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.

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.

Parotid gland carcinoma: 32 years' experience from a single institute.

BACKGROUND: Parotid gland carcinoma is a rare and complicated histopathological classification. Therefore, assembling a sufficient number of cases with long-term outcomes in a single institute can present a challenge. METHOD: The medical records of 108 parotid gland carcinoma patients who were treated at Kyushu University Hospital, Fukuoka, Japan, between 1983 and 2014 were reviewed. The survival outcomes were analysed according to clinicopathological findings. RESULTS: Forty-six patients had low clinical stage tumours (I-II), and 62 patients had high clinical stage tumours (III-IV). Fifty-two, 10 and 46 patients had low-, intermediate- and high-grade tumours, respectively. Twenty-seven of 65 cases had positive surgical margins. In high clinical stage and intermediate- to high-grade tumours, adjuvant radiation therapy was correlated with local recurrence-free survival (p = 0.0244). Intermediate- to high-grade tumours and positive surgical margins were significantly associated with disease-specific survival in multivariate analysis (p = 0.0002 and p = 0.0058). CONCLUSION: The results of this study show that adjuvant radiation therapy is useful for improved local control in patients with high clinical stage and intermediate- to high-grade tumours.

Imaging of Temporal Bone.

Multidetector computed tomography has been the benchmark for visualizing bony changes of the ear, but has recently been challenged by cone-beam computed tomography. In both methods, all inner ear bony structures can be visualized satisfactorily with 2D or 3D imaging. Both methods produce ionizing radiation and induce adverse health effects, especially among children. In 3T magnetic resonance imaging, the soft tissue can be imaged accurately. Use of gadolinium chelate (GdC) as a contrast agent allows the partition of fluid spaces to be visualized, such as the bulging of basilar and Reissner's membranes. Both intravenous and intratympanic administration of GdC has been used. The development of positive endolymph imaging method, which visualizes endolymph as a bright signal, and the use of image subtraction seems to allow more easily interpretable images. This long-awaited possibility of diagnosing endolymphatic hydrops in living human subjects has enabled the definition of Hydropic Ear Disease, encompassing typical Meniere's disease as well as its monosymptomatic variants and secondary conditions of endolymphatic hydrops. The next challenge in imaging of the temporal bone is to perform imaging at the cellular and molecular levels. This chapter provides an overview of current temporal bone imaging methods and a review of emerging concepts in temporal bone imaging technology.

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.

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.

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.

Reduced Mastication Impairs Memory Function.

Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated. Here, we show that the reduced mastication resulted in impaired spatial memory and learning function owing to the morphological change and decreased activity in the hippocampus. We used an in vivo model for reduced masticatory stimuli, in which juvenile mice were fed with powder diet and found that masticatory stimulation during the growth period positively regulated long-term spatial memory to promote cognitive function. The functional linkage between mastication and brain was validated by the decrease in neurons, neurogenesis, neuronal activity, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These findings taken together provide in vivo evidence for a functional linkage between mastication and cognitive function in the growth period, suggesting a need for novel therapeutic strategies in masticatory function-related cognitive dysfunction.

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.

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.

Three-dimensional morphology of the human embryonic brain.

The morphogenesis of the cerebral vesicles and ventricles was visualized in 3D movies using images derived from human embryo specimens between Carnegie stage 13 and 23 from the Kyoto Collection. These images were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. Three-dimensional images using the same scale demonstrated brain development and growth effectively. The non-uniform thickness of the brain tissue, which may indicate brain differentiation, was visualized with thickness-based surface color mapping. A closer view was obtained of the unique and complicated differentiation of the rhombencephalon, especially with regard to the internal view and thickening of the brain tissue. The present data contribute to a better understanding of brain and cerebral ventricle development.

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.

Squamous cell carcinoma of the oropharynx: single-institution outcome analysis of patients treated with concurrent chemoradiotherapy.

PURPOSE: The object of this study was to analyse our experience with the effects of concurrent chemoradiotherapy for oropharyngeal squamous cell carcinoma, the treatment results of this therapeutic strategy and a salvage treatment for recurrent oropharyngeal squamous cell carcinoma. METHODS: Seventy-five patients with oropharyngeal squamous cell carcinoma were treated with chemoradiotherapy. The study included twenty-five of these patients who had recurrent oropharyngeal squamous cell carcinoma after chemoradiotherapy Results: The three-year actuarial survival rates for 75 patients by disease stage were as follows: stage II, 100 per cent; stage III, 71.1 per cent; stage IV, 51.7 per cent and overall, 58.2 per cent. The mean time of detection of recurrence was 6.2 months. The total salvage rates of recurrence were 21 per cent. The one and three-year tumour-free actuarial survival rates of those patients who received salvage treatment were 83 and 33 per cent. CONCLUSIONS: Surgical salvage was only feasible for early recurrent tumour. Close follow-up surveillance of early recurrence is essential after primary treatment of patients with chemoradiotherapy.

Well-differentiated liposarcoma arising in the parapharyngeal space: a case report and review of the literature.

BACKGROUND: Liposarcomas rarely occur in the parapharyngeal space and only a few case reports exist. For curative therapy of liposarcoma, surgical excision remains the dominant modality. Although a wide surgical margin is important to prevent local recurrence, wide excision is often difficult in the head and neck region. CASE REPORT: We report a case of a 19-year-old female with a well-differentiated liposarcoma arising in the parapharyngeal space. We removed the tumour surgically utilising a cervical-parotid approach. The histological diagnosis was well-differentiated sclerosing liposarcoma. There is no recurrence after five years and nine months of follow up. CONCLUSION: The patient's age and the tumour site made it difficult for us to make a quantitative diagnosis before the operation. Well-differentiated liposarcoma rarely develop distant metastasis, but often recur locally. The benefit of adjuvant radiotherapy for well-differentiated liposarcoma is still not clear and careful and long-term follow up is necessary.

Extrapulmonary small cell carcinoma in head and neck.

PURPOSE: The management of extrapulmonary small cell carcinoma has not been standardised to date. This study reviewed the clinical course, management and survival outcomes of patients with extrapulmonary small cell carcinoma in the head and neck region. METHODS: Nine patients with extrapulmonary small cell carcinoma in the head and neck were included in this study. RESULTS: Five patients received radical surgery followed by adjuvant chemotherapy or radiotherapy or both. Two other patients were treated with chemotherapy consisting of CPT11 plus cisplatin or CPT11 plus cisplatin plus VP-16 three times. Two other patients received chemoradiotherapy consisting of S-1 or CPT11 plus cisplatin. The median overall survival was 14.5 months, with a three-year survival rate of 23.7 per cent. CONCLUSIONS: The prognosis of extrapulmonary small cell carcinoma is generally poor. Further prospective multicentre studies are required for better understanding of disease entities and response to treatment modalities.

Hyalinizing clear cell carcinoma of the nasopharynx operated by trans-oral and trans-palatal approach.

BACKGROUND: Hyalinizing clear cell carcinoma is a rare minor salivary gland neoplasm. The treatment of choice is surgical resection with or without post-operative radiotherapy. This tumour often demonstrates a good prognosis. CASE REPORT: We report a case of hyalinizing clear cell carcinoma arising in the nasopharynx. A 27-year-old female presented with progressive hearing disturbance and tinnitus. On examination, an expansile mass was observed in her nasopharynx. Biopsy was performed and the pathology results returned as clear cell carcinoma. RESULTS AND CONCLUSION: Surgical resection was performed trans-orally accompanied by trans-palatal approach. She has no recurrence during more than two years of follow up.

Is there a role of adjuvant treatment for salivary duct carcinoma?

OBJECTIVE: To determine the clinical effect of post-operative radiotheraphy and systemic chemotherapy for the treatment of salivary duct carcinoma. STUDY DESIGN: Retrospective review. DESIGN: The medical records of 26 patients treated by surgery with or without radiotheraphy and/or systemic chemotherapy for salivary duct carcinoma were retrospectively reviewed to investigate the role of post-operative adjuvant treatment for the patients' prognosis. RESULTS: The overall three-year and five-year survival rates were 54 and 48.1 per cent, respectively. There was no correlation with the clinical stage and the patients' prognosis. The overall three-year survival of the patients with or without post-operative radiotheraphy was 64 and 33 per cent, respectively (p = 0.29). The overall three-year survival of the patients with or without post-operative chemotherapy was 53 and 56 per cent, respectively (p = 0.78). CONCLUSION: Post-operative adjuvant therapy did not improve the patients' overall prognosis with salivary duct carcinoma. Developing novel treatment modalities may be necessary to improve the prognosis of this aggressive disease.

Patient with an SLC26A4 gene mutation who had low-frequency sensorineural hearing loss and endolymphatic hydrops.

OBJECTIVE: To report magnetic resonance imaging findings in a patient with an SLC26A4 gene mutation who had low-frequency sensorineural hearing loss. CASE REPORT: A 13-year-old girl had bilateral and symmetric low-frequency sensorineural hearing loss. Upon genetic testing, a heterozygous c.1105A > G (p.K369E) mutation of the SLC26A4 gene was detected. Mild endolymphatic hydrops in the right cochlea and marked endolymphatic hydrops in the left vestibulum were seen by magnetic resonance imaging 4 hours after an intravenous gadolinium injection. CONCLUSION: This is the first reported case of a patient with the SLC26A4 gene mutation c.1105A > G (p.K369E) who had low-frequency sensorineural hearing loss. Co-occurrence of cochlear and vestibular endolymphatic hydrops suggests an association with that pathology.