Draft Genome Sequence of the Aspergillus terreus High-Itaconic-Acid-Productivity Strain IFO6365.

Itaconic acid is an important organic acid used in the chemical industry. Aspergillus terreus strain IFO6365 is one of the highest-yielding itaconic acid-producing wild-type strains. Here, we report the draft genome sequence of IFO6365, enhancing the understanding of the role and biosynthesis of itaconic acid in this fungus.

Phase II/III, randomized, double-blind, parallel-group study of monthly delayed-release versus daily immediate-release risedronate tablets in Japanese patients with involutional osteoporosis.

Absorption of oral immediate-release (IR) risedronate tablets is reduced by food intake, thus a delayed-release (DR) tablet has been developed to overcome the necessity of taking IR tablets under fasting conditions. This randomized, double-blind, phase II/III study compared efficacy and safety of risedronate IR once-daily (QD) and DR once-monthly (QM) tablets in Japanese patients with involutional osteoporosis. Patients received 2.5 mg IR on awakening QD, or 25 or 37.5 mg DR on awakening, following breakfast, or 30 min after breakfast, QM for 12 months. Primary endpoint was non-inferiority in mean percent change from baseline to end of study (month 12, last observation carried forward [M12, LOCF]) in mean lumbar spine (L2-L4) bone mineral density (BMD) between risedronate IR on awakening and DR following breakfast. Mean percent changes in (L2-L4) BMD at M12, LOCF were 5.07% (IR at awakening, n = 190), 3.36% (25 mg DR following breakfast, n = 194), and 4.11% (37.5 mg DR following breakfast, n = 181). Mean percent change in (L2-L4) BMD was numerically lower in the DR following breakfast groups versus the respective on awakening and 30 min after breakfast DR groups. Overall incidences of treatment-emergent adverse events (TEAEs) were comparable between groups. In the DR groups, 1.5-4.0% of patients reported TEAEs potentially associated with acute-phase reactions versus 0% in the IR group. In this study, non-inferiority could not be declared for 37.5 or 25 mg DR following breakfast QM (p = 0.1346 or p = 0.6711, respectively) versus 2.5 mg IR on awakening QD.

Draft Genome Sequence of Aspergillus terreus High-Itaconic-Acid-Productivity Mutant TN-484.

Itaconic acid is an important organic acid used in the chemical industry. Aspergillus terreus strain TN-484 is a high-itaconic-acid-productivity mutant derived from strain IFO6365. Here, we report the draft genome sequence of strain TN-484, advancing the understanding of the biosynthesis of itaconic acid in filamentous fungi.

Draft Genome Sequence of Saccharomyces cerevisiae Strain Pf-1, Isolated from Prunus mume.

Saccharomyces cerevisiae strain Pf-1 is a yeast isolated from Prunus mume; it potentially can be used to produce wine and traditional Japanese sake. Here, we report the draft genome sequence of this strain. The genomic information will provide a deeper understanding of the brewing characteristics of this strain.

Comparison of quality of life between 2-year and 3-or-more-year administration of leuprorelin acetate every-3-months depot in combination with tamoxifen as adjuvant endocrine treatment in premenopausal patients with endocrine-responsive breast cancer: a randomized controlled trial.

BACKGROUND: We conducted an open-label, randomized controlled trial evaluating the appropriate treatment duration of leuprorelin acetate 3-month depot, TAP-144-SR (3M), administered postsurgically every 3 months for 2 years versus 3 or more (up to 5) years, in combination with tamoxifen, for 5 years in premenopausal endocrine-responsive breast cancer patients and reported similar survival benefit in the two treatment groups. We hereby present patient-reported quality of life (QOL) data obtained from this trial. METHODS: Three self-administered QOL questionnaires (QOL-ACD, QOL-ACD-B, FACT-ES subscale) were used, and the difference in QOL score changes between the two groups was analyzed using a mixed-effects model for repeated measures. RESULTS: Eligible patients (N = 222) were randomly assigned to a 2-year (2YG, N = 112) or 3-or-more-year treatment group (3YG, N = 110). The time courses of the three QOL scores during the trial period were similar in the two groups. The mean changes in the QOL scores from week 96 were largely stable through week 240 in the 3YG, but showed significantly greater improvement in the score changes from week 96 in the 2YG than the 3YG. Symptoms associated with menopause such as hot flashes and sweating contributed to these results. Menstruation recovery was associated with significantly greater improvement of these symptoms in the 2YG than the 3YG. CONCLUSIONS: Patient-reported menopause-associated symptoms and QOL improved after discontinuation of the LH-RH agonist administration and menstruation recovery. QOL information should be a consideration in long-term treatment.

Efficacy and safety of leuprorelin acetate 6-month depot, TAP-144-SR (6M), in combination with tamoxifen in postoperative, premenopausal patients with hormone receptor-positive breast cancer: a phase III, randomized, open-label, parallel-group comparative study.

BACKGROUND: Leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, is used worldwide in premenopausal women with hormone receptor-positive breast cancer. This study was conducted to assess the non-inferiority of the 6-month depot formulation, TAP-144-SR (6M) 22.5 mg to the 3-month depot formulation, TAP-144-SR (3M) 11.25 mg in postoperative, premenopausal patients with hormone receptor-positive breast cancer. METHODS: This was a 96-week phase III, randomized, open-label, parallel-group comparative study. All patients concomitantly received oral tamoxifen (20 mg daily). The primary endpoint was the suppression rate of serum estradiol (E2) to the menopausal level (≤30 pg/mL) from Week 4 through Week 48. RESULTS: In total, 167 patients were randomized to receive TAP-144-SR (6M) (n = 83) or TAP-144-SR (3M) (n = 84) and the E2 suppression rate was 97.6 and 96.4 %, respectively. The estimated between-group difference was 1.2 % (95 % confidence interval -5.2 to 7.8). The non-inferiority of TAP-144-SR (6M) to TAP-144-SR (3M) for E2 suppression was confirmed. As for safety, common adverse events were hot flush and injection site reactions including induration, pain, and erythema in both treatment groups, which were of ≤Grade 2 in severity and not serious. No significant between-group differences in safety profiles and tolerability were observed. CONCLUSIONS: TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for its suppressive effect on serum E2. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).

A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.

BACKGROUND: Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin. METHODS: We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety. RESULTS: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2. CONCLUSIONS: Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.

Efficacy and safety of leuprorelin acetate 6-month depot in prostate cancer patients: a Phase III, randomized, open-label, parallel-group, comparative study in Japan.

OBJECTIVE: Leuprorelin acetate (TAP-144-SR) is commonly used worldwide in prostate cancer patients. This study was conducted to assess the non-inferiority of a 6-month depot formulation of TAP-144-SR (TAP-144-SR [6M]) 22.5 mg to a 3-month depot formulation of TAP-144-SR (TAP-144-SR [3M]) 11.25 mg in prostate cancer patients in Japan. METHODS: This was a 48-week Phase III, open-label, parallel-group comparative study. TAP-144-SR (6M) 22.5 mg (6M group) and TAP-144-SR (3M) 11.25 mg (3M group) were administered to 81 and 79 subjects, respectively. The primary endpoint was the rate of serum testosterone suppression to the castrate level (≤100 ng/dl). RESULTS: Serum testosterone of all subjects excluding one subject in the 3M group was suppressed to the castrate level throughout 48 weeks. The estimated between-group difference (6M group - 3M group) in suppression rate was 1.3% (95% confidence interval: -3.4, 6.8), and its lower confidence interval was more than -10% of the pre-determined allowable limit value to judge the non-inferiority. The prostate-specific antigen concentrations were stable throughout the study in both groups. Progressive disease in the best overall response based on the Response Evaluation Criteria In Solid Tumors was 0.0% for the 6M group and 2.6% for the 3M group. Adverse events occurred in 92.6% in the 6M group and 89.9% in the 3M group. Adverse events leading to discontinuation were reported in 2.5% in the 6M group and 3.8% in the 3M group. CONCLUSIONS: TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for the suppressive effect on serum testosterone level. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).

[A phase II pharmacological study of leuprolide acetate 6-month depot, TAP-144-SR (6M), in treatment-Nazve patients with prostatic cancer who received a single subcutaneous or intramuscular injection].

The aim of this phase II study was to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and safety of a 6- month depot formulation of a luteinizing hormone-releasing hormone (LH-RH) agonist, TAP-144-SR (6M), in Japanese treatment-naÏve patients with prostatic cancer. Each subject received a single subcutaneous or intramuscular injection of TAP- 144-SR (6M) and was monitored for 24 weeks. The primary endpoint was the change in serum testosterone levels. The serum testosterone level in six subjects who received 22.5 mg of TAP-144 (SR) subcutaneously decreased below the castrate level after 4 weeks and remained suppressed during the 24 weeks of follow-up. With regard to safety, TAP-144-SR (6M)was not associated with any additional concerns compared to those reported for the approved 1-month and 3-month depot formulations of TAP-144-SR. In addition, 30 mg of TAP-144-SR (6M) was administered subcutaneously to six subjects, and, on the basis of the results, the optimal clinical dosage of TAP-144-SR (6M) in Japan was considered to be 22.5 mg. Outcomes with 22.5mg TAP-144-SR (6M) administered intramuscularly were similar to those with TAP-144-SR (6M) administered subcutaneously.

Cerebral oxygenation in the frontal lobe cortex during incremental exercise tests: the regional changes influenced by volitional exhaustion.

The present study examined the regional differences of cortical oxygenation in the frontal lobe by near-infrared spectroscopy (NIRS) during incremental exercise tests and the precise location of NIRS was examined by brain magnetic resonance imaging (MRI). Pulmonary gas exchange and NIRS measurement during incremental cycling ergometry tests were investigated in 14 men. In 7 of these subjects, the right middle cerebral artery mean velocity (MCA Vmean) was simultaneously measured by transcranial Doppler (TCD). In the right medial of the frontal lobe cortex, Tissue Oxygenation Index (TOI) increased by 8.8% with its peak value at respiratory compensation threshold (RCT) and Normalized Tissue Hemoglobin Index (nTHI) increased until endpoint by 16.2%. During incremental exercise tests, the changing pattern of TOI was different according to the distribution of the probes. Volitional exhaustion by exercise induced the deteriorated TOI and MCA Vmean, whereas nTHI increased.

[Efficacy of preoperative radiation therapy in hyper-vascular solitary fibrous tumor].

The hyper-vascular form of solitary fibrous tumors (SFTs) is rare and there have been few therapeutic evaluations of this entity. We encountered a hyper-vascular SFT and had difficulty removing it surgically. Following radiotherapy, both tumor size and feeder vessels were reduced and we could proceed with gross total removal. A 29-year-old woman was admitted with a 1-year history of decreasing visual acuity on the right side. Magnetic resonance imaging with gadolinium enhancement showed a homogenous enhancing mass (6x5x5 cm) which expanded the superior and inferior tentorium cerebelli. The tumor was fed by the left posterior cerebral artery, bilateral middle meningeal arteries and the right occipital artery. The first operation employed an occipital transtentorial approach and a highly vascular tumor was found. Tumor resection was limited due to severe bleeding. Histologically, the tumor showed focal hypercellularity with spindle cells and numerous capillaries. Immunohistochemically, the tumor was diffusely positive for CD34 and a diagnosis of SFT, hyper-vascular subtype, was made. After the first operation, local irradiation of a total of 40 Gy was performed. Both the tumor size and vascularity decreased dramatically. At the second operation, gross total removal was able to be performed. Radiotherapy appears effective in reducing the hyper-vascular subtype of SFT and would be one possible therapy to deal with these tumors, given their propensity of excessive bleeding during initial surgery.

Effect of linezolid against postneurosurgical meningitis caused by methicillin-resistant Staphylococcus epidermidis: case report.

A 67-year-old man who had twice previously undergone operations for a tuberculum sellae meningioma was admitted to hospital for further treatment. After the third surgical intervention, the patient developed persistent low-grade fever and impaired consciousness. Computed tomography, 1 week after surgery, showed postsurgical hydrocephalus. Cerebrospinal fluid (CSF) studies revealed high intracranial pressure (above 30 cm H2O), and increased cell count (1232/3). One week after the ventricular drainage, coagulase-negative Staphylococcus epidermidis was recovered from his CSF, and antimicrobial susceptibility results indicated that the organism was methicillin-resistant. After 14 days of intravenous vancomycin (VCM) administration failed, linezolid (LZD) was initialized intravenously, resulting in a resolution of the meningitis. After a ventriculoperitoneal shunt procedure was performed, LZD was continued orally, which resulted in a cure. CSF penetration by VCM is reported to be poor, i.e., approximately 10% of serum concentration, which may explain its lack of efficacy. In this case, the penetration of LZD into the CSF was 58.9% of the peak value and 133% of the trough value of serum concentrations. LZD must be considered one of the first-line treatments against surgical-site infection in neurosurgery caused by methicillin-resistant Staphylococci.

[The influence on the images of computed tomography caused by the use of artificial cranial reconstructive materials].

Various materials have been used for cranioplasty; however, these materials frequently produce artifacts that appear when examined with conventional radiography. Computed tomography (CT), in particular, detects high density artifacts near artificial bones, which is manipulated by increased noise, and limits diagnostic performance. The purpose of this study was to evaluate the extent and shape of the artifacts due to artificial cranial bones and to consider CT imaging parameters necessary for accurate recognition of structures under the materials. Four different artificial bone materials were evaluated in this study: hydroxyapatite with 1) 40% or 2) 50% porosity, 3) titanium plate, and 4) hydroxyapatite-polymethylmethacrylate composite (HA-PMMA). CT scanning was performed with standard clinical settings. Sample specimens were placed on the right side, under the artificial bones, and CT was performed to evaluate specimen visibility. We compared the artifacts created by the four bone types listed above, and measured the CT values of those materials. With ordinary scan settings, all the artificial bones revealed high-density artifact surrounding the materials, including the inability to accurately measure specimen thickness. The upper part of the specimen in contact with the artificial bones could not be distinguished from the artifact. The CT value in the medial aspect of the artificial bones increased more than the actual CT values. Of the four artificial bone materials studied, HA-PMMA produced the fewest artifacts. Description of the structures under the artificial bones can be improved by extending the window width to approximately twice that of normal settings.

Conspicuous endoscopic appearance of ventriculitis caused by coagulase-negative staphylococci.

To date, reports about the macroscopic appearance of ventriculitis have been rare, consisting only of a few autopsy cases. A patient in our hospital had ventriculitis caused by coagulase-negative staphylococci, and under neuroendoscopy we obtained clear findings of granular ependymitis. A 44-year-old man was admitted for disturbance of consciousness caused by progressive hydrocephalus. He had experienced subarachnoid hemorrhage (SAH) from a left vertebral dissecting aneurysm, and had subsequently received a ventriculoperitoneal shunt against post-SAH hydrocephalus. After admission, he was found to have retrograde shunt infection from peritonitis caused by cholecystitis. Coagulase-negative staphylococci were detected in cerebrospinal fluid (CSF), and the infection persisted even with intrathecal administration of gentamycin, and intravenous administration of vancomycin and arbekacin. Endoscopic rinsing was performed, and multiple small yellowish microgranulations, less than 1 mm in diameter, were observed in the lateral ventricles and the third ventricle. Rinsing of the CSF after intensive antimicrobial treatment resulted in a cure. Because there have been no reports of endoscopic observations of bacterial ventriculitis, we were unable to be certain about the origin or significance of the microgranulations. However, whether or not the microgranulations were bacterial colonies, infection did not recur during a 2-year follow-up period.

[Spontaneous closure of dural arteriovenous fistula after performing diagnostic angiography].

The pathogenesis and clinical treatment of dural arteriovenous fistulas (DAVF) has been well established. However, only 15 cases of spontaneous closure of DAVFs have been reported. We describe a case of spontaneous closure of a DAVF. A 60-year-old male presented with pulsatile tinnitus. Selective cerebral angiography revealed a left posterior DAVF fed by the left occipital artery and the middle meningeal artery, which drained into the left transverse sinus and sigmoid sinus. Following the initial angiography, the patient exhibited vomiting with transient disorientation and amnesia. These symptoms, along with the tinnitus, disappeared by the following day. Seven days after the initial angiography, a second angiography was performed that revealed the complete disappearance of the DAVF. Previous reports have described a long period of closure for DAVFs following initial diagnosis. Possible mechanisms for spontaneous closure of DAVFs include the development of scar tissue or a sinus thrombosis that leads to occlusion of the DAVF In this case, the DAVF closure may have been due to a sinus thrombosis induced by sinus stenosis, since occlusion of the draining sinuses coincided with the spontaneous closure of the DAVF. In cases of non-traumatic DAVF without cortical venous reflex that do not present severe symptoms, a prudent course of treatment is necessary since there is a chance of spontaneous closure of the DAVF occuring.

[Evaluation of cerebral blood perfusion with IVR-CT/angio system during interventional procedures].

An interventional-radiology computed-tomography (IVR-CT)/angio system is a combination of an angiographic unit and a CT scanner. This system allows patient's movement in and out of the two imaging units, on the same table. Since June 2003, we have applied our conventional protocol for evaluation of cerebral blood perfusion during interventional radiology (IVR) procedures. We reviewed our experience using the IVR-CT/angio system and investigated the efficacy and limitations of this technique. No complications relating to radiation exposure, contrast medium use, or IVR procedures were observed. CT perfusion was useful for detecting cerebral perfusion impairment during IVR procedures. This was helpful in deciding the postoperative management. Because patients do not need to be transported to another radiographic suite to evaluate cerebral blood perfusion, the IVR-CT/angio system is ideal for safely and simply detecting cerebral perfusion defects during IVR procedures. However, it is important to consider whether there is sufficient indication for the procedure, because radiation exposure and the amount of contrast medium use are increased if the IVR procedures become difficult.

Dural invasion of meningioma: a histological and immunohistochemical study.

Meningioma usually grows and expands into the brain, but invasion into the brain parenchyma is relatively rare. Meningioma arises from arachnoid cap cells, and infiltration into dura mater is the main growth pattern of meningiomas. However, little is known about the mechanism of meningioma invasion into the dura mater. In this study, seven specimens, including dural attachments, from seven cases of meningioma were used for immunohistochemical analysis. Matrix metalloproteinase (MMP)-1, -2, -9, urokinase-type plasminogen activator (uPA), vascular endothelial growth factors (VEGF), flt-1, E-cadherin, estrogen receptor (EgR), progesterone receptor (PgR), and aquaporin (AQP)-1, -4 were used as primary antibodies. There were several patterns of meningioma invasion into the dura mater: papillary-shaped invasion with destruction of dural structure, infiltration along the fibers of the dura mater, and invasion of several tumor cell units with fibroblast infiltration. Strong immunostaining was obtained with MMP-1, followed by AQP-1 and uPA, within the invading tumor cells. Neovasculature and extravasated erythrocytes, which stained with AQP-1, were also occasionally observed around the invading tumor cells. Simpson grade II removal of meningiomas results in high recurrence rates, and the inhibition of meningioma growth via dural invasion will facilitate improved remission in many cases with meningioma. In this study, MMP-1, AQP-1, and uPA are considered to have some role in the dural infiltration of meningioma cells. The fact that AQP-1 was highly expressed at the dural attachment and invading front of meningioma may indicate that dural invasion of the meningioma may be facilitated by AQP-1-induced water flow and neovascularization.

[Antibiotic treatment for traumatic brain injury patients without positive bacterial cultures].

Prophylactic administration of antibiotics is prevalent for traumatic patients including head injury, when the patients have contaminated wounds, CSF leakage, and multiple injuries. In cases with prolonged fever and inflammatory signs, other antibiotics must be selected without confirming the infections by cultures. Usually, 1st or 2nd generation cefalosporins are selected as empiric therapy for traumatic patients, but, successive antibiotics are usually selected according to the situation. In this study, we analyzed 60 cases of head injured patients with Glasgow Coma Scale under 12, in terms of the selection of antibiotics and the reasons for the antibiotic selections. CEZ > PIPC > FMOX were used for initial treatment without any culture results. The second selection was made without any positive culture results in 85.7%, and tertiary selection without culture results in 50% of the patients. CPR > CFSL > FMOX > PAPM/BP were mainly used as second selection, and IPM/CS > CPR = PIPC were mainly used as tertiary selection. In cases with traumatic brain injuries, it is important to prevent antibiotic resistances. 1) by selecting appropriate antibiotics, 2) by using antibiotics after excluding catheter related infections, 3) by not using antibiotics and performing frequent cultures when no apparent infection focuses are detected.

Transcranial echo-guided transsphenoidal surgical approach for the removal of large macroadenomas.

OBJECT: Transsphenoidal surgery for the removal of macroadenomas has some disadvantages, including the risk of performing procedures without adequate visualization, difficulties in estimating the amount of residual tumor, and the risk of injuring major vessels. To overcome these disadvantages, the authors have developed transcranial echo-guided transsphenoidal surgery. METHODS: Three patients with large macroadenomas and two patients with irregularly shaped macroadenomas were selected for this operation. In addition to standard preparations for transsphenoidal surgery, in each case the right frontal bone was trephined and an echo probe was inserted transdurally through the trephination hole. During tumor removal, brightness-mode echo images and Doppler color flow images were obtained. The echo images allowed for real-time visualization of the tumor and surrounding brain structures including major arteries and the cisterns; histological heterogeneities of the tumor could also be appreciated. The tumors were removed safely and maximal tumor removal was achieved. CONCLUSIONS: Transcranial echo-guided transsphenoidal surgery provides real-time visualization of tumor removal. The method enhances the safety of this surgery, maximizes the removal of the tumor, and is inexpensive.

A case of prolactin-secreting pituitary carcinoma and its histological findings.

Pituitary carcinomas are very rare. The diagnosis of pituitary carcinoma is defined by evidence of craniospinal and/or systemic metastasis, rather than by histological malignancies. We report a case of prolactin-secreting pituitary macroadenoma invading the cavernous sinuses at the time of initial treatment, which later metastasized to the cerebellum, medulla oblongata, and spinal axis. The patient survived approximately nine years following the initial diagnosis of a pituitary tumor and two years following the diagnosis of metastatic disease. Histological examination of the metastatic cerebellar tumor showed an adenoma with high cellularity and hyperchromasia, but no mitoses.