Kiyoshi Kitamura

Long-term Results of a Multicenter Randomized, Comparative Trial of Modified CHOP versus THP-COP versus THP-COPE Regimens in Elderly Patients with Non-Hodgkin's Lymphoma

In treating elderly non-Hodgkin’s lymphoma (NHL) patients, it is particularly important to use drugs that have a low incidence of adverse events and high efficacy. In this multicenter study, THP (pirarubicin)-COP (cyclophosphamide, vincristine, and prednisolone) was compared to two thirds dosage of full CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen with regard to both adverse events and efficacy. For a third group, etoposide (E) was added to the THP-COP regimen (THP-COPE) in order to achieve high dose-intensity. Subjects were 486 previously untreated patients, aged 65 or older (range, 65–92 years; median, 74 years), with NHL. Subjects were randomly assigned to receive THP-COP, two thirds CHOP, or THP-COPE. Four hundred and forty-three patients were assessed for response and followed for 8 years after the last subject registered. The complete remission rates for the THP-COP, CHOP, and THP-COPE groups were 42.5%, 41.4%, and 48.0%, respectively. There was no difference in overall survival or progression-free survival among these 3 groups. In aggressive lymphoma, there was also no difference in complete response (CR) rate (45.3% in THP-COP, 44.9% in CHOP, 48.0% in THP-COPE), overall survival, and progression-free survival among these groups. The 5- and 8-year survival rates for all patients were 29.4% and 18.7%, respectively. The 5- and 8-year survival rates for patients with aggressive lymphoma were 27.4% and 17.4%, respectively. Although long-term survival for patients with aggressive lymphoma on our regimens was not worse compared to previous reports, the CR rate was lower. Because severe adverse events were not observed, higher dose chemotherapy may be directed to achieve better CR rates. In patients with T-cell-type lymphoma, the CR rate was greater after treatment with THP-COP (51.4%) or THP-COPE (57.7%) compared to treatment with CHOP (19.4%). Pirarubicin may be more useful for T-cell lymphoma than doxorubicin. Because adverse cardiac events were reported only in CHOP, adverse cardiac events might be low in the THP group.

Effects of an immunosuppressant, FK506, on interleukin 1α production by human macrophages and a macrophage-like cell line, U937

A recently discovered immunosuppressive agent, FK506, has been shown to be effective primarily as an inhibitor of T cell responses in vitro, but little is known about its effects on accessory cell function. This study was undertaken to determine the effect of FK506 on interleukin 1 (IL-1) production by macrophages, by using a sensitive and specific enzyme-linked immunosorbent assay. FK506 partially suppressed IL-1 alpha release, from macrophage-like U937 cells stimulated with phorbol myristate acetate and from human monocytes and alveolar macrophages activated with lipopolysaccharide, in a dose-dependent manner. Moreover, it was indicated that FK506 suppressed not only IL-1 release but also IL-1 synthesis itself, by measurement of cell-associated IL-1 alpha of U937 cells. The optimal concentrations of FK506 for suppressing IL-1 alpha did not affect cell viability or proliferation, and were 10- to 100-fold lower than those of cyclosporin A. It is concluded that FK506 affects macrophage physiology, suppressing IL-1 alpha production significantly. Thus, FK506 has the potency to act on non-T cells and the effect on macrophages may play an additional role in preventing graft rejection.

Pirarubicin, a novel derivative of doxorubicin : THP-COP therapy for Non-Hodgkin's lymphoma in the elderly

Pirarubicin (tetrahydropyranyl adriamycin, THP) is a derivative of doxorubicin. Forty-three non-Hodgkins lymphoma (NHL) patients 65 years of age or older were treated with a combination therapy including cyclophosphamide (CPA), vincristine (VCR), prednisone (PSL), and THP (THP-COP). The THP-COP regimen consisted of THP, 30 mg/m2 i.v. on day 1; CPA, 500 mg/m2 i.v. on day 1: VCR, 1.0 mg/m2 i.v. on day 1; and PSL, 60 mg orally for 5 consecutive days. The sequence was repeated at 21− to 28-day intervals for a minimum of four cycles. Of the 43 patients, 13 (30.2%) achieved a complete response (CR) and 21 (48.8%) a partial response (PR). Nine patients (21.0%) had primary treatment failure, which included a minimal response, no change, and progressive disease. Thus, the response rate (CR or PR) was 79.1%. Twenty-six of 29 previously untreated patients (89.7%) achieved a CR or PR, whereas only 8 of 14 previously treated patients (57.1%) did (p < 0.05). Because THP is a derivative of doxorubicin, the results for the eight patients previously treated with doxorubicin are noteworthy: four achieved a CR or PR. No patients had any cardiac toxicity, including congestive heart failure, attributable to THP. Furthermore, four patients who showed a decreased ejection fraction before treatment completed the full course of THP-COP chemotherapy without any progression of the cardiac complication. THP is considered to be active against NHL in the elderly and comparable to doxorubicin in combination chemotherapy.

Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms of CHD

We evaluated a 69-year-old Japanese woman with apolipoprotein (apo) A-I deficiency, high levels of low-density lipoprotein (LDL)-cholesterol, hypertension and impaired glucose tolerance. The patient had corneal opacity, but neither xanthomas, xanthelasma, nor tonsillar hypertrophy. She was not symptomatic for coronary heart disease (CHD), and had normal electrocardiograms at rest and exercise using a cycle ergometer. She had severely reduced levels of high-density lipoprotein (HDL)-cholesterol (0.10-0.18 mmol/l) and no apo A-I (<0.6 mg/dl). LDL-cholesterol and apo B as well as apo E were increased even under treatment with 10 mg pravastatin per day. Gel filtration chromatography revealed that in addition to VLDL and LDL fractions, she had apo A-II rich and apo E rich fractions, which were present in the HDL fraction separated by ultracentrifugation. A cytosine deletion was identified by genomic DNA sequencing of the apo A-I gene of the patient at the third base of codon 184 in the fourth exon, which led to a frame shift mutation and early termination at codon 200. This patient is the oldest among those with apo A-I deficiency reported in the literature, and she had no symptoms of CHD despite the accumulated risk for the disease.

Membranous glomerulonephritis mediated by renal tubular epithelial antigen-antibody complex

Abstract Autologous renal tubular epithelial antigen was demonstrated together with immunoglobulins and β 1 c along the glomerular capillary walls in 4 out of 9 patients with idiopathic membranous glomerulonephritis, and the existence of the clinical entity of glomerulonephritis mediated by tubular epithelial antigen-antibody complexes was suggested. Although no differences in laboratory data were noted between tubular antigen-positive and -negative groups, clinical remission occurred only in the negative group. The fact that no remission was observed in the tubular antigen-positive group may be explained by the continuous supply of the antigen from endogenous sources that maintained the production of immune complexes and subsequent glomerular injury.

Thiopurine S-methyltransferase activity in Japanese subjects: metabolic activity of 6-mercaptopurine 6-methylation in different TPMT genotypes.

BACKGROUND Thiopurine S-methyltransferase (TPMT), which exhibits autosomal codominant polymorphism, plays an important role in the metabolism of thiopurine drugs such as mercaptopurine, thioguanine and azathioprine. Decreased activity of TPMT is associated with severe hematopoietic toxicity after administration of standard doses of these drugs. METHODS We developed a specific high-performance liquid chromatographic (HPLC) assay for measuring 6-methylmercaptopurine (6-MMP) formed from 6-mercaptopurine (6-MP) in red blood cells (RBC) lysates. The assay was used to study the distribution of TPMT activities in 44 healthy Japanese subjects with different TPMT genotypes. RESULTS The TPMT activities in the subjects ranged from 17.9 to 37.1 pmol/h/mgHb. The TPMT activity of one subject with TPMT*1/*3C (17.9 pmol/h/mgHb) was 40% lower than the mean value of TPMT activities in 43 subjects with TPMT*1/*1 (29.6+/-4.3 pmol/h/mgHb). CONCLUSIONS This sensitive and reproducible HPLC assay for determination of TPMT activity in RBC clinical studies has been designed to optimize dosage regimens of thiopurine drugs.

Angiotensin converting enzyme polymorphism is associated with severity of coronary heart disease and serum lipids (total cholesterol and triglycerides levels) in Japanese patients.

BACKGROUND Much past research has concerned the relationship between coronary heart disease and the angiotensin converting enzyme (ACE) genotype, with many lines of evidence demonstrating polymorphism to be an independent risk factor for myocardial infarction. Interestingly, however, association of ACE polymorphism and severity of coronary artery stenosis according to racial background has recently been proposed. OBJECTIVE To clarify the relationship between the ACE genotype and severity of coronary artery stenosis in Japanese patients. METHODS In 36 consecutive patients undergoing coronary catheterization, comparative examination of coronary angiography findings with the ACE genotype was conducted. RESULTS The severity of coronary artery stenosis indeed showed a relationship with the ACE genotype, with more severe coronary artery stenosis associated with the deletion (D) allele (P < 0.05). The serum lipids, total cholesterol and triglycerides levels, were also elevated in patients with the D allele (P < 0.05). CONCLUSION We have provided further evidence that ACE polymorphism is associated with severity of coronary heart disease in a Japanese population. A possible relationship between serum lipids and the ACE genotype is also suggested.

Recombinant human interferon α-2b (rh IFNα-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP)

The efficacy of recombinant human interferon α‐2b (rh IFNα‐2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases.

Psychometric item analysis and validation of the Indonesian version of the Readiness for Interprofessional Learning Scale (RIPLS).

Abstract Complex health care needs in developing countries are stimulating development and implementation of interprofessional education (IPE). To better understand IPE, it is necessary to develop and evaluate an educational program that focuses on interprofessional learning (IPL) in Indonesia. However, no instrument in the Indonesian language has been developed to measure attitudes toward IPL. The aim of this study is to describe the process of a cross-cultural adaptation of the Readiness for Interprofessional Learning Scale (RIPLS) in an Indonesian version including determining its reliability and validity. The study was conducted among students enrolled in medical, nursing, pharmacy and public health courses at the State Islamic University, Jakarta, Indonesia, in 2012. The completed responses to RIPLS were collected from 755 students. The psychometric properties were analyzed by both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). EFA on 18-items revealed three factors accounting for 59.9% of the total variance. CFA resulted in a three-factor model over 16 items with satisfactory reliability (alpha coefficients >0.7), construct validity and acceptable indices of goodness of fit. We conclude that this Indonesian version of RIPLS with a three-factor model over 16 items is a valid tool to measure students’ attitudes toward IPL.

Anti‐tumor Effects of Interleukin‐4 and Interleukin‐5 against Mouse B Cell Lymphoma and Possible Mechanisms of Their Action

We investigated the anti‐tumor effects of recombinant mouse interleukin (IL)‐4 and IL‐5 by using a transplantable B cell lymphoma 38C13 cell line as a model. Daily local administration of either IL‐4 or IL‐5 produced moderate but significant inhibition of the rate of local tumor growth and prolongation of mean survival time (MST) in syngeneic C3H/HeJ mice; these anti‐tumor effects appeared to plateau at low doses. Histopathologic and immuno‐histochemical examination revealed necrotic changes in the cytokine‐treated tumors, associated with infiltration of inflammatory cells such as eosinophils, macrophages, and lymphocytes. The infiltrating lymphocytes were found to be Thy‐1.2+ T cells. To elucidate the importance of T cells, the rate of tumor growth and the MSTs were compared between athymic T cell‐deficient BALB/c nude mice and immunocompetent C3H/HeJ mice. In the nude mice the transplanted tumor grew more rapidly and the MST was shorter than in the normal mice, suggesting a significant contribution of infiltrating T cells in the anti‐tumor effects of the interleukins. Lastly, in vitro, growth inhibition of the 38C13 cells was observed in a dose‐dependent manner at relatively high concentrations of either cytokine. Therefore, we conclude that both IL‐4 and IL‐5 have moderate anti‐tumor effects against 38C13 B cell lymphoma both in vivo and in vitro, and that the observed in vivo anti‐tumor effects are probably mediated both by tumoristatic action of infiltrating cells, such as eosinophils, macrophages and T lymphocytes, and by direct anti‐proliferative action of the recombinant cytokines.