolerated pre-operative HTA therapy well with no early or late complications. The initial mean tumour size was 122.1+/-71.5 cm3 and the post-HTA tumour size was 82.2+/-63.4 cm3; the reduction rate was significant (p = 0.000 293). After the pre-operative HTA, all patients underwent surgery with Level III nodal extirpation. Post-operatively, no locoregional recurrence was observed. Microscopic examination of the primary focus showed complete coagulation necrosis expanding for a diameter of 3.5-5.0 cm. Taken together, the pre-operative HTA was a safe, well-tolerated and effective treatment, achieving tumour reduction as well as complete coagulation necrosis that resulted in a large volume of destruction in breast cancer tissue.

Office blood pressure variability as a predictor of acute myocardial infarction in elderly patients receiving antihypertensive therapy.

Larger variability of office blood pressure (BP) was reportedly associated with a higher risk of stroke or mortality from all causes. In the present study, we focused on the relationship of variability of office BP and occurrence of acute myocardial infarction (MI). We registered 139 patients receiving antihypertensive therapy for more than 1 year who experienced first-ever episode of MI at the age of 60 years or over. At least two sex- and age-matched (+/- 5 years) control patients were registered for every MI patient. Average systolic and diastolic BP during the 12-month period prior to the occurrence of MI, or the time of registration in the case of control patients, was similar in both patient groups. The office BP variability was evaluated by calculating the variation coefficient (VC) of BP. VC of diastolic BP was significantly higher in the MI patients (10.0 +/- 4.0%) compared with the control patients (8.8 +/- 3.4%). VC of systolic BP was not different between the MI and the control patients. Multiple logistic analysis revealed the relationship of the VC for office diastolic BP to the occurrence of MI was significant after adjustment for BP level, age, gender, body mass index, serum total cholesterol concentrations, diabetes mellitus, and current smoking. In conclusion, larger long-term variability of office diastolic BP during antihypertensive therapy is a predictor of MI.

Reduced expression of syndecan-1 affects metastatic potential and clinical outcome in patients with colorectal cancer.

Syndecan-1 is a transmembrane heparansulfate proteoglycan which regulates cell-to-cell or cell-to-extracellular matrix interactions and may influence malignant cell behavior. We investigated the alterations of syndecan-1 expressions in colorectal cancers and analyzed the relationship between histological and clinical characteristics. Syndecan-1 protein expression in colorectal cancer tissues was investigated with immunohistochemical staining of resected specimens. In situ hybridization was performed using syndecan-1 riboprobe to confirm the transcriptional signals. Syndecan-1 mRNA expression in cancer cell lines cultured with or without methylation inhibitor was also analyzed by quantitative PCR. Out of 105 specimens tested, less than 25% of tumor cells were stained with anti-syndecan-1 monoclonal antibody in 36 (34.3%). In situ hybridization showed a similar staining profile to that of immunohistochemistry. Syndecan-1 mRNA expression was increased by the methylation inhibitor 5-aza-2'-deoxycytidine, suggesting that the hypermethylation is involved in the suppression of syndecan-1 expression. Clinically, the incidence of metastasis to lymphnode or liver in patients with syndecan-1-negative tumors was significantly high. Among T1 colorectal cancers displaying a primary invasive phase, lymphnode metastasis, undifferentiated characters and 'budding' of cancer cells were more common in syndecan-1-negative tumors. The survival rate in patients with syndecan-1-negative tumors was decreased significantly in a stage-independent manner. These results suggest that the reduction of syndecan-1 expression in colorectal cancer cells, which is supposed to be regulated at the transcription level, is closely related to invasive character. The evaluation of syndecan-1 expression in colorectal cancer may allow prediction of patients' survival after surgery.

Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload.

OBJECTIVES: We examined whether measurement of the plasma BNP concentrations might be useful for the early diagnosis of the existence and severity of disease in patients with heart disease in daily clinical practice. METHODS AND RESULTS: The plasma BNP and ANP concentrations in 415 patients with heart disease and hypertension and 65 control subjects were measured. Patients with heart disease had higher plasma BNP and ANP concentrations than did those with hypertension or control subjects. Among the etiology of cardiac diseases, specifically dilated cardiomyopathy and hypertrophic cardiomyopathy, was associated with the highest plasma BNP concentrations, whereas dilated cardiomyopathy was associated with the highest plasma ANP concentrations. Plasma BNP concentrations showed an increase as the severity of the heart disease, as graded according to the NYHA classification of cardiac function, increased. In both patients with heart disease and hypertension, the plasma BNP values were higher in those who had abnormalities in their echocardiogram and electrocardiogram as compared to those without any abnormalities. The plasma BNP levels also showed a significant correlation with left ventricular wall thickness and left ventricular mass. On the other hand, the plasma ANP levels showed significant correlations with left ventricular dimension. Receiver operative characteristic analysis revealed that plasma BNP levels showed substantially high sensitivity and specificity to detect the existence of heart diseases. CONCLUSION: Measurements of the plasma BNP concentrations is useful to detect the existence of the diseases, and abnormalities of left ventricular function and hypertrophy in patients with heart disease in daily clinical practice.

Profiles of patients who control the doses of their antihypertensive drugs by self-monitoring of home blood pressure.

The present study profiled patients who control doses of antihypertensive drugs by themselves based on self-monitoring of their blood pressure (self-controllers). A total of 1,028 consecutive outpatients who were taking antihypertensive drugs and who were attending the cardiovascular outpatient clinic of our institute responded to a questionnaire in 1998. They were asked how often they measured their blood pressure, how often they missed taking their medication, and whether or not they had a chance to adjust the doses of antihypertensive drugs by themselves based on self-monitored blood pressure. The frequency of self-controlling of antihypertensive drugs was also examined in 918 patients on antihypertensive drugs in 1997. In 1997, 23 of 918 patients (2.5%) were self-controllers, and 26 of 1,028 patients (2.5%) were self-controllers in 1998. The frequency of home blood-pressure measurement was significantly greater in self-controllers than in the remaining patients (non self-controllers) (p<0.01). The prevalence of proteinuria was significantly less in the former than in the latter. Prior to the start of antihypertensive drugs, blood pressure was significantly lower for the self-controllers (154.4+/-3.8/96.4+/-1.4 mmHg) than for the non self-controllers (169.3+/-0.7/101.7+/-0.4 mmHg) (p<0.001). Clinically measured blood pressures did not differ significantly between the self-controllers and non self-controllers. Thus, about 2.5% of patients on antihypertensive drugs controlled their drug doses by themselves based on self-monitoring of their blood pressure. These patients were characterized by having a milder form of hypertension and by more frequent home blood-pressure measurement than non self-controllers.

[Treatment of hypertension with dyslipidemia].

Lifestyle modifications are the first approach to the treatment of dyslipidemia and hypertension, that is, control of overweight; reduced intake of saturated fat, cholesterol, sodium chloride, and alcohol; and increased physical activity. In high doses, thiazide diuretics and loop diuretics can induce at least short-term increases in levels of total plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol. Low-dose thiazide diuretics do not produce these effects. beta-blockers may increase levels of plasma triglycerides transiently and reduce levels of high-density lipoprotein cholesterol. alpha-blockers may decrease serum cholesterol concentration to a modest degree and increase high-density lipoprotein cholesterol. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium antagonists, and central adrenergic agonists have clinically neutral effects on levels of serum lipids and lipoproteins.

Concentration of progenitor cells collected from bone marrow fluid using a continuous flow cell separator.

In ABO major incompatibility on bone marrow transplantation (BMT), red cells must be removed from collected marrow fluid to prevent hemolysis. We report the concentration of progenitor cells collected using a continuous flow cell separator (Cobe Spectra). The average volume of concentrated bone marrow was 132 +/- 47 ml and that of red cells included was 5.1 +/- 2.4 ml. The red cell removal rate was 97.6%. The recovery rate was 40.6% for total nuclear cells, 77.9% for mononuclear cells, 100% for CD34+ cells, and 93.9% for colony forming unit granulocyte-macrophage. Eighteen patients undergoing allogeneic BMT showed no signs of fever or hemolysis during concentrated marrow fluid transfusion. The recovery rate of progenitor cells was high, indicating sufficient recovery of hemopoiesis. This technique is applicable in ABO-incompatible BMT and in frozen-storage stem cells.

Medication management skill and regimen compliance are deteriorated in the elderly even without obvious dementia.

We investigated whether regimen comprehension deteriorated in the elderly patients who did not suffer from obvious dementia. Eligible patients were ambulatory elderly patients who did not show any signs of dementia and could visit our outpatient clinic by themselves. 138 patients (age: 43-89, 75 males and 63 females, underlying diseases: hypertension, hyperlipidemia, arrhythmia etc.) were tested with a regimen comprehension scale (RCS: Jpn J Geriat 1997; 34: 209-214). The differences in scores among individuals increased with age. Scores of 5 or less in the RCS were recorded in 10 out of 69 patients aged 65 or more, but no such scores were recorded in younger patients (p < 0.01). The 60 patients who scored less than full marks were classified into two groups, the T-group (tutored by pharmacists), and a Non Tutored group. RCS was tested again in both groups. Only in the T-group (n = 28), did the second scores increase significantly (from 7.2 +/- 0.9 to 8.6 +/- 2.0 (m +/- SD); p < 0.01) after tutorial by pharmacists. Comparing the 7 patients who obtained an RCS score of 5 or less and age- and gender-matched controls who got full marks, there was no difference in the HDS-R test. These results suggest that even in elderly patients who did not show any signs of dementia, the regimen comprehension deteriorated with age, and tutorials in medication protocols were considered to be effective.

[Differential diagnosis of chronic myeloid leukemia and the related disorders].

Chronic myeloid leukemia(CML) is a generic term that includes five subtypes; i.e. chronic granulocytic leukemia(CGL) (95% of all CML, 90% are Ph+, 5% are Ph-, BCR/ABL+), atypical CML(survival is worse than that of CGL), chronic myelomonocytic leukemia(a subtype of myelodysplastic syndrome), chronic neutrophilic leukemia (Ph-, BCR/ABL-) and juvenile CML(Ph-, BCR/ABL-). It is not so easy to make a diagnosis of Ph-negative CML. Also, about 25% of adult acute lymphoid leukemia(ALL) patients and some essential thrombocythemia patients have Ph chromosome. In addition, about a half of cases with Ph-positive ALL have the same size of BCR/ABL fusion protein as that in Ph-positive CML. It is necessary to distinguish them by the distinctive morphological, cytogenetical and immunological characteristics of these diseases.

[An autopsied case of marked cardiac hypertrophy due to multifactorial heart disease in an 85 year-old man who had been socially active].

An autopsied 85-year-old man had suffered from a mild form of diabetes mellitus since the age of 67 and had experienced the first episode of heart failure with arapid ventricular rate of atrial fibrillation at the age of 72. He had remained socially active until he died suddenly of ventricular fibrillation, although he had complications of aortic regurgitation at the age of 76 and later mitral regurgitation at the age of 80. Chest roentgenograms showed gradual increase in the cardiothoratic ratio which reached 68.1% at the final stage. Autopsy revealedmarked left ventricular hypertrophy with a heart weight of 580 g, degeneration ofaortic valves, thickening of mitralvalve cusps and moderate coronary atherosclerosis without ischemic myocardial lesions. There were no specific lesions suggestive of primary cardiomyopathies on microscopic observations and the lesions of both aortic and mitral valves were not significant enough to explain the clinical findings of aortic and mitral regurgitation. Because the pathological examination failed to identify a single disease which was responsible for the marked cardiachypertrophy, we eventually reached the conclusion that the cardiac hypertrophy developed based on a multifactorial heart disease.

Serum KL-6 levels in patients with pulmonary complications after allogeneic bone marrow transplantation.

KL-6, a mucinous high-molecular weight glycoprotein expressed on type 2 pneumocytes, has been shown to be elevated in the serum and bronchoalveolar lavage fluid of patients with interstitial pneumonitis (IP). We measured the serum levels of KL-6 in patients after they had undergone allogeneic bone marrow transplantation (BMT) to determine whether KL-6 could be a clinically useful indicator for the development of IP. The serum concentrations of KL-6 were determined by a sandwich-type enzyme-linked immunosorbent assay using an anti-KL-6 monoclonal antibody. A total of 1028 samples were tested from 76 patients (78 transplantations) who received BMTs. The KL-6 values were markedly elevated in patients with pulmonary complications, but not in those with acute and chronic graft-versus-host disease, hemorrhagic cystitis, herpes encephalitis, sepsis, and veno-occlusive disease. The serum levels of KL-6 from patients with pulmonary complications were significantly higher than from those without pulmonary complications (P < .001) and those with other complications (P < .001). Of the 12 patients with pulmonary complications, 6 had idiopathic IP (IIP). The levels were not high at the onset of IIP. Four of 6 IIP patients showed marked elevations of KL-6 levels in parallel with the severity of IP and died of respiratory failure without response to treatment. Assessment of serum KL-6 levels might not be useful for the early diagnosis of IP, but may be a useful indicator for monitoring the severity of IP after BMT.

Office blood pressure variability as a predictor of brain infarction in elderly hypertensive patients.

Large 24-h blood pressure (BP) variability and an excessive drop in BP during nighttime are associated with a higher risk of cardiovascular events. Data are lacking regarding the prognostic significance of variability in BP measured during office visits. We analyzed the relationship between office BP variability and the risk of brain infarction in elderly patients receiving antihypertensive therapy. Patients who experienced their first-ever stroke at the age of 60 years or over were registered in the study. At least 2 sex- and age-matched control patients were registered for each case patient. Office BP at each clinic visit and known cardiovascular risk factors were recorded. The BP variability was defined as the variation coefficient (VC) of office BP. In this report, we analyze the data of brain infarction patients. The VC of both systolic and diastolic BPs was significantly higher in the brain infarction patients than in the control patients. Higher office BP variability was associated with a higher risk of brain infarction after adjustment for BP level and other confounding factors. Regarding diastolic BP, the association of brain infarction with the maximal value for the difference of office BPs taken at any consecutive two visits (Max-deltaBP) or the difference between the highest and lowest values of office BP (BP-range) recorded during a 1-year period prior to the event was also significant. In conclusion, a retrospective case-control study suggested that office BP variability was an independent predictor of brain infarction. Either the Max-deltaBP or the BP-range may be surrogate indices of diastolic BP variability.

Distinct increase in hematocrit associated with paroxysm of atrial fibrillation.

In a previous study we found that hemoconcentration, which was identified by an increase in hematocrit, occured during a paroxysm of atrial fibrillation. In the present study we investigated the changes in hematocrit from sinus rhythm to paroxysm in 10 patients who had multiple paroxysms of atrial fibrillation in order to assess the ranges of the changes in hematocrit among the paroxysms. In these patients hematocrit was measured simultaneously with electrocardiographic recording during 3 or more paroxysms and sinus rhythm just before each paroxysm. The changes in hematocrit varied among the paroxysms. The maximum increase in hematocrit in each patient ranged from 3.5 to 8.0 points with an average of 5.1 points. Such a distinct increase in hematocrit which abruptly develops with a paroxysm of atrial fibrillation may be a potential risk for thrombus formation.