Classic Rett syndrome in a boy with R133C mutation of MECP2

About 80% of female patients with Rett syndrome (RTT) display a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, but most males with MECP2 mutation experience severe fatal encephalopathy or non-specific X-linked mental retardation (XLMR). The existence of male RTT has been extensively discussed. We report herein a boy with classic RTT in a family with a missense mutation in MECP2. The mother exhibited slight mental retardation and was a carrier for R133C. The patient could stand with support at 12-months-old, and stereotypic hand movements appeared at 3-years-old. He became bed-ridden by 8-years-old. The R133C mutation was present in MECP2 without somatic mosaicism. A sister with R133C displayed classic RTT. The R133C mutation has been detected in female patients with classic and preserved speech variant RTT, but not in males with non-specific XLMR. These results suggest that clinical phenotypes caused by DNA mutation in MECP2 are determined by position of the mutation in the gene, and R133 represents a critical amino acid residue in the induction of RTT symptoms in humans.     

Isolation and transplantation of highly purified autologous peripheral CD34<Superscript>+</Superscript> progenitor cells: purging efficacy,hematopoietic reconstitution following high dose chemotherapy in patients with breast cancer: results of a feasibility study in Japan

BACKGROUND: High-dose chemotherapy with autologous stem cell support may have some therapeutic impact on certain groups of the patients with advanced breast cancer(BRCA). Since stem cell contamination by tumor cells might contribute to relapse, development of a tumor cell purging technique would improve the clinical outcome. The present study was undertaken to evaluate the purging efficacy of autologous mobilized CD34+peripheral stem cells in patients with breast cancer (BRCA) in an advanced stage or relapse. METHODS: CD34+cells were selected from autologous peripheral blood stem cells (PBSC) using a clinical scale of magnetic-activated cell sorting system (CliniMACS), followed by high-dose chemotherapy with transplantation of CD34+ selected cells. Amplification of cytokeratin 19 (CK19) and 20 (CK20) gene in leukapheresis products were measured to evaluate the performance of tumor cell elimination. RESULTS: Seven patients were entered into this study. After leukopheresis, 1 patient was dropped form this study due to poor mobilization. Among 6 patient, a total of 8 CD34+ selection was performed. The median purity and recovery rate of the CD34+ cells post selection was 85.1% (range 62.5-98.1%) and 74.2% (range 50.2-90.2%), respectively. After isolation of CD34+cells, the elimination rate in the logarithmic transformation of CK19 was 2.77 log, and that of CK20 were 2.43 log and 2.53 log. In 4 patients, high-dose chemotherapy was performed, followed by the transplantation of the isolated CD34+cells. Rapid neutrophil recovery, as well as platelet recovery was seen with a median time to reach 0.5 x 109/l neutrophils of 9 days(range 8-9), and 20 x 109/l platelets of 12 days (range 10-13). There was no treatment related death and no serious adverse events directly associated with the selection procedure or infusion of selected cells. CONCLUSIONS: The present study demonstrated that the CliniMACS system is a highly effective positive selection method and that a high purging efficacy could be obtained without compromising the hematopoietic reconstitution capacity of the graft in BRCA patients undergoing high-dose chemotherapy.     

Value of Three-Dimensional Helical CT Image-Guided Planning for Made-to-Order Lumpectomy in Breast Cancer Patients

The authors reviewed Niigata Cancer Center Hospital's experience treating patients with lumpectomy to evaluate the utility of three-dimensional helical computed tomography (3D-CT) image-guided made-to-order lumpectomy and determine a positive margin rate. From April 1993 to September 2000, 251 breasts in 248 patients were treated with lumpectomy with a 1 cm macroscopic free margin. In 213 breasts (85%), 3D-CT image-guided made-to-order lumpectomy was performed. Thirty-eight breasts (15%) underwent a lumpectomy without 3D-CT. The lumpectomy specimen was sectioned at 5 mm intervals. Margin status was classified as negative (no invasive or ductal carcinoma in situ (DCIS) within 2 mm from the cut surface) or positive. Positive margins were classified as focally positive (invasive or DCIS transected at the margin within 5 mm or one slide) or massively positive. With 3D-CT image-guided lumpectomy, 21% (45/213) of lesions had a positive margin and 42% (16/38) of lesions without 3D-CT image-guided lumpectomy had a positive margin (p = 0.0055). For lesions with massively positive margins, the rates were 9% (4/45) for 3D-CT image-guided lumpectomy and 38% (6/16) for lumpectomy without 3D-CT (p = 0.0152). 3D-CT image-guided made-to-order lumpectomy decreased the positive surgical margin rate. Among patients with positive margins, those with 3D-CT image-guided lumpectomy have less residual cancer than those without 3D-CT.     

Long-term results of breast-conserving treatment for early-stage breast cancer in Japanese women from multicenter investigation

BACKGROUND: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan. METHOD: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered. RESULTS: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence. CONCLUSION: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.     

Efficacy of cardiac monitoring with echocardiography in adult patients receiving adriamycin

The usefulness of adriamycin is limited by its cardiotoxicity. The purpose of the present study was to examine the usefulness of sequential monitoring of cardiac function of patients undergoing adriamycin therapy. In this cardiologic monitoring procedure a baseline echocardiogram should be obtained when the cumulative adriamycin dose was between 450 mg/m2 and 550 mg/m2. Subsequent echocardiograms should be obtained for every increase of 100 mg/m2 after the baseline study. Adriamycin was withheld when the left ventricular ejection fraction fell below 58%. This protocol was performed in 128 adult patients who received adriamycin at Niigata Cancer Center Hospital between 1995 and 2001. Forty-seven adult patients were able to tolerate more than 550 mg/m2 of adriamycin under this protocol. None of the 128 adult patients developed congestive heart failure when this protocol was used. This cardiologic monitoring procedure can be useful in adult patients receiving adriamycin.     

Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double-blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration-time curve of 2-oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.     

Sources and distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans in sediments from Masan Bay, Korea

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/DFs) were measured in sediments collected from Masan Bay, Korea. Almost all tetra- through octachlorinated PCDDs/DFs were identified, including the 17 2,3,7,8-substituted PCDDs/DFs. Total concentrations of PCDDs/DFs in sediments ranged from 102 to 6,493 pg/g dry weight. Concentrations of 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TeCDD) equivalents (TEQs) in sediments estimated based on I-TEFs were in the range of 1 to 76 pg/g dry weight. Total concentrations of PCDDs/DFs in Masan Bay sediments were comparable to those reported for the Rhine and Humber Rivers on the North Sea, the Housatonic River in the United States, and some rivers and lakes in Japan and the United Kingdom. A spatial gradient of total concentrations of PCDDs/DFs decreased toward the open sea. Two of the 11 sampling sites near the coastal zone contained relatively great concentrations, suggesting the presence of point sources. The homologue composition of PCDFs in sediments from two highly contaminated locations in Masan Bay was correlated with that of commercial polychlorinated biphenyl (PCB) preparations, such as Kanechlors 300, 400, or 500. The wide range of PCDD isomers and greater concentrations of PCDDs than of PCDFs at certain locations suggest that, in addition to technical PCB preparations such as Kanechlors, other sources, like solid waste incineration, uncontrolled trash burning, and pentachlorophenol, have contributed to the contamination.     

Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats.

In this study, we investigated whether components of pomegranate could inhibit CYP3A-mediated drug metabolism. The ability of pomegranate to inhibit the carbamazepine 10,11-epoxidase activity of CYP3A was examined using human liver microsomes, and pomegranate juice was shown to be a potent inhibitor of human CYP3A. Addition of 25 microl (5.0% v/v) of pomegranate juice resulted in almost complete inhibition of the carbamazepine 10,11-epoxidase activity of human CYP3A (1.8%). The inhibition potency of pomegranate juice was similar to that of grapefruit juice. In addition, we investigated the in vivo interaction between pomegranate juice and carbamazepine pharmacokinetics using rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.5-fold higher when pomegranate juice (2 ml) was orally injected 1 h before the oral administration of the carbamazepine (50 mg/kg). On the other hand, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the injection of pomegranate juice. These data suggest that pomegranate juice component(s) impairs the function of enteric but not hepatic CYP3A. Thus, we discovered that a component(s) of pomegranate inhibits the human CYP3A-mediated metabolism of carbamazepine. Furthermore, pomegranate juice alters the carbamazepine pharmacokinetics in rats.