Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis.

BACKGROUND: Postmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis. METHODS: This study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged ≥50 years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of ≥6.18 µkat/L (≥370 U/L), a bone-specific alkaline phosphatase (BAP; bone formation marker) level of ≥0.59 µkat/L (≥35.4 U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of ≥4.2 U/L. RESULTS: A total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed. CONCLUSION: The study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy.

Retrospective evaluation of CO(2) laser conization in pregnant women with carcinoma in situ or microinvasive carcinoma.

BACKGROUND: We evaluated the safety and efficacy of CO(2) laser conization in pregnant women with cervical intraepithelial neoplasia 3/carcinoma in situ (CIN3/CIS) or microinvasive carcinoma (MIC). OBJECTIVES: A total of 49 pregnant women with biopsy-proven CIN3/CIS (30 patients) or MIC (19 patients) were studied. METHODS: Retrospective analysis based on clinical records. RESULTS: Median age and median week of gestation were 31 years (range: 22-39) and 17 weeks (range: 7-33), respectively. The median length of cervix resected by conization, median duration of surgery and median blood loss were 14 mm (range: 5-23), 20 min (range: 7-35) and 78 ml (range: 10-797), respectively. One biopsy-proven CIN3/CIS patient was diagnosed with Federation of Gynecology and Obstetrics (FIGO) Ia2 and 3 biopsy-proven MIC patients were diagnosed with FIGO Ib1 based on conization specimens. A total of 35 patients could be followed until delivery, of which 27 (77.1%) patients delivered transvaginally. Although 8 patients (22.9%) had a cesarean section and 6 patients (17.1%) delivered preterm, no conization-related obstetric complications were observed. CONCLUSION: Since it results in few obstetric complications, CO(2) laser conization within 20 mm of length can be considered a safe procedure for pregnant women.

AST-120 treatment in pre-dialysis period affects the prognosis in patients on hemodialysis.

BACKGROUND/AIMS: An oral adsorbent, AST-120, has been shown to retard the deterioration of renal function in patients with chronic kidney disease (CKD) by decreasing serum nephrotoxic substances such as indoxyl sulfate. Recent studies have suggested that a high level of serum indoxyl sulfate may be one of the mechanisms underlying the progression of atherosclerotic lesion, which is the leading cause of cardiovascular event or death in dialysis patients. In this study, we examined retrospectively whether AST-120 given to patients in the pre-dialysis period influences the prognosis after the initiation of dialysis. METHODS: One hundred and ninety-two CKD patients on dialysis were studied. The survival and causes of death after the initiation of dialysis were compared between patients who were administrated AST-120 (AST-120 group, n = 101) and those not administrated AST-120 (non-AST-120 group, n = 91) prior to the initiation of dialysis. RESULTS: The five-year survival rate was 72.6% in the AST-120 group and 52.6% in the non-AST-120 group, and was significantly higher in the AST-120 group (p = 0.018). The risk of death was increased 1.91-fold in the non-AST-120 group. However, no difference in the causes of death was observed between two groups. CONCLUSION: This study suggests that AST-120 given prior to the initiation of dialysis improves the prognosis of CKD patients under dialysis, although there is no association between AST-120 treatment and death caused by cardiovascular diseases such as heart failure, myocardial infarction, and cerebral hemorrhage. Further studies are needed to elucidate the effect of AST-120 on cardiovascular events and the prognosis in dialysis patients.

Benign esophageal schwannoma compressing the trachea in pregnancy.

A rare case of esophageal schwannoma compressing the trachea in pregnancy is presented. A 29-year-old pregnant woman was hospitalized due to severe dyspnea. Imaging studies revealed a homogeneous tumor (8 cm in diameter) in the posterior mediastinum with compression of the lower trachea. After an uneventful cesarean section, the patient underwent a mini-axillary thoracotomy with video-assisted thoracic surgery. The tumor arose from within the muscular layers of the esophagus and was enucleated by gentle blunt dissection. Pathologic and immunohistochemical examinations revealed a benign esophageal schwannoma.

Roles of chymase in stenosis occurring after polytetrafluoroethylene graft implantations.

Chymase is an important enzyme for the generation of angiotensin (Ang) II and in the activation of transforming growth factor (TGF)-beta1. Therefore, chymase may be involved in the hemodialysis access dysfunction, which is caused by intimal hyperplasia that occurs after polytetrafluoroethylene (PTFE) graft implantations. Bilateral U-shaped PTFE grafts were placed between the femoral vein and artery in dogs. Chymase inhibitor (NK3201, 1 mg/kg per day, p.o.) treatments were initiated 3 days before the operation. After the implantation, the stenosis by neointima proliferation was most frequently observed in the venous side of the PTFE grafts. In the hyperplastic neointima, myofibroblasts were the main cellular components. On the other hand, fibroblasts only occupied cellular components in a much smaller proportion in the neointima. However, these cells seem to be rich in the properties of proliferation and migration. After PTFE graft implantations, extensive accumulations of chymase-positive mast cells were found mainly in the tissue surrounding the grafts. The Ang II- and TGF-beta-positive cells were found in an adjacent section that was in close proximity to the chymase-positive cells. In contrast, the AT(1) receptors, as well as TGF-beta type II receptors, were expressed either in the neointima or in the outside adventitia of the PTFE grafts. Chymase inhibitor treatment resulted in a reduction of chymase, Ang II and TGF-beta1 expression, leading to a significant inhibition of neointimal formation. These findings indicating that an increase of chymase via promoting Ang II and TGF-beta1 generation plays a pivotal role in the neointimal formation after the implantation of PTFE grafts and also suggesting that chymase inhibition may be a new strategy that can be used to prevent PTFE graft dysfunctions in clinical settings.

Acute rejection of allografted CTL-susceptible leukemia cells from perforin/Fas ligand double-deficient mice.

The generation of knockout mice demonstrated that CD4(+), but not CD8(+), T cells were essential for the rejection of allografted skin or heart, presumably because these targets were CTL resistant. In the case of CTL-susceptible targets (e.g., P815 mastocytoma cells and EL-4 or RLmale1 T lymphoma cells), however, it is assumed that the CTL is the effector cell responsible for allograft rejection and that perforin and Fas ligand (FasL) pathways are the killing mechanisms. In the present study, we examined the role of these cytotoxic molecules in the rejection of i.p. allografted CTL-susceptible leukemia cells. Unexpectedly, the allografted leukemia cells were acutely rejected from gld (a mutation of FasL), perforin(-/-), or double-deficient mice. The peritoneal exudate cells from gld or normal mice showed T cell-, TCRalphabeta-, and perforin-dependent cytotoxic activity against the allograft, whereas the exudate cells from perforin(-/-) mice exhibited almost full cytotoxic activity in the presence of Fas-Fc. Furthermore, the infiltrates from double-deficient mice showed a high cytotoxic activity against the allografted cells even in the presence of anti-TCRalphabeta Ab or in the absence of T cells. The cytotoxic cells appeared to be macrophages, because they were Mac-1(+) mononuclear cells with a kidney- or horseshoe-shaped nucleus and because the cytotoxic activity was completely suppressed by the addition of N(G)-monomethyl-l-arginine, an inhibitor of inducible NO synthase. These results indicate that macrophages are ready and available to kill CTL-susceptible allografts when CTLs lack both perforin and FasL molecules.

A change in promoter methylation of hMLH1 is a cause of acquired resistance to platinum-based chemotherapy in epithelial ovarian cancer.

BACKGROUND: Acquired resistance to platinum-based chemotherapy (Pt-chemo) is a major problem for improving the prognosis for patients with advanced epithelial ovarian cancer (EOC). However, the molecular mechanism of acquired resistance to Pt-chemo is not well understood. MATERIALS AND METHODS: hMLH1 promoter methylation (hMLH1 MET) and hMLH1 protein expression was examined in 36 paired samples of primary and secondary resected tumors by methylation-specific polymerase chain reaction (PCR). RESULTS: No primary tumors exhibited hMLH1 MET, while 56.3% of secondary tumors showed hMLH1 MET. Moreover, no significant correlation was observed between hMLH1 MET and histological subtype, while hMLH1 MET was significantly greater (p < 0.001) in partially responsive secondary tumors compared with no change or progressive disease, and hMLH1 MET also occurred more frequently (p = 0.059) in tumors treated with four or more courses of Pt-chemo. CONCLUSION: A change in hMLH1 MET is a major molecular cause of acquired resistance to Pt-chemo in EOC.

AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases.

The effects of an oral adsorbent, AST-120, in chronic kidney disease (CKD) patients was evaluated by the 24-month dialysis-free rate and 50% dialysis-free period. This study retrospectively analyzed 193 patients admitted to the Osaka Medical College Hospital between January 1994 and December 2001 because of CKD and who later started dialysis. The propensity score on multiple factors was used to match two groups of patients (AST-120 group, n = 78; non-AST-120 group, n = 78). Then, the proportion of patients remaining dialysis-free and the 50% dialysis-free period during the 24 months after starting treatment with or without AST-120 were analyzed. The impact of AST-120 on the risk of dialysis initiation was also determined by multivariate analysis. There were no significant differences in the clinical background and laboratory values after matching the two groups using the propensity score. The 50% dialysis-free period was significantly prolonged in the AST-120 group compared to the non-AST-120 group for all patients analyzed, as well as for the subgroup with diabetic or non-diabetic renal disease. When AST-120 treatment was started at a serum creatinine level below 3 mg/dL, the dialysis-free period was longer than 24 months in the AST-120 group, compared with 16.2 months in the non-AST-120 group. The 24-month dialysis-free rate was higher in the AST-120 group in every patient category. The risk of dialysis initiation was increased 3.48-fold in patients who were not administered AST-120. These results show that AST-120 delays the initiation of dialysis in CKD patients. Thus, AST-120 is an effective supplementary therapy to prevent the initiation of dialysis in CKD patients.

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients.

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.

Infiltration of H-2d-specific cytotoxic macrophage with unique morphology into rejection site of allografted meth A (H-2d) tumor cells in C57BL/6 (H-2b) mice.

It is assumed that CD8(+) cytotoxic T lymphocytes (CTLs) mediate direct lysis of allografts and that their growth, differentiation, and activation are dependent upon cytokine production by CD4(+) helper T lymphocytes. In the present study, the effector cells responsible for the rejection of i.p. allografted, CTL-resistant Meth A tumor cells from C57BL/6 mice were characterized. The cytotoxic activity was associated exclusively with peritoneal exudate cells and not with the cells in lymphoid organs or blood. On day 8, when the cytotoxic activity reached a peak, 3 types of cells (i.e., lymphocytes, granulocytes, and macrophages) infiltrated into the rejection site; and allograft-induced macrophages (AIM) were cytotoxic against the allograft. Bacterially-elicited macrophages also exhibited cytotoxic activity (approximately 1/2 of that of AIM) against Meth A cells, whereas the cytotoxic activity of AIM against these cells but not that of bacterially-elicited macrophages was completely inhibited by the addition of donor (H-2(d))-type lymphoblasts, suggesting H-2(d)-specific cytotoxicity of AIM against Meth A cells. In contrast, resident macrophages were inactive toward Meth A cells. Morphologically, the three-dimensional appearance of AIM showed them to be unique large elongated cells having radiating peripheral filopodia and long cord-like extensions arising from their cytoplasmic surfaces. The ultrastructural examination of AIM revealed free ribosomes in their cytoplasm, which was often deformed by numerous large digestive vacuoles. These results indicate that AIM are the H-2(d)-specific effector cells for allografted Meth A cells and are a more fully activated macrophage with unique morphological features.

Hypoxia inducible factor 1-alpha expression as a factor predictive of efficacy of taxane/platinum chemotherapy in advanced primary epithelial ovarian cancer.

To investigate the impact on survival of HIF 1-alpha expression on primary advanced epithelial ovarian cancer (EOC), we examined the correlations between prognosis and HIF 1-alpha expression by Western blot analysis in 52 cases of stage III/IV EOC. HIF 1-alpha expression was confirmed in 36 cases (69.2%) of EOC, and HIF 1-alpha-expressing tumors had a significantly higher rate of response (p<0.01) to postoperative paclitaxel/carboplatin combination chemotherapy (TC) than tumors without HIF1-alpha expression. Moreover, patients with HIF 1-alpha-expressing tumors with suboptimal resection of stage III/IV tumors indicated for postoperative TC exhibited significantly better survival (p<0.01).

Microsatellite status and immunohistochemical features of ovarian clear-cell carcinoma.

BACKGROUND: Ovarian clear-cell carcinoma (OCC) is known to have a poor prognosis and selected genetic features of OCC remain unknown. We investigated microsatellite instability (MSI) and the expression of the DNA mismatch repair-related protein, p53. MATERIALS AND METHODS: MSI was examined by polymerase chain reaction using mono-, di-, tri- and tetranucleotide repeat markers, and hMSH2, hMLH1, hMSH6, MSH3 and p53 were determined immunohistochemically in 24 cases of OCC. RESULTS: A total of 9 (37.5%) cases exhibited MSI. Two cases (8.3%) exhibited MSI-H in mononucleotide repeat loci with the negative expression of hMLH1, while another 7 cases (29.2%) exhibited selected trinucloetide repeat MSI (MSI-TR). Of these MSI-TR cases, 4 cases (57.1%) were determined to be negative for MSH3, while hMSH2, hMSH6, MSH3 and p53 expressions were normal. CONCLUSION: Our findings suggest that MSI-TR would be a feature indicating the microsatellite status in OCC, and that the loss of MSH3 expression may promote MSI-TR.

Preoperative administration of FTY720 prolonged renal allograft survival.

BACKGROUND: FTY729 is an immunomodulator obtained by chemical modification of Myriocin(ISI-1) which exists in the culture filtrate of an ascomycete, Isaria sinclairii. It has been reported that postoperative administration of FTY720 prolonged survival of various kinds of transplanted organs. In the present study, we evaluated the effect of 2-day preoperative administration of FTY 720 on graft survival. MATERIALS AND METHODS: We used a rat renal transplantation model in which Wistar King Aptekman Hokkaido (WKAH, RT1K) served as the organ donor and Lewis (LEW, RTl) as the recipient. FTY720 was given to the recipients consecutively 2 days (day-2, day-1) before transplantation at the doses of 1, 3 or 5 mg/kg/day. Renal allograft survivals, hematological parameters of recipient blood and phenotypic analysis of recipient splenic cells and graft infiltrate were evaluated. RESULTS: Consecutive 2-day preoperative oral administration of FTY 720 at the doses of 1, 3 or 5 mg/kg/day significantly prolonged WKAH allograft survivals compared with those of the untreated recipients. The number of peripheral blood lymphocytes was markedly decreased in the recipients treated with FTY720 at the doses of 3 mg/kg/day or 5 mg/kg/day on the 5th postoperative day. Preoperative FTY 720 administration significantly decreased the number of CD4 positive cells and the percentage of interleukin 2 receptor (IL-2 R) positive cells infiltrating both spleen and allograft at the dose of 3 mg/kg/day or 5 mg/kg/day. CONCLUSION: FTY 720 could act as a safe and potent immunomodulator by decreasing the number of peripheral lymphocytes, especially CD4 positive cells and IL-2R positive cells when it is given to the recipient preoperatively.

Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs.

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-beta1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 +/- 25%). The chymase- and TGF-beta-positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II-, AT(1) receptor-, and TGF-beta-positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 +/- 9%, P < 0.001; region B, 54 +/- 14%, P < 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell-derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.

Evaluation of weekly low-dose paclitaxel and carboplatin treatment for patients with platinum-sensitive relapsed ovarian cancer.

OBJECTIVE: Although paclitaxel and carboplatin therapy (TC) is an established effective standard regimen for patients with ovarian cancer, both treatment delay for hematologic toxicity and discontinuation of treatment due to neurotoxicity have occasionally been reported. To achieve therapeutic density, we evaluated the usefulness of weekly low-dose TC therapy (WTC) in patients with platinum-sensitive (median PFI was 11.4 +/- 2.7 months) recurrent epithelial ovarian cancer. METHODS: A total of 25 patients were treated with paclitaxel at 60 mg/m(2) and carboplatin at AUC = 2 using 3 weekly courses with a 1-week break schedule. Eighteen patients had assessable tumors for response, and the other seven patients were evaluated by CA-125-based response. All of the patients were assessable for toxicity. RESULTS: The overall response rate (OR) based on WHO criteria was 84.2% (95% CI; 0.65-0.98), including nine complete responses (CR); OR based on CA-125 was 85.7% (95% CI; 0.42-0.99), including 3 CR. The total response rate was 88.0% (95% C.I.; 0.68-0.97). The median progression-free survival of the patients was 13.5 months during the mean follow-up period of 21.9 +/- 9.2 months. No patients had grade 1 or higher thrombocytopenia, and although 44% of the patients developed neurotoxicity, all cases remained grade 1. Treatment delay of over 7 days due to toxicity was observed in only two patients (16.0%) and in six cycles (1.3%) in a total of 451 cycles. CONCLUSION: WTC combination, as used in this study, produced a high response rate with acceptable toxicity, and the optimal combination in a weekly regimen remains to be determined.

[Complete avulsion of ureter caused by abdominal blunt injury: a case report].

A 21-year-old woman who had been injured in a traffic accident appeared with abdominal pain and macroscopic hematuria. Computed tomography (CT) performed 6 hours after the injury showed extravasation of contrast medium in the right retroperitoneal space. Retrograde pyelography (RP) showed the interruption of right ureter at the site of ureteropelvic junction. We performed an abdominal operation 15 hours after the injury under the diagnosis of right ureteral avulsion. We observed a completely separated right ureter at the ureteropelvic junction, and performed an end to end anastomosis. The patient was discharged three weeks after surgery, and has not had any problems for three years.

Prevalence of Helicobacter pylori antibodies in long-term dialysis patients.

BACKGROUND: Helicobacter pylori has been reported to play an important role in the development of gastritis and gastric ulcer. METHODS: This study included 168 patients with end-stage renal disease (ESRD; 30 non-dialysis patients, 138 patients receiving dialysis; mean duration of dialysis: 57.3 +/- 61.7 months) and 138 control volunteers. We investigated the prevalence of H. pylori infection by measuring H. pylori antibody (IgG) levels. RESULTS: The prevalence of H. pylori infection was 62.3% in the control group, 53.3% in the non-dialysis patients, and 36.9% in the dialysis patients. The percentage decreased with a reduction of renal function. In addition, the proportion of H. pylori-positive patients decreased with the duration of dialysis, and the antibody titre was also significantly decreased. There was no association between long-term oral administration of H2RA (H2 receptor antagonist) and the incidence of H. pylori infection. CONCLUSION: Among dialysis patients, the proportion of H. pylori-positive patients was low. An aetiological factor other than H2RA agents was suggested. Renal failure or dialysis treatment may influence H. pylori infection.

Platelet-derived endothelial cell growth factor predicts of progression and recurrence in primary epithelial ovarian cancer.

We investigated the clinical significance of platelet-derived endothelial cell growth factor (PD-ECGF) as measured by enzyme-linked immunosorbent assay in primary epithelial ovarian cancers (EOC), finding amounts to be significantly greater in cancers than in normal ovarian tissue (p<0.01). PD-ECGF was significantly more abundant in stages III and IV than in lower stages (p<0.05), and also was high in tumors with macroscopically evident metastases in the peritoneal cavity (p<0.05), or pelvic (p<0.01) or paraaortic (p<0.01) lymph node metastases. Further, PD-ECGF was significantly lower in mucinous than in serous adenocarcinomas (p<0.05). No significant correlation was seen between PD-ECGF and histologic grade, maximum intraperitoneal metastatic tumor diameter (<2 vs.>2 cm), or presence of demonstrable malignant cells in peritoneal fluid. In stage III disease, PD-ECGF exhibited significant correlation with recurrence (p<0.05). Our data suggested that results of PD-ECGF assays in primary tumors can predict progression and recurrence of EOC.