Does presence of prostate cancer affect serum testosterone levels in clinically localized prostate cancer patients?

The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03+/-1.50 ng ml(-1)) than in patients with nonorgan-confined cancer (pT3; 3.42+/-1.06 ng ml(-1); P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60+/-1.90 ng ml(-1)) was significantly elevated compared to preoperative level (3.89+/-1.43 ng ml(-1); P<0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86+/-3.64 ng ml(-1)) compared to preoperative level (5.11+/-2.47 ng ml(-1); P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic-pituitary axis.

Genetic changes in pT2 and pT3 prostate cancer detected by comparative genomic hybridization.

Prostate-specific antigen (PSA) screening has led to a remarkable increase in prostate cancer cases undergoing operative therapy. Over half of patients with locally advanced cancer (>or=pT3) develop rising PSA levels (biochemical failure) within 10 years. It is very difficult to predict which patients will progress rapidly to advanced disease following biochemical failure (BF). Therefore, a more useful prognostic factor is needed to suggest the most appropriate therapies for each patient. To determine chromosomal aberrations, we examined 30 patients with stage pT2 or pT3 primary prostate adenocarcinomas and no metastases (pN0M0) by comparative genomic hybridization (CGH). Laser capture microdissection (LCM) was used to gather cancer cells from frozen prostate specimens. Common chromosomal alterations included losses on 2q23-24, 4q26-28, 6q14-22, 8p12-22 and 13q21-31, as well as gains on 1p32-36, 6p21 and 17q21-22. Losses at 8p12-22 and 13q21-31 were observed more frequently in pT3 than pT2 tumors (P<0.05 and P<0.01, respectively). Losses at 8p12-22 were more frequent in tumors with BF (P<0.05), and those at 13q12-21 were more frequent in tumors with Gleason score (GS) 7 or more than lower GS (P<0.05). These findings suggest that losses of 8p12-22 and 13q21-31 are important determinants of prostate cancer progression.

Clinical significance of pulmonary metastases in stage D2 prostate cancer patients.

Several prognostic factors such as the extent of bone metastases (EOD) in advanced prostate cancer (PCa) have been reported. Metastasis of the lung is rarely a significant clinical factor in the management of prostate cancer. The present study evaluates the clinical significance of lung metastases. We retrospectively reviewed the PCa database to identify patients with pulmonary metastases at initial diagnosis. The medical records of the patients were examined with respect to age, histologic grade, EOD score, marker response to endocrine therapy and clinical outcome. We then compared several potential clinical factors between patients with and without pulmonary metastases. Next, we retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with particular focus upon metastatic profiles. A comparative study of stage D(2) patients with (n=20) and without (n=77) pulmonary metastases found no significant differences in EOD score, performance status, marker response and survival. Only tumor grade was better in the group with, than without pulmonary metastases (P=0.0120, chi-square analysis). In the series of autopsies, we found pulmonary metastases in 38 cases (63%), following metastases of the bone (57 cases, 95%) and lymph nodes (52 cases, 87%). A retrospective analysis of survival showed that patients with bone or lymph node metastases had a positive relative risk. In contrast, lung metastasis could be a positive prognostic indicator, although the findings were not statistically significant. These data suggest that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.

Laparoscopic adrenalectomy for pheochromocytoma.

We reviewed 10 cases of laparoscopic adrenalectomy for pheochromocytoma and compared the results with those of a recent series of 11 patients who underwent open adrenalectomy. Of the 10 cases, the tumor was removed successfully in all cases except in one case with laparoscopy that required open laparotomy. A pair of laparoscopic coagulating scissors was utilized in all except the initial two cases. In the laparoscopy group (excluding the initial two cases and the case that required conversion to open surgery), mean operative time and blood loss were 145 min and 55 ml, respectively. No significant difference was observed in mean operative time between the laparoscopy group and the open surgery group (165 min for open surgery). Mean blood loss of the laparoscopy group was significantly less than that of the open surgery group (330 ml for open surgery, P = 0.01). Mean intervals to first ambulation and oral intake, and postoperative hospital stay of the laparoscopy group, tended to be less than those of the open surgery group, although no statistical significance was observed (2.3 versus 3.2 d, 2.9 versus 3.6 d, and 12 versus 14 d, respectively). We conclude that laparoscopic adrenalectomy for pheochromocytoma is equally effective and less invasive than open adrenalectomy and should be considered the therapy of choice even for pheochromocytoma.

Asymmetric hydrogenation of enamides with Rh-BisP and Rh-miniPHOS catalysts. scope, limitations, and mechanism.

The asymmetric hydrogenation of aryl- and alkyl-substituted enamides catalyzed by Rh-BisP complex affords optically active amides with very high ee values. The Rh-MiniPHOS catalyst gives somewhat less satisfactory results. Hydrogenation of the aryl-substituted enamides with (S,S)-BisP-Rh catalyst gives R-amides, whereas the t-Bu- and 1-adamantyl-substituted enamides give S-products with 99% ee. Reaction of [Rh(BisP)(CD(3)OD)(2)]BF(4) (11) with CH(2)=C(C(6)H(5))NHCOCH(3) (5) gives two diastereomers of the catalyst-substrate complex (12a,b), which interconvert reversibly by both intra- and intermolecular pathways as shown by EXSY data. Only one isomer in equilibrium with solvate complex 11 was detected for each of the catalyst-substrate complexes 17 and 18 obtained from CH(2)=C(t-Bu)NHCOCH(3) (6) or CH(2)=C(1-adamantyl)NHCOCH(3) (7). Hydrogenation of these equilibrium mixtures at -100 degrees C gave monohydride intermediates 19 and 20, respectively. In these monohydrides the Rh atom is bound to the beta-carbon. A new effect of the significant decrease of ee was found for the asymmetric hydrogenation of CH(2)=C(C(6)H(4)OCH(3)-o)NHCOCH(3) (21), when H(2) was substituted for HD or D(2).

Stereospecific reduction of phosphine oxides to phosphines by the use of a methylation reagent and lithium aluminum hydride.

[figure: see text] Various phosphine oxides are efficiently reduced by the use of a methylation reagent and lithium aluminum hydride. Optically active P-chirogenic phosphine oxides are also reduced with inversion of configuration at phosphorus atom by treatment with methyl triflate, followed by reaction with LiAlH4.

Highly enantioselective hydrogenation of alpha-dehydroamino acids by rhodium complexes with new unsymmetric P-chirogenic bisphosphine ligands.

[figure: see text] New rhodium catalysts with unsymmetric P-chirogenic bis(phosphino)ethanes, BisP*-Rh, exhibited very high enantioselectivity (98-99%) in the hydrogenation of alpha-dehydroamino acid derivatives. Such high enantioselectivity should result from the asymmetric environment around the Rh atom, as was shown in the molecular structure of the catalyst analyzed by X-rays. The asymmetry can be controlled by the combination of the alkyl groups on the two phosphorus atoms.

Highly enantioselective hydrogenation of (E)-beta-(acylamino)acrylates catalyzed by Rh(i)-complexes of electron-rich P-chirogenic diphosphines.

Excellent enantioselectivities up to 99.7% were achieved in the hydrogenation of (E)-beta-(acylamino)acrylates by the use of Rh(I)-complexes of electron-rich diphosphines, t-Bu-BisP and t-Bu-MiniPHOS. Low-temperature NMR experiments testify that monohydrides with beta-carbon atom of the substrate bound to rhodium are involved in the catalytic cycle.

Constitution of Grignard reagent RMgCl in tetrahydrofuran.

The constitution of Grignard reagent, RMgCl (R = Me, tBu, Ph or benzyl), was investigated in the solid state by means of X-ray crystallography and in THF by coldspray ionization mass spectrometry (CSI-MS). Three types of crystal structures, (a) [Mg2(mu-Cl3)(THF)6](+)*[RMgCl2(THF)](-), (b) R2Mg4Cl6(THF)6, and (c) [2Mg2(mu-Cl3)(THF)6](+)*[R4Mg2Cl2]2-, were identified, and MeMg2(mu-Cl3)(THF)4-6 were detected as major species of MeMgCl in solution.

Pretreatment serum level of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer.

Pretreatment serum level of testosterone (T) is a potential prognostic factor for prostate cancer. However, T levels in Japanese prostate cancer patients are unknown to date. To evaluate the clinical significance of pretreatment serum T level in such patients, serum T level was analyzed in relation to several clinical factors in a total of 130 patients with various stages of prostate cancer, 74 of whom had metastatic disease (stage D2) and received endocrine therapy as first-line treatment. The mean pretreatment T level in patients with non-metastatic prostate cancer (stages B + C) was significantly lower than that in stage D2 patients (B + C: 4.05 +/- 2.01 ng/ml; D2: 4.85 +/- 2.18 ng/ml, p = 0.0344). On the other hand, the mean serum level of T was higher in stage D2 patients who showed good response to endocrine therapy (CR: 5.42 +/- 1.55 ng/ml; non-CR: 4.30 +/- 2.63 ng/ml, p = 0.0320). When the 74 stage D2 patients were divided into high and low T level groups according to the median value, those patients with a high T level had significantly better cause-specific and progression-free survival. Multivariate analysis demonstrated that extent of bone metastases (EOD) grade, pretreatment serum T level and tumor marker response to endocrine therapy were significant predictors for progression-free survival. In conclusion, a higher pretreatment T level appears to be predictive of the marker response to endocrine therapy, showing positive prognostic value and indicating good prognosis in patients at the metastatic stage. However, a higher T level was also associated with stage progression of this disease.

Synthesis of a new enantiomerically pure P-chiral phosphine and its use in probing the mechanism of the Mitsunobu reaction.

A new enantiomerically pure P-chiral phosphine, (S)-cyclohexylmethyl- (1-naphthyl)phosphine (1) was prepared by phosphine-borane methodology and used in a mechanistic study of the Mitsunobu reaction. Enantiomerically enriched (S)-cyclo- hexylmethyl(1-naphtyl)phosphine oxide (8) is obtained if the reaction proceeds through the phosphonium salt 4, whereas the intermediate dialkoxyphosphorane 5 leads to racemic phosphine oxide 8. The results of the experiments including the variation of the reaction conditions and the natures of alcohol and carboxylic acid used in the Mitsunobu reaction prove the competition of two alternative mechanisms (reaction via 4 or 5) on the second stage of the Mitsunobu reaction.

A novel alpha-helix-liked metallohelicate series and their structural adjustments for the isomorphous substitution.

A novel metallohelical motif is well designed and synthesized by mimicking the alpha-helical fold structure of protein. The 1D helical structures of [Cd(CH2(COO)2)(SC(NH2)2)2]n (I) and [Zn(CH2(COO)2) (SC(NH2)2)2]n (II) are primarily induced and stabilized by the multiple long-range intrahelix hydrogen bonds. Malonate dianion acts as a bidentate ligand coordinated with metal ions to form the backbone of the helix, and thiourea molecules that bend into the helical turn are involved in the intrahelix hydrogen-bond system. The metal ion occupations in the helix of I and II can be freely substituted by simply controlling the initial ratio of those two metal ions. Single crystals of three mixed metal ion complexes of [Cd0.77Zn0.23(CH2(COO)2)(SC(NH2)2)2]n (III), [Cd0.50Zn0.50(CH2(COO)2)(SC(NH2)2)2]n (IV), and [Cd0.21Zn0.79(CH2(COO)2)(SC(NH2)2)2]n (V) were synthesized from systems with an initial Cd/Zn mole ratio of 1:1 for III, 1:2 for IV, and 1:8 for V. They are isomorphous as confirmed by X-ray characterization. When the metal ion is substituted, the multiple intrahelix hydrogen interaction motifs of the coordination polymer structure are self-adjusted to sustain their 1D helical motifs.

[Intra-arterial chemotherapy for invasive bladder cancer].

Between July 1993 and May 1999, 36 patients with invasive bladder cancer were treated with intra-arterial chemotherapy using cisplatin and pirarubicin, and their treatment outcome was evaluated. Clinical CR was obtained in 18 patients, PR in 13, and NC in 5, for an overall response rate of 86%. The median follow-up for evaluating patients was 24 months (2-70 months). The bladder was preserved in 13 of 18 patients showing CR and in 4 of 13 patients showing PR. The 5-year cause-specific survival rate for the 36 patients was 56%. The grade factor did not effect the survival rate significantly. Compared with stage T2, stage T3 yielded a significantly poor prognosis, especially with grade 3. Intra-arterial chemotherapy was confirmed useful as a regional treatment, but not sufficient as a systemic treatment. Thus the selection of patients for this therapy was considered to require exact staging and assessment of the effectiveness.

Metanephric adenoma of the kidney.

BACKGROUND: Metanephric adenoma is a rare renal neoplasm that is histologically and clinically unique. We found this neoplasm in a 62-year-old female, whose renal tumor was incidentally detected on abdominal ultrasound examination. METHODS/RESULTS: Ultrasound, computed tomography and magnetic resonance imaging were compatible with those of renal cell carcinoma. With a diagnosis of renal cell carcinoma, right partial nephrectomy was performed. This tumor showed histologic similarity to developing metanephric tubular epithelium. It was composed of uniformly small epithelial cells, which formed tubules. CONCLUSIONS: The patient has been well and healthy for 20 months after surgery. The unique features of metanephric adenoma should be clinically and pathologically recognized because of its invariably benign course.

Beneficial effects of TDN-345, a novel Ca2+ antagonist, on ischemic brain injury and cerebral glucose metabolism in experimental animal models with cerebrovascular lesions.

The effects of TDN-345 on mortality and ischemic neurological deficit following transient global cerebral ischemia in Mongolian gerbils and also the rate of local cerebral glucose utilization (LCGU) in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions were investigated. In Mongolian gerbils, ischemia was produced by clamping the bilateral common carotid arteries for 15 min. TDN-345 (0.1-1.0 mg/kg) dose-dependently decreased the mortality and ischemic neurological deficit score when administered orally twice, 60 min before ischemia and 90 min after recirculation. Additionally, TDN-345 (0.2 or 1.0 mg/kg, p.o. once daily for 3 weeks after the onset of stroke) decreased the mortality and recurrence of stroke in SHRSP. To determine the site of action of TDN-345 in the brain, the rate of LCGU in various brain regions in SHRSP with stroke was examined using a [14C]2-deoxy-D-glucose method. The rate of LCGU decreased significantly in all the brain regions in SHRSP with stroke compared with Wistar-Kyoto (WKY) control rats, whereas the reduction in the rate of LCGU in SHRSP with stroke was prevented by TDN-345 treatment, especially in the sensorimotor cortex and locus coeruleus. These results suggest that TDN-345 has therapeutic efficacy in the treatment of cerebrovascular disease.

[Heparin affinity high-performance liquid chromatography as an alternative to bioassay of CS23 mutein of recombinant human basic fibroblast growth factor].

We investigated whether a chemical assay by high-performance liquid chromatography (HPLC) as an alternative to the complicated and time-consuming bioassay for CS23 mutein of recombinant human basic fibroblast growth factor (rhbFGF-CS23) using the fetal bovine heart endothelial cell line ATCC CRL 1395. Physically, chemically or enzymatically denatured rhbFGF-CS23 was subjected to heparin affinity (HA)-HPLC and the bioassay. Good agreement was observed between the results obtained by these two methods. Moreover, HA-HPLC gave much more reproducible results (RSD = 1.9%, n = 6) than the bioassay (RSD = 7.4%, n = 18). HA-HPLC is therefore a simple, accurate and reproducible alternative to the bioassay for quality control and stability studies for rhbFGF-CS23 preparations. HA-HPLC is also considered to be applicable to assays for FGFs which have heparin affinity and biological activity similar to those of the CS23 mutein.