The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter,open-label,noncomparative phase 3 study

IntroductionRelebactam, a novel class A/C β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens.MethodsThis phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5–14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis.ResultsOf 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT.ConclusionsA favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.     

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.     

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 .     

Peripheral T‐cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factor

Myelofibrosis is often observed in chronic myeloproliferative disorders (CMPD), but non‐Hodgkin's lymphoma with diffuse myelofibrosis is rare. We describe an elderly case with peripheral T‐cell lymphoma‐unspecified (PTCL) presenting as diffuse myelofibrosis. Bone marrow biopsy revealed infiltration of atypical lymphocytes and diffuse myelofibrosis without any increase in megakaryocytes. To discuss the pathogenesis of fibrosis, we examined cytokines relative to fibrosis using immunostaining. The expression of basic fibroblast growth factor (bFGF) was diffusely detected in the area of extracellular matrix of bone marrow. In addition, in situ hybridization revealed that infiltrating lymphoma cells expressed bFGF mRNA. Basic FGF, originally identified based on its mitogenicity for fibroblasts, has multiple potential, influencing neoangiogenesis, bone marrow fibrosis and the proliferation of tumor cells. Basic FGF might play an important role in the pathogenesis of myelofibrosis in the present case.     

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.     

A retrospective survey of autotransplantation of teeth in dental clinics

The aim of this study was to investigate the usage of tooth autotransplantation in dental clinics which offer the treatment and evaluate its practicality. Participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. A total of 614 teeth from 552 patients (37 dentists) ranging in age from 17 to 79 (mean age: 44·1) were examined. Cumulative survival rate and mean survival time were calculated using the Kaplan-Meier method, and log rank test was used for analysis of factors. The mean number of autotransplantation patients per clinic per year was 1·4. Upper third molars constituted 36·8% of donor teeth, while 37·1% were lower third molars. The lower first molar region was the most common recipient site at 32·6%, followed by the lower second molar region (28·0%). Prosthodontic treatment of transplanted teeth involved coverage with a single crown (72·5%) and abutment of bridge (18·9%). A total of 102 transplanted teeth were lost owing to complications such as attachment loss (54·9%) and root resorption (25·7%). The cumulative survival rate in cases where donor teeth had complete root formation was 90·1% at 5 years, 70·5% at 10 years and 55·6% at 15 years. The mean survival time was 165·6 months. Older age was a significant risk factor (P < 0·05) for survival. In cases where suitable donor teeth are available, autotransplantation of teeth may be a plausible treatment option for dealing with missing teeth in dental clinics.     

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.