Serum thymidine kinase,a possible marker for monitoring the effect of bone marrow transplant treatment in early recovery phase

We measured serum thymidine kinase (TK) activity with a radioenzyme assay system employing [I-125]-iododeoxyuridine as the tracer on serial specimens from five bone marrow transplant (BMT) patients before and after transplantation. The serum level of TK activity in the 4 patients with effective BMT treatment ranged from 3.0 to 16.9 U/L (mean, 7.80 U/L) before transplantation and from 27.3 to 236.1 U/L (mean, 82.95 U/L) after the BMT treatment. Mean serum TK activity increased 13.17-fold (range, 1.68 to 29.14-fold). In contrast, the activity in the patient with ineffective BMT treatment was not significantly different during, before, or after BMT treatment. In addition, serum TK activity in BMT patients was well correlated with the change in the number of leukocytes before and after BMT treatment [r = +0.709 (p less than 0.01), y = 0.012 x +0.87]. We conclude that the determination of serum TK activity in BMT patients is very useful in monitoring the course of bone marrow transplantation in the early recovery phase.     

Phase II study of etoposide (VP-16) in the form of intravenous injection for malignant lymphomas and acute leukemias: Hanshin Cooperative Study Group for Hematological Disorders

Twenty patients with malignant lymphomas and 12 with acute leukemias were treated with intravenous administration of etoposide, 60-100 mg/m2/day for five days, repeated for three to four weeks. Eighteen cases of malignant lymphoma and nine of acute leukemia were evaluable. CR was achieved in three cases (16.7%) and PR in four cases (22.2%) of malignant lymphoma. Although CR was not achieved in any patients with acute leukemia, and PR was in three (33.3%), it was found that etoposide was most effective for the patients with the M4 or M5 subtype in the FAB classification. The most serious adverse effect of the drug was leukopenia in patients with lymphoma. In three patients (30.0%), the leukocyte count was lower than 1,000/mm3. Gastrointestinal complications, such as anorexia, nausea, vomiting and diarrhea occurred in 60.7% of all patients, but were not serious. Alopecia was observed in 73.1%. Intravenous administration of etoposide was apparently effective for the patients with malignant lymphoma of the diffuse mixed type, and this efficacy found in our study was the same as that for oral administration of etoposide reported by us previously.     

Nondomain biopolymers: Flexible molecular strategies to acquire biological functions

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of “nondomain biomolecules,” whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment.     

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

Summary Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m²) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 g/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 g/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 g/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.     

Guidelines for treatment of ulcerative colitis in children

This paper introduces the guidelines for treatment of ulcerative colitis in children, created by the working group of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (Chair: Yuichiro Yamashiro) and the Japanese Society for Pediatric Inflammatory Bowel Disease (IBD) (Chair: Akio Kobayashi). The ideas of the working group, with regard to the fundamental differences in medical treatment between children and adults, included: (1) for children, intensive medical treatment including appropriate systemic management is important during the acute phase of illness. (2) Treatment with steroids, which can cause growth disturbances, should not be continued for long periods of time. (3) Pulsed steroid therapy, selective removal of blood cells, and intravenous infusion of cyclosporin should be included in the therapeutic option for severe and fluminant cases.     

Sarcoma-like tumor originating from oligodendroglioma

We present a case of sarcoma occurring at a site of resected oligodendroglioma without preceding radiotherapy or chemotherapy. Oligosarcoma occurring at sites of resected oligodendroglioma or anaplastic oligodendroglioma with sarcomatous components are rare. Although meningioma or sarcoma-like lesions are sometimes reported after glioma-targeted radiotherapy, those without preceding radiotherapy are quite rare. Moreover, cases of sarcoma without oligodendroglial components occurring at a site of resected oligodendroglioma have never been reported. In this case, fluorescent in situ hybridization analysis revealed 1p/19q co-deletion in both the first tumor and second tumors. Additionally, immunohistochemistry revealed mutated isocitrate dehydrogenase 1 in both tumors. Taken together, these findings suggest a monoclonal tumor origin. Consequently, this case may indicate a new mechanism of development of sarcomatous lesions occurring at the site of a resected glioma.     

The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.     

Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients

A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P < 0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.