Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study.

AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Halo Structure of the Neutron-Dripline Nucleus

The heaviest bound isotope of boron ^{19}B has been investigated using exclusive measurements of its Coulomb dissociation, into ^{17}B and two neutrons, in collisions with Pb at 220 MeV/nucleon. Enhanced electric dipole (E1) strength is observed just above the two-neutron decay threshold with an integrated E1 strength of B(E1)=1.64±0.06(stat)±0.12(sys) e^{2} fm^{2} for relative energies below 6 MeV. This feature, known as a soft E1 excitation, provides the first firm evidence that ^{19}B has a prominent two-neutron halo. Three-body calculations that reproduce the energy spectrum indicate that the valence neutrons have a significant s-wave configuration and exhibit a dineutronlike correlation.

First Observation of

The most neutron-rich boron isotopes ^{20}B and ^{21}B have been observed for the first time following proton removal from ^{22}N and ^{22}C at energies around 230 MeV/nucleon. Both nuclei were found to exist as resonances which were detected through their decay into ^{19}B and one or two neutrons. Two-proton removal from ^{22}N populated a prominent resonancelike structure in ^{20}B at around 2.5 MeV above the one-neutron decay threshold, which is interpreted as arising from the closely spaced 1^{-},2^{-} ground-state doublet predicted by the shell model. In the case of proton removal from ^{22}C, the ^{19}B plus one- and two-neutron channels were consistent with the population of a resonance in ^{21}B 2.47±0.19 MeV above the two-neutron decay threshold, which is found to exhibit direct two-neutron decay. The ground-state mass excesses determined for ^{20,21}B are found to be in agreement with mass surface extrapolations derived within the latest atomic-mass evaluations.

Contribution of pharmacists with expertise in infectious diseases to appropriate individualized vancomycin dosing.

BACKGROUND/AIM: Dose adjustment of vancomycin (VCM) is important in improving clinical outcomes and avoiding adverse effects such as nephrotoxicity. Although pharmacist-managed VCM therapy has been reported to optimize treatment, there are no studies focused on pharmacist expertise to date. In this study, we compared the contribution of pharmacists trained for infectious diseases and general pharmacists to dose adjustment of VCM. PATIENTS AND METHODS: We retrospectively investigated VCM trough concentration after dose adjustment by both trained (n = 67) and general (without special training for infectious diseases; n = 85) pharmacists. We also compared the incidence of nephrotoxicity during VCM treatment in both groups. RESULTS: The rate of achieving therapeutic VCM trough concentration (10-20 µg/mL) was higher in the trained group than in the control group (80.6 vs. 54.1%, p < 0.001). No significant differences in incidence of nephrotoxicity were observed between the two groups (p = 0.744). Trained pharmacists could contribute more successfully to the achievement of therapeutic VCM concentration ranges without increasing the risk of nephrotoxicity.

The comparison of nasal surgery and CPAP on daytime sleepiness in patients with OSAS.

OBJECTIVE: Residual sleepiness after continuous positive airway pressure (CPAP) is a critical problem in some patients with obstructive sleep apnea syndrome (OSAS). However, nasal surgery is likely to reduce daytime sleepiness and feelings of unrefreshed sleep. The aim of this study is to clarify the effects of nasal surgery and CPAP on daytime sleepiness. METHODOLOGY: This is a retrospective and matched-case control study. The participants were consecutive 40 patients with OSAS who underwent nasal surgery (Surgery group) and 40 matched patients who were treated with CPAP (CPAP group). RESULTS: In the Surgery group, although the nasal surgery did not decrease either apnea or hypopnea, it improved oxygenation, the quality of sleep. In the CPAP Group, the CPAP treatment reduced apnea and hypopnea, and improved oxygenation, quality of sleep. The degree of relief from daytime sleepiness was different between the two groups. The improvement of Epworth Sleepiness Scale was more significant in the Surgery Group than those in the CPAP Group (Surgery from 11.0 to 5.1, CPAP from 10.0 to 6.2). DISCUSSION: These findings suggest that the results of the nasal surgery is more satisfactory for some patients with OSAS than CPAP on daytime sleepiness.

Nucleus

The unbound nucleus ^{26}O has been investigated using invariant-mass spectroscopy following one-proton removal reaction from a ^{27}F beam at 201 MeV/nucleon. The decay products, ^{24}O and two neutrons, were detected in coincidence using the newly commissioned SAMURAI spectrometer at the RIKEN Radioactive Isotope Beam Factory. The ^{26}O ground-state resonance was found to lie only 18±3(stat)±4(syst) keV above threshold. In addition, a higher lying level, which is most likely the first 2^{+} state, was observed for the first time at 1.28_{-0.08}^{+0.11} MeV above threshold. Comparison with theoretical predictions suggests that three-nucleon forces, pf-shell intruder configurations, and the continuum are key elements to understanding the structure of the most neutron-rich oxygen isotopes beyond the drip line.

Morphology and morphometry of the human embryonic brain: A three-dimensional analysis.

The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing Amira™ software. The brain volume, excluding the ventricles (brain tissue), was 1.15 ± 0.43 mm(3) (mean ± SD) at CS13 and increased exponentially to 189.10 ± 36.91 mm(3) at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26 ± 0.15 mm(3) at CS13. The volume increased exponentially until CS23, when it reached 110.99 ± 27.58 mm(3). The mean volumes of the mesencephalon and rhombencephalon were 0.20 ± 0.07 mm(3) and 0.69 ± 0.23 mm(3) at CS13, respectively; the volumes reached 21.86 ± 3.30 mm(3) and 56.45 ± 7.64 mm(3) at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6-15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development.

Electrospray droplet impact secondary ion mass spectrometry using a vacuum electrospray source.

RATIONALE: In electrospray droplet impact (EDI) developed in our laboratory, an atmospheric pressure electrospray source has been used. To increase the ion beam intensity and reduce the evacuation load, a vacuum electrospray cluster ion source using a silica capillary was developed. METHODS: A silica capillary with a tip inner diameter of 8 µm was used for vacuum electrospray using aqueous 10% methanol. To stabilize the flow rate of the liquid for nano-electrospray, a home-made constant pressure liquid pump was also developed. RESULTS: By using the silica tip nano-electrospray emitter and a constant pressure pump, stable electrospray with flow rate of 22 nL/min was realized without using any heating system such as laser irradiation. Comparative study of mass spectra obtained by atmospheric pressure EDI (A-EDI) and vacuum EDI (V-EDI) was made for various samples such as thermometer molecule, peptide, polystyrene, Alq(3), NPD, C(60), indium, and SiO(2). V-EDI showed slightly milder ionization than A-EDI. CONCLUSIONS: Because V-EDI gave higher target current (5-10 nA) than A-EDI (a few nA at most), V-EDI secondary ion mass spectrometry (SIMS) would be a useful technique for the surface and interface analysis.

Characterization of putative toxin/antitoxin systems in Vibrio parahaemolyticus.

AIM: To obtain more information about the toxin/antitoxin (TA) systems in the Vibrio genus and also to examine their involvement in the induction of a viable but nonculturable (VBNC) state, we searched homologues of the Escherichia coli TA systems in the Vibrio parahaemolyticus genome. METHODS AND RESULTS: We found that a gene cluster, vp1842/vp1843, in the V. parahaemolyticus genome database has homology to that encoding the E. coli TA proteins, DinJ/YafQ. Expression of the putative toxin gene vp1843 in E. coli cells strongly inhibited the cell growth, while coexpression with the putative antitoxin gene vp1842 neutralized this effect. Mutational analysis identified Lys37 and Pro45 in the gene product VP1843 of vp1843 as crucial residues for the growth retardation of E. coli cells. VP1843, unlike the E. coli toxin YafQ, has no protein synthesis inhibitory activity, and that instead the expression of vp1843 in E. coli caused morphological change of the cells. CONCLUSIONS: The gene cluster vp1842/vp1843 encodes the V. parahaemolyticus TA system; VP1843 inhibits cell growth, whereas VP1842 serves as an antitoxin by forming a stable complex with VP1843. SIGNIFICANCE AND IMPACT OF THE STUDY: The putative toxin, VP1843, may be involved in the induction of the VBNC state in V. parahaemolyticus by inhibiting cell division.

Prediction of oral appliance treatment outcome in obstructive sleep apnoea syndrome: a preliminary study.

OBJECTIVE: Predictors of treatment outcome of oral appliances (OAs) in patients with obstructive sleep apnoea syndrome (OSAS) are not known. There is a pressing need for simple, clinically useful tools to predict treatment outcome. This study aimed to identify predictors of successful OA therapy for OSAS, including evaluation of pharyngeal morphology, which can be measured during routine examination by an otorhinolaryngologist. METHODOLOGY: This was a prospective study of 26 OSAS patients treated with OAs. A favourable outcome was obtained in 14 patients (responders) but not in 12 patients (nonresponders). The baseline patient characteristics and polysomnography and rhinopharyngeal findings were analysed. RESULTS: Body mass index (BMI) was significantly lower in responders versus nonresponders (23.6 ± 2.8 vs. 27.9 ± 4.7 kg/m2; p < 0.05). Pharyngeal morphology, age, sex and nasal resistance did not differ between the groups. Multiple regression analysis showed that BMI was a significant predictor of improvement in the apnoea/hypopnoea index after OA treatment (p < 0.05). CONCLUSION: Here we demonstrated that BMI is a favourable predictor of OA treatment outcome in OSAS patients. Among the OSAS patients, responders had wider retroglossal spaces than nonresponders.

Administration of interferon (IFN)-α exacerbates reovirus type-2-triggered autoimmune insulitis in DBA/1J mice.

The aim of this study is to clarify the effects of administrated interferon (IFN)-α on Reovirus type-2 (Reo-2)-triggered autoimmune insulitis. Newborn DBA/1J mice infected with Reo-2 (on day 0) showed the highest titre in the pancreas on day 5 and thereafter the titre declined. Similar viral growth curve with lower titre was found in the spleen and thymus. Insulitis with impaired glucose tolerance developed in infected mice on day 10, but not on day 5. IFN-α was produced in the blood on days 3 and 5, but not on days 7 and 10. During the virus growth phase, IFN-α positive((+)) cells were detected in some pancreatic islet cells and infiltrated dendritic cells (DCs) in interstitium. Virus antigen positive cells were detected in islet cells, but not in DCs. Administration with IFN-α (10(2) , 10(3) or 10(4) international unit) on day 7, which is the time of the disappearance of virus from the pancreas and IFN-α from the blood, exacerbated insulitis with increased glucose values compared to only infected mice. IFN-α administration at the same time of infection did not develop insulitis. In addition, IFN-α administration in uninfected mice on day 7 did not cause any damage to islet cells. The present study suggests that IFN-α may have a possibility to exacerbate Reo-2-tiggered mild insulitis.

Association of interleukin-1 gene polymorphisms with sudden sensorineural hearing loss and Ménière's disease.

Sudden sensorineural hearing loss (SSNHL) and Ménière's disease are the most common inner ear diseases in which the causes are unknown. As recent magnetic resonance imaging has demonstrated disruption of the blood-labyrinth barrier in these inner ear diseases, inflammatory reaction associated with increased permeability of the blood vessels may be involved. The genotypes of interleukin 1A (IL1A) (-889C/T; rs1800587) and interleukin 1B (IL1B) (-511C/T; rs16944) were determined using an allele-specific primer-polymerase chain reaction method in 72 patients with SSNHL, 68 patients with Ménière's disease, and 2202 control subjects living almost in the same area as the patients. A significantly higher prevalence of the IL1A-889T allele was observed in SSNHL and Ménière's disease compared with controls, although no significant difference in distribution of IL1B-511C/T genotypes was observed between the patients and controls. Adjusted odd ratios for SSNHL and Ménière's disease risks in the -889TT genotypes were 25.89 (95% confidence interval (CI) 12.19-54.98) and 18.20 (95% CI 7.80-42.46), respectively, after age and gender were taken as moderator variables. Our results suggested that IL1A is closely associated with susceptibility of SSNHL and Ménière's disease.

Morphological features of elderly patients with obstructive sleep apnoea syndrome: a prospective controlled, comparative cohort study.

OBJECTIVES: To investigate the pharyngeal morphologic features and its pathogenic role on obstructive sleep apnoea syndrome in the elderly population. DESIGN: Prospective controlled, comparative cohort study. SETTING: Territory referral centre. PARTICIPANTS: We enroled 320 consecutive patients with complaints of snoring who visited Nagoya University Hospital from January 2004 to December 2007. We also collected 26 control subjects aged over 60 years from community-dwelling people. MAIN OUTCOME MEASURES: We underwent a morphological evaluation, measurement of nasal resistance, assessment of daytime sleepiness and nocturnal polysomnography. RESULTS AND CONCLUSIONS: Two hundred and ninety-two patients were analysed. The constitution ratio of men, the body mass index and Epworth sleepiness scale were decreased with ageing. Tonsil size was reduced progressively with ageing. Retroglossal space was wider, and soft palate was lower in ≥ 60 year group than in < 40 year group. Retroglossal space was wide in elderly patients with sleep apnoea compared with control subjects. Tonsil size was not correlated to apnoea/hypopnoea index in ≥ 60 year group unlike the other generations. Modified Mallampati Score and tongue size were significantly but mildly correlated only in ≥ 60 year group. Width of fauces was correlated in all the groups. Multiple regression analysis showed that body mass index, age, gender, tonsil size and width of fauces were independent factors for apnoea/hypopnoea index. CONCLUSIONS: Morphologically, the tonsil could play a minor role but the width of fauces could play relatively a major role. Additionally, wide retroglossal space, low positional soft palate and large tongue size may be characteristics for elderly patients of obstructive sleep apnoea syndrome.

Salvage esophagectomy after definitive chemoradiotherapy for synchronous double cancers of the esophagus and head-and-neck.

Head-and-neck cancer is frequently associated with esophageal cancer. Because the operative procedures for these synchronous double cancers are too invasive, definitive chemoradiotherapy tends to be applied as an initial treatment. A salvage esophagectomy for either recurrent or residual disease after definitive chemoradiotherapy in patients with such double cancer has never been reported. We reviewed 21 patients with esophageal cancer who underwent a salvage esophagectomy after definitive chemoradiotherapy. Among them, the treatment course of five patients who underwent a salvage esophagectomy for patients with synchronous double cancers of the esophagus and head-and-neck region was analyzed. Because head-and-neck cancer was well controlled after chemoradiotherapy in all five patients, a salvage esophagectomy was indicated for either recurrent or residual esophageal cancer after definitive chemoradiotherapy. Anastomotic leakage developed in four patients; however, no other complications including pulmonary complications were recognized. All of them were discharged to home and three of them are still alive without any recurrence for 20-43 months. A salvage esophagectomy should be considered as a treatment option for either recurrent or residual esophageal cancer with well-controlled head-and-neck cancer after definitive chemoradiotherapy when complete resection of the esophagus is expected.

In silico experiments of bone remodeling explore metabolic diseases and their drug treatment.

Bone structure and function are maintained by well-regulated bone metabolism and remodeling. Although the underlying molecular and cellular mechanisms are now being understood, physiological and pathological states of bone are still difficult to predict due to the complexity of intercellular signaling. We have now developed a novel in silico experimental platform, V-Bone, to integratively explore bone remodeling by linking complex microscopic molecular/cellular interactions to macroscopic tissue/organ adaptations. Mechano-biochemical couplings modeled in V-Bone relate bone adaptation to mechanical loading and reproduce metabolic bone diseases such as osteoporosis and osteopetrosis. V-Bone also enables in silico perturbation on a specific signaling molecule to observe bone metabolic dynamics over time. We also demonstrate that this platform provides a powerful way to predict in silico therapeutic effects of drugs against metabolic bone diseases. We anticipate that these in silico experiments will substantially accelerate research into bone metabolism and remodeling.

IL-12p40 is essential for the down-regulation of airway hyperresponsiveness in a mouse model of bronchial asthma with prolonged antigen exposure.

BACKGROUND: We previously reported a mouse model of bronchial asthma showing eosinophilic inflammation, but not airway hyperresponsiveness (AHR), after prolonged antigen exposure. This model showed an increase of IL-12 in the lung. OBJECTIVE: The aim of this study was to investigate the role of IL-12p40 in a murine asthma model with prolonged antigen exposures. METHODS: An ovalbumin (OVA)-induced asthma model was first established in wild-type (WT) and IL-12p40-deficient (IL-12p40(-/-)) mice. Both strains of mice were further exposed to either OVA (prolonged exposure group) or phosphate-buffered saline (positive control group) 3 days per week for 3 weeks. During week 4, both groups of mice were given a final challenge with OVA. RESULTS: Prolonged antigen exposures resulted in marked suppression of airway eosinophilia in both WT and IL-12p40(-/-) mice. However, AHR persisted in IL-12p40(-/-) but not in WT mice. There were no significant differences of IL-5, IL-13 or IFN-gamma levels in bronchoalveolar lavage fluid between WT and IL-12p40(-/-) mice. The hydroxyproline content of the lung and peribronchial fibrosis were, however, significantly increased in IL-12p40(-/-) mice. CONCLUSION: The results suggest that endogenous IL-12p40 is essential for inhibition of AHR and peribronchial fibrosis, but not eosinophilic inflammation, in a murine asthma model with prolonged antigen exposures.

The utility of FDG-PET for detecting multiple primary cancers in hypopharyngeal cancer patients.

AIM: To examine the utility of 2'-[18F]-fluoro-2'-deoxy-D-glucose positron emission tomography (FDG-PET) for detecting multiple primary cancers (MPC) in patients with hypopharyngeal cancer (HPC). PATIENTS, METHODS: Seventy patients with HPC underwent FDG-PET to determine the staging. Routine clinical examinations were carried out, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and oesophagealgastroduodenoscopy (EGDS). The detection rate of synchronous and metachronous cancer was calculated based on FDG-PET alone or FDG-PET combined with clinical routine examination. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and accuracy were used to diagnose oesophageal cancer using FDG-PET. RESULTS: Of the 70 patients, 12 (17.1%) had 15 synchronous tumours, and 2 of the 58 remaining patients (3.4%) had metachronous tumours. Oesophageal cancer was discovered most frequently: superficial type (n=6), advanced type (n=4). On a per-patient basis, 11 of 12 patients (91.6%) were diagnosed with synchronous tumours, and on a per-lesion basis, 12 of 15 lesions (80.0%) were detected by FDG-PET. The sensitivity, specificity, accuracy, PPV, and NPV of FDG-PET regarding oesophageal cancer were 70%, 100%, 95.7%, 100%, and 95.2% respectively. Three of the six superficial types were positive on FDG-PET. Both of the metachronous tumour lesions were detected by FDG-PET. CONCLUSION: FDG-PET is useful for estimating the MPC in HPC patients. Since 3 of 10 synchronous oesophageal cancer were missed with PET alone, a combination with EGDS should be considered to exclude synchronous oesophageal cancer.

Endoscopic surgical treatment of posterior glottic stenosis.

A six-year-old girl developed posterior glottic stenosis following surgery for lateral curvature. She was post-operatively intubated for 17 days and had inspiratory stridor after extubation. Laryngoscopy revealed an adhesion at the posterior commissure which severely limited abduction of the bilateral vocal folds and arytenoids. Initially, tracheal fenestration was performed and the scar tissue of the posterior commissure was vaporised using a CO2 laser under endolaryngeal microsurgery. However, despite this procedure the stenosis reformed and an interarytenoid adhesion developed.Endolaryngeal microsurgery was performed again three months later. Using endoscopic microscissors, the posterior commissure and interarytenoid scar tissue were submucosally separated and the bilateral corniculate cartilages of the superior arytenoids were debulked using CO2 laser. A posteriorly based mucosal flap obtained from the postcricoid region was extended to approximate to the mucosa of the posterior commissure. The mucosal flap was sutured to the inferior subglottic mucosa by two 4-0 polyglactin absorbable sutures. Three months later, the patient's respiratory and phonatory function was satisfactory.Based on the successful results of the present case, the authors highly recommend the use of a posterior mucosal flap for the treatment of posterior glottic stenosis. This procedure does not require the use of either a laryngofissure or a laryngeal stent.