Docetaxel, low-dose estramustine, and doxifluridine in hormone-refractory metastatic prostate cancer

Purpose Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate (estramustine) has been reported to be effective for HRPC. Low-dose estramustine suppresses the pituitary–gonadal axis. Docetaxel plus 5-fluoro-5′-deoxyuridine (5′-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5′-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine. Methods All of the HRPC patients were treated with estramustine 140 mg orally twice 5′-dFUrd 200 mg orally four times daily on days 1–21, and docetaxel 60 mg/m² was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL). Results Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially. Conclusions This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients.     

Amyloid deposition and CBF patterns predict conversion of mild cognitive impairment to dementia

Mild cognitive impairment (MCI) can include the transition from a normal state to dementia. To explore biomarkers for the development of dementia, we performed an 18-month follow-up study in 28 patients with amnestic MCI. Amyloid deposition was examined using PiB PET, and cerebral blood flow (CBF) was examined using SPECT. Cognitive function was periodically assessed. The rate of conversion to dementia was higher in the PiB-positive/equivocal group (74%) than in the PiB-negative group (33%) (p?=?0.041). Perfusion SPECT was performed in 16 patients. MCI patients with an AD-characteristic pattern of reduced CBF had a higher PiB-positive/equivocal rate (82%) than those with a non-AD pattern (20%) (p?=?0.018), and patients with an AD pattern had a higher conversion rate (82%) than those with a non-AD pattern (40%) (p?=?0.094). Clinically, all PiB-positive converters were diagnosed as having Alzheimer’s disease (AD), whereas PiB-negative converters were thought to have some form of dementia other than AD. Amyloid PET is useful for predicting conversion to AD in MCI patients. A pattern analysis of perfusion SPECT findings might also be helpful for predicting conversion to AD, but with a lower specificity.     

Vascular risk factors and progression in Alzheimer's disease

Aim: To determine whether vascular risk factors such as hypertension, diabetes and hypercholesterolemia affect the progression of Alzheimer's disease (AD). Methods: We followed up 150 consecutive outpatients with probable AD for 24–60 months. Severity of cognitive impairment was assessed using the Mini‐Mental State Examination (MMSE). We investigated the influence of vascular risk factors and other demographic and clinical conditions (including age, sex, education, initial MMSE score and follow‐up time) on annual MMSE score changes. Results: Multiple regression analysis revealed that age, education and hypertension were significant variables associated with annual MMSE score changes. Younger, more educated patients with hypertension showed greater decline in annual MMSE scores. There were no significant correlations of annual MMSE score changes with other vascular factors or demographics, including sex, initial MMSE score, diabetes or hypercholesterolemia. Conclusion: Younger, more educated patients are more likely to have faster cognitive decline. In addition, hypertension may also be associated with a greater rate of disease progression. Our results suggest the importance of prevention and treatment for hypertension in patients with AD. Geriatr Gerontol Int 2011; 11: 211–214 .     

Dimenhydrinate effect on cerebral oxygen status and salivary chromogranin-A during cognitive tasks

To investigate the effects of dimenhydrinate on cerebral oxygen status (COS; cerebral oxygenated hemoglobin concentration changes) and salivary chromogranin-A (CgA) during a cognitive test battery, a double-blind, placebo-controlled, randomized, crossover protocol was used to examine the effect of 50 mg of dimenhydrinate or placebo in 12 subjects. This test battery includes tests of both reaction time and fundamental cognitive ability and was used in the assessment of pilots. Poor cognitive performance was observed in the subjects taking dimenhydrinate. We used two-channel near-infrared spectroscopy to investigate the effects of dimenhydrinate on the COS. With the one exception of shifting attention task in the left forehead, no significant difference was found between dimenhydrinate and placebo during the tasks of the test battery. Under placebo treatment, on the other hand, CgA levels were significantly elevated during cognitive testing when compared with baseline. However, CgA levels were not significantly elevated above baseline following dimenhydrinate. The present study is one of the first to demonstrate that the first-generation antihistamine drugs altered the responses of salivary CgA during cognitive tasks. The changes in salivary CgA secretion, as a result of dimenhydrinate administration, may serve as a sensitive biomarker of a psychological status such as a drug-induced sedation during the performance of a cognitive test battery. Further studies, however, are required to examine the usefulness of this sensitive biomarker in investigation of psychological agents during cognitive tasks.     

Selection and characterization of promoters based on genomic approach for the molecular breeding of oleaginous fungus Mortierella alpina 1S-4

To express a foreign gene effectively, a good expression system is required. In this study, we investigated various promoters as useful tools for gene manipulation in oleaginous fungus Mortierella alpina 1S-4. We selected and cloned the promoter regions of 28 genes in M. alpina 1S-4 on the basis of expression sequence tag abundance data. The activity of each promoter was evaluated using the β-glucuronidase (GUS) reporter gene. Eight of these promoters were shown to enhance GUS expression more efficiently than a histone promoter, which is conventionally used for the gene manipulation in M. alpina. Especially, the predicted protein 3 and the predicted protein 6 promoters demonstrated approximately fivefold higher activity than the histone promoter. The activity of some promoters changed along with the cultivation phase of M. alpina 1S-4. Seven promoters with constitutive or time-dependent, high-level expression activity were selected, and deletion analysis was carried out to determine the promoter regions required to retain activity. This is the first report of comprehensive promoter analysis based on a genomic approach for M. alpina. The promoters described here will be useful tools for gene manipulation in this strain.     

Relationship between Eichner Index and number of present teeth

The aim of this study was to determine the percentage of participants in each of the six Eichner Index groups by number of present teeth (PT). The data were obtained from a periodontal disease examination carried out under a health promotion law in a city located northeast of Tokyo, Japan, in 2005. Data from a total of 1,549 (524 male and 1,025 female) 60-year-old participants were analyzed in this study. Number of occlusal supports was counted by analyzing dental charts. The Eichner Index was used to group the participants into six groups based on distribution of occlusal support teeth. The percentage of patients in Group A with 24 PT was 31.4%; none in Group A had fewer than 19 PT. The percentage in Groups A, B1, and B2 with between 20 and 28 PT was above 50%; the number of participants in these groups with fewer than 20 PT decreased rapidly. Those with fewer than 16 PT were almost found in Groups B3, B4 and C. Only a few patients in Group C had between 10 and 14 PT; those with fewer than 9 PT were only found in Groups B4 or C. Based on these results, the Eichner Index category of a given participant can be estimated from number of PT.     

Diffusion-weighted imaging of a malignant brenner tumor

Microscopically, ovarian malignant Brenner tumor shows components of malignant transitional cell tumor intermixed with benign and borderline elements. We report a case of this tumor with components that transition from benign to malignant on diffusion-weighted images (DWI) and in histologic findings. The benign component showed low signal intensity on T(2)-weighted images, whereas the malignant component showed high signal intensity on T(2)-weighted images and high signal intensity on DWI with low apparent diffusion coefficient (ADC) value.     

Cysteinyl leukotrienes in the bile of patients with obstructive jaundice

Background: Cysteinyl leukotrienes (LTs) are potent proinflammatory mediators. They are predominantly excreted from blood by hepatobiliary elimination. To explore the clinical significance of biliary cysteinyl LTs, we determined their concentration changes in bile during treatment in patients with obstructive jaundice. Methods: Bile samples were obtained during endoscopic or transhepatic biliary drainage. Leukotrienes C₄, D₄, and E₄ were quantified by two-step reversed-phase high-performance liquid chromatography and subsequent radioimmunoassay. Results: The increased excretion of cysteinyl LTs (LTC₄ + LTD₄ + LTE₄) decreased between day 1 and 14 after drainage (means, 171 pmol/h to 79 pmol/h; P < 0.02). During drainage, the excretion was higher when there was additional cholangitis (mean, 225 and 86 pmol/h, with and without cholangitis, respectively; P < 0.001). The concentrations of LTD₄ and LTE₄ were also higher with additional cholangitis than without (LTD₄, mean 6.0 vs 2.0 nM; P < 0.05; LTE₄, 6.8 vs 2.4 nM; P < 0.02, respectively). Biliary LTC₄ was detected only in patients with cholangitis. The biliary excretion of cysteinyl LTs was positively correlated with leukocyte concentration (r = 0.68; P < 0.005) and C-reactive protein (r = 0.73; P < 0.005) in blood. Furthermore, only in the absence of cholangitis, the excretion was positively correlated with serum γ-glutamyl transferase (r = 0.76; P < 0.02) and alanine aminotransferase (r = 0.72; P < 0.02). Conclusions: The excretion of biliary cysteinyl LTs increases with the severity of cholestasis and hepatic inflammation in patients with obstructive jaundice. An additional increase of cysteinyl LTs was observed during bacterial cholangitis. The increased biliary excretion of biologically active cysteinyl LTs may contribute to the aggravation of cholestasis and inflammatory reaction in obstructive jaundice. Received: October 1, 2001 / Accepted: March 8, 2002 Acknowledgements. We are indebted to Dr. Gabriele Jedlitschky and Dr. Inka Leier for valuable advice throughout this work. This work was supported by a fellowship awarded to Dr. Masahito Uemura by the Alexander-von-Humboldt Foundation, Bonn, Germany, and in part by the Deutsches Krebsforschungszentrum, Heidelberg, Germany. Reprint requests to: M. Uemura