Effects of Alfaxalone on the Induction and Maintenance of Total Intravenous Anesthesia in Gentoo Penguins (Pygoscelis papua).

Systemic anesthesia in penguins is often achieved using inhalation anesthetic agents alone, and information on injectable drugs for systemic anesthesia is limited. General anesthesia with a minimal effect on circulatory dynamics is necessary to perform noninvasive examinations and treatments in animals, including penguins. In this study, alfaxalone (ALFX), an injectable anesthetic agent, was examined to establish the optimal anesthetic method for gentoo penguins (Pygoscelis papua). Alfaxalone was administered intravenously through the metatarsal vein, and anesthesia was maintained by a constant rate infusion (CRI). A biological monitor was used to record numerous clinical indices, and the anesthetic depth was evaluated every 5 minutes during anesthesia; the CRI was adjusted until the optimal anesthetic depth was obtained. Anesthesia depth was assessed, and the CRI rate was adjusted. The CRI was stopped, and the time until recovery was recorded. Blood samples were collected to analyze plasma concentrations of ALFX. The mean total dose of ALFX required for anesthetic induction was 9 ± 1.9 mg/kg, the intubation time was 126 ± 21 seconds, and the maintenance infusion rate of ALFX was 0.3 ± 0.08 mg/kg/min. The time from discontinuation of anesthesia to extubation was 42 ± 23 minutes, and the time to recovery was 90 ± 33 minutes. Significant changes in the heart rate and blood pressure were not observed during the anesthetic events. The plasma concentration of ALFX under stable anesthesia was 6734 ± 4386 ng/mL (range, 3315-14 326 ng/mL). Although anesthesia using ALFX tended to result in a prolonged time to recovery in gentoo penguins, rapid induction of anesthesia and stable hemodynamics during anesthetic maintenance were achieved. Therefore, ALFX may be considered a suitable anesthetic method for noninvasive examinations and treatments in penguins.

Boron neutron capture therapy and add-on bevacizumab in patients with recurrent malignant glioma.

BACKGROUND: Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. METHODS: Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1-4 weeks after boron neutron capture therapy and was administered every 2-3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. RESULTS: Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1-83.0) and 81.8% (95% confidence interval: 44.7-95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0-36.7) and 73.6 months (95% confidence interval: 11.4-77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2-12.1) and 15.6 months (95% confidence interval: 3.1-29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. CONCLUSIONS: Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.

Intronic Enhancer Is Essential for Nr5a1 Expression in the Pituitary Gonadotrope and for Postnatal Development of Male Reproductive Organs in a Mouse Model.

Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. Furthermore, the molecular functions of NR5A1 in the pituitary gonadotrope have not been fully elucidated. In the present study, we generated mice lacking the pituitary enhancer located in the 6th intron of the Nr5a1 gene. These mice showed pituitary gland-specific disappearance of NR5A1, confirming the functional importance of the enhancer. Enhancer-deleted male mice demonstrated no defects at fetal stages. Meanwhile, androgen production decreased markedly in adult, and postnatal development of reproductive organs, such as the seminal vesicle, prostate, and penis was severely impaired. We further performed transcriptomic analyses of the whole pituitary gland of the enhancer-deleted mice and controls, as well as gonadotropes isolated from Ad4BP-BAC-EGFP mice. These analyses identified several genes showing gonadotrope-specific, NR5A1-dependent expressions, such as Spp1, Tgfbr3l, Grem1, and Nr0b2. These factors are thought to function downstream of NR5A1 and play important roles in reproductive organ development through regulation of pituitary gonadotrope functions.

Boron neutron capture therapy for malignant brain tumors.

BACKGROUND: Boron neutron capture therapy (BNCT) is tumor-selective particle radiation therapy that depends on the nuclear capture and fission reactions. These reactions occur when a non-radioactive boron isotope (10B) is irradiated with low-energy thermal neutrons to yield high linear energy transfer α-particles and lithium-7 nuclei within a limited path length, i.e., an almost one-cell diameter. The 10B-containing cells can then be selectively destroyed by these potent particles. BNCT has been applied in the field of malignant brain tumors for newly diagnosed and recurrent malignant gliomas (chiefly glioblastomas). CLINICAL RESULTS: These clinical applications of BNCT have been performed with reactor-based neutron sources over the past decades. We also applied reactor-based BNCT for 58 newly diagnosed glioblastomas and 68 recurrent malignant gliomas including 52 glioblastomas. In this review article, we summarize the clinical results from the literature concerning BNCT for these high-grade gliomas (including our research). We also applied reactor-based BNCT for 46 cases of recurrent and refractory high-grade meningiomas, and some of the results will be presented herein. FUTURE PROSPECTS: In Japan, neutron sources have been shifted from reactors to accelerators. Phase 1 and 2 clinical trials have been performed for recurrent malignant gliomas using accelerator-based neutron sources, and now fortunately, a cyclotron-based neutron generator has been approved as a medical device by Japanese regulatory authority, as the world's first accelerator-based BNCT system for medical use. We also discuss the future prospects of accelerator-based BNCT in hospitals as therapy for malignant brain tumors.

Clinical indications for the use of computed tomography in children who underwent frequent computed tomography: a near-13-year follow-up retrospective study at a single institution in Japan.

Recent studies suggest a causal link of childhood leukemia and brain tumor with repeated computed tomography (CT) scans. The reasons why frequent CT scans are taken in a specific child remain unclear. The present study aimed to clarify the medical reasons why frequent CT examinations in children, and the characteristics of the diseases of those children that required multiple CT scans. A long-term follow-up retrospective study was conducted over a 12.75-year period at a single institution. Radiological reports were investigated that contained the indications for the CT scans. The clinical indications were classified for the examination of children under 16 years of age who underwent more than three CT scans into trauma, tumor, inflammation, and others. This study showed that 8.5% of CT examinations were done three times or more. The numbers of patients by indication were 23.3% for trauma, 5.3% for hydrocephalus, and 2.3% for appendicitis. The frequencies of trauma and inflammation decreased rapidly with an increasing number of CT scans. In particular, hydrocephalus brought high frequency more than ten scans. Regarding the frequencies of clinical indications by age groups, there was a significant difference (p<0.05). The near-13-year follow-up study indicated the main clinical indications for frequent CT scans in children were trauma and hydrocephalus. Multiple follow-up CT scans in children with hydrocephalus would be traded off against the resultant increase in brain tumor risk associated with CT exposure.

Computed tomography of the head and the risk of brain tumours during childhood and adolescence: results from a case-control study in Japan.

To clarify whether medical radiation exposure, especially from head computed tomography (CT), increases the risk of brain tumours in young patients in Japan, which ranks the second highest in the world in the number of paediatric CT examinations following the US. From 2011 to 2015, we performed a case-control study of 120 brain tumour patients and 360 appendicitis patients as controls. Reasons, the number of brain and head CT scans date were available from interviews. A cumulative radiation dose to the brain was calculated as a sum of doses received from head CT scans and from conventional X-rays and estimated using a reference table derived from a literature review of published studies. We performed conditional logistic regression to assess the risk of brain tumours from brain and head CT, and from conventional head X-ray procedures. The case group received on average 1.8 CTs to the brain area and 2.2 CTs to the whole head, with a mean estimated brain dose of 32 ±13 mGy. The odds ratio for developing a brain tumour from having a brain CT was 0.93 (95% confidence interval: 0.38-1.82). This was hardly altered when adjusting for parental educational history and for other diseases (history of neurological disease and attention-deficit disorder/attention-deficit hyperactivity disorder). Neither whole head CT nor cumulative brain dose to the brain increased the risk of glioma or of all brain tumours. Although this study conducted in Japan, where ranks second in the number of CT scans conducted in the world, did not show an increased risk of brain tumours related to CT scans, it should be taken with caution due to a case-control study with limited sample size.

Japanese population dose from natural radiation.

The radiation doses from natural radiation sources in Japan are reviewed using the latest knowledge. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and the Nuclear Safety Research Association report the annual effective doses from cosmic rays, terrestrial radiation, inhalation, and ingestion as natural sources. In this paper, the total annual effective dose from cosmic-ray exposure is evaluated as 0.29 mSv. The arithmetic mean of the annual effective dose from external exposure to terrestrial radiation is 0.33 mSv for the Japanese population using the data of nationwide surveys by the National Institute of Radiological Sciences. Previously in Japan, although three different groups have conducted nationwide indoor radon surveys using passive-type radon monitors, to date only the Japan Chemical Analysis Center (JCAC) has performed a nationwide radon survey using a unified method for radon measurements conducted indoor, outdoor, and in the workplace. Consequently, the JCAC results are used for the annual effective dose from radon and that for radon inhalation is estimated as 0.50 mSv using a current dose conversion factor. In this paper, UNSCEAR values are used for the mean indoor and outdoor thoron-progeny concentrations, and the annual effective dose from thoron is reported as 0.09 mSv. Thus, the annual effective dose from radon and thoron inhalation is 0.59 mSv. From a JCAC large-scale survey of foodstuffs, the committed effective dose from the main radionuclides in dietary intake is 0.99 mSv. Finally, the Japanese population dose from natural radiation is given as 2.2 mSv, which is similar to the reported global average of 2.4 mSv.

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

Non-Invasive Pulmonary Capillary Wedge Pressure Assessment on Speckle Tracking Echocardiography as a Predictor of New-Onset Non-Valvular Atrial Fibrillation　- Four-Year Prospective Study (NIPAF Study).

BACKGROUND: Although new-onset atrial fibrillation (AF) increases with ageing, the prediction of new-onset AF is complicated. We previously reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial volume index (LAVI) and active left atrial emptying function (aLAEF) had a strong relationship with PCWP on catheterization (r=0.92): ePCWP=10.8-12.4×log (aLAEF/minimum LAVI). We sought to determine the usefulness of ePCWP to predict new-onset AF. Methods and Results: We measured LAVI, aLAEF and ePCWP on speckle tracking echocardiography (STE) in 566 consecutive elderly patients (72±6 years) without a history of AF. A total of 63 patients (73±6 years) developed electrocardiographically confirmed AF during a mean follow-up period of 50 months. Baseline aLAEF was significantly lower in patients with than without new-onset AF (17.9±6.5 vs. 28.2±7.5%), whereas ePCWP was significantly higher (14.8±3.7 vs. 10.3±3.1 mmHg). In multivariate logistic regression analysis, ePCWP and aLAEF were strong independent predictors of AF. Using ePCWP >13 mmHg or aLAEF ≤22% on univariate Cox regression analysis, the HR for new-onset AF were 3.53 (95% CI: 1.68-7.44, P<0.001) and 4.06 (95% CI: 1.90-8.65, P<0.001), respectively. By combining these 2 criteria (>13 mmHg and ≤22%), the HR increased to 11.84 (95% CI: 6.85-20.5, P<0.001). CONCLUSIONS: ePCWP and aLAEF measured on STE are useful predictors of new-onset AF. ePCWP provides added value for risk stratification of new-onset AF.

[Evaluation of Entrance Surface Dose in Chest Radiography Using Clinical Images: Estimation of Subject Thickness Using Two-direction Radiography].

The International Commission on Radiological Protection recommends adaptation of the diagnostic reference levels as an indicator of optimization of protection, and diagnostic reference levels of 2015 were also published in Japan in 2015 (Japan DRLs 2015). The entrance surface dose (ESD) is evaluated to the published standard subject thickness in Japan DRLs 2015. However, the standard radiographic settings of each facility may not be a radiographic condition of the standard subject thickness of Japan DRLs 2015. We measure and record the thickness of the subject in every examination, and it can solve this problem, but it is difficult to carry out it in the actual clinical scene. In this study, we aimed to estimate the subject thickness by using chest clinical images and to calculate ESD for each radiography. We evaluated and compared with Japan DRLs 2015 using these data. The subject thickness was estimated from 200 cases of digital imaging and communications in medicine (DICOM) image obtained by both the frontal and lateral views of the chest radiography. Also, at the same time, the radiographic settings were acquired from the information of the DICOM tag. The subject thickness was 23.60 cm on the average, and the median of the ESD was 0.104 mGy. Also, the median of the ESD at the standard subject thickness of 20 cm in Japan DRLs 2015 was 0.075 mGy. The ESD can be calculated without measuring the body thickness of the patient of every examination by using the method of this study.

Cerebrospinal fluid dissemination of high-grade gliomas following boron neutron capture therapy occurs more frequently in the small cell subtype of IDH1R132H mutation-negative glioblastoma.

We have used boron neutron capture therapy (BNCT) to treat patients in Japan with newly diagnosed or recurrent high-grade gliomas and have observed a significant increase in median survival time following BNCT. Although cerebrospinal fluid dissemination (CSFD) is not usually seen with the current standard therapy of patients with glioblastoma (GBM), here we report that subarachnoid or intraventricular CSFD was the most frequent cause of death for a cohort of our patients with high-grade gliomas who had been treated with BNCT. The study population consisted of 87 patients with supratentorial high-grade gliomas; 41 had newly diagnosed tumors and 46 had recurrent tumors. Thirty of 87 patients who were treated between January 2002 and July 2013 developed CSFD. Tumor histology before BNCT and immunohistochemical staining for two molecular markers, Ki-67 and IDH1R132H, were evaluated for 20 of the 30 patients for whom pathology slides were available. Fluorescence in situ hybridization (FISH) was performed on 3 IDH1R132H-positive and 1 control IDH1R132H-negative tumors in order to determine chromosome 1p and 19q status. Histopathologic evaluation revealed that 10 of the 20 patients' tumors were IDH1R132H-negative small cell GBMs. The remaining patients had tumors consisting of other IDH1R132H-negative GBM variants, an IDH1R132H-positive GBM and two anaplastic oligodendrogliomas. Ki-67 immunopositivity ranged from 2 to 75%. In summary, IDH1R132H-negative GBMs, especially small cell GBMs, accounted for a disproportionately large number of patients who had CSF dissemination. This suggests that these tumor types had an increased propensity to disseminate via the CSF following BNCT and that these patients are at high risk for this clinically serious event.

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives.

To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50: 0.76nM, CDK19 IC50: 1.7nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound 52h showed excellent in vitro potency (CDK8 IC50: 0.46nM, CDK19 IC50: 0.99nM), physicochemical properties, and kinase selectivity (only 5 kinases showed <35% unbound fraction at 300nM. CDK19: 4.6%, CDK8: 8.3%, HASPIN: 23%, DYRK1B: 27%, HIP1: 32%). Based on a docking model of 52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl group of 52h interacting with Met174 of the CDK8 DMG activation loop. In vitro pharmacological evaluation of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: -1% (2.5mg/kg, qd)].

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.

We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.

Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion.

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers.

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Evaluation of systolic and diastolic properties of hypertensive heart failure using speckle-tracking echocardiography with high volume rates.

Left ventricular (LV) properties in hypertension (HTN) could be deteriorated by pressure overload, especially in endocardium, resulting in hypertensive heart failure (HHF). We sought to noninvasively examine LV systolic and diastolic functions at three myocardial layers in HTN and elucidate features of HHF by speckle-tracking echocardiography (STE) with high volume rates. We examined normotensive controls (n = 54), HTN patients without LV hypertrophy (LVH) (n = 50), and HTN patients with LVH (n = 40) and HHF patients (n = 45). The HHF group was divided into two subgroups based on their LVEF (20 heart failure with preserved ejection fraction: HFpEF and 25 heart failure with reduced ejection fraction: HFrEF). LV layer systolic function was assessed by strain rate during systole. Pulmonary capillary wedge pressure (PCWP) was estimated (ePCWP) using kinetics-tracking index (KT index) that we previously reported. HTN patients with LVH had a significant deterioration of systolic and diastolic properties compared with normotensive controls in the absence of a significant reduction in LVEF. Patients with HHF had further deterioration of systolic and diastolic properties compared with HTN patients with LVH. LV strain at entire myocardium and ePCWP in HFrEF was deteriorated compared with those in HFpEF. Deterioration of LV layer SR was more typical during systole, isovolumic relaxation, and early diastole compared with control. LV dilation was independently associated with LVEF (r = -0.48, p < 0.001) and ePCWP (r = 0.47, p < 0.001), and LVH (LV mass index) was independently associated with E/e' (r = 0.37, p = 0.025), LVEF (r = -0.44, p < 0.001), and ePCWP (r = 0.67, p < 0.001). LV layer analysis by STE could detect subtle impairments in systolic function before the deterioration of LVEF in patients with HTN. The ePCWP that was estimated using KT index was the independent factor associated with HHF. The ePCWP may be useful to noninvasively detect the early stage of HHF.

Evaluation of the Patient Exposure in General Radiography for Some Facilities: Comparison with DRL and Evaluation of the Difference among Facilities.

The first diagnostic reference levels (DRLs 2015) in Japan were published in June 2015. The purpose of this study was to compare the calculated entrance surface doses with the values of DRLs 2015, and evaluate differences in patient exposure among facilities. Semiconductor dosimeter was installed, and dosimetry was performed using equipment and radiographic condition of each facility. As a result, a dose higher than the value of DRLs 2015 was used in 12 kinds of examination. In child chest examination, the doses of the three facilities (0.26 mGy, 0.28 mGy, 0.60 mGy) exceeded the value of DRLs 2015 (0.2 mGy). Review of the radiographic condition is necessary because the doses exceeding DRLs 2015 tended to have a high current time product. The examination with the largest difference between facilities was the lateral of thoracic spine, with a difference of about 46 times, and the examination with the smallest difference was the ankle joint, with a difference of about three times. When reviewing, it is necessary to focus mainly on examinations that have a large difference between facilities. In the future, it can be said that it is necessary to set diagnostic reference range (DRR) or achievable dose (AD) to understand how high or low dose of the own facility are compared with facilities nationwide.

Comparison of the pharmacokinetics between L-BPA and L-FBPA using the same administration dose and protocol: a validation study for the theranostic approach using [18F]-L-FBPA positron emission tomography in boron neutron capture therapy.

BACKGROUND: Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. L-p-Boronophenylalanine (L-BPA) is a boron compound now widely used in clinical situations. Determination of the boron distribution is required for successful BNCT prior to neutron irradiation. Thus, positron emission tomography with [18F]-L-FBPA, an 18F-labelled radiopharmaceutical analogue of L-BPA, was developed. However, several differences between L-BPA and [18F]-L-FBPA have been highlighted, including the different injection doses and administration protocols. The purpose of this study was to clarify the equivalence between L-BPA and [19F]-L-FBPA as alternatives to [18F]-L-FBPA. METHODS: SCC-VII was subcutaneously inoculated into the legs of C3H/He mice. The same dose of L-BPA or [19F]-L-FBPA was subcutaneously injected. The time courses of the boron concentrations in blood, tumour tissue, and normal tissue were compared between the groups. Next, we administered the therapeutic dose of L-BPA or the same dose of [19F]-L-FBPA by continuous infusion and compared the effects of the administration protocol on boron accumulation in tissues. RESULTS: There were no differences between L-BPA and [19F]-L-FBPA in the transition of boron concentrations in blood, tumour tissue, and normal tissue using the same administration protocol. However, the normal tissue to blood ratio of the boron concentrations in the continuous-infusion group was lower than that in the subcutaneous injection group. CONCLUSIONS: No difference was noted in the time course of the boron concentrations in tumour tissue and normal tissues between L-BPA and [19F]-L-FBPA. However, the administration protocol had effects on the normal tissue to blood ratio of the boron concentration. In estimating the BNCT dose in normal tissue by positron emission tomography (PET), we should consider the possible overestimation of the normal tissue to blood ratio of the boron concentrations derived from the values measured by PET on dose calculation.

Estimated pulmonary capillary wedge pressure assessed by speckle tracking echocardiography predicts successful ablation in paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with left atrial (LA) remodeling caused by pressure and/or volume (LAV) overload. Increased pulmonary capillary wedge pressure (PCWP) represents LA pressure overload. We recently reported that pulmonary capillary wedge pressure (ePCWP) can be estimated by the kinetics-tracking (KT) index that combines LA function and volume using speckle tracking echocardiography (STE), and has a strong correlation with PCWP measured by right heart catheterization (r = 0.92). Therefore, we hypothesized that ePCWP is the best echocardiographic predictor of successful AF ablation. METHODS: We enrolled 137 patients with paroxysmal AF (age: 61 ± 10 years) who underwent pulmonary vein isolation. We measured LAV index, LA emptying function (EF) and LA stiffness during sinus rhythm before ablation using STE. PCWP was noninvasively estimated by STE as we previously reported. Parameters were compared between a group with AF recurrence (n = 30, age: 59 ± 11 years) and a group with successful ablation (sinus rhythm maintained for >1 year) (n = 107, age 61 ± 11 years). RESULTS: The ePCWP was correlated with PCWP measured by right heart catheterization (r = 0.76, p < 0.01). Compared with the non-recurrence group (n = 107, age: 61 ± 11), the AF recurrence group had significantly increased ePCWP (10.6 ± 3.5 vs 14.6 ± 2.9 mmHg, p < 0.01), minimum LAV index (29 ± 12 ml/m(2) vs 37 ± 14 ml/m(2), p < 0.01) and LA stiffness (0.47 ± 0.33 vs 0.83 ± 0.59, p < 0.01), but lower total LA EF (44 ± 11% vs 39 ± 13%, p < 0.01) before ablation. In multivariate logistic regression analysis, ePCWP was the most significant independent predictor of successful ablation. Using 13 mmHg of PCWP as the optimal cutoff value, the sensitivity and specificity for successful ablation were 73 and 77% (area under the curve = 0.81), respectively. CONCLUSION: The ePCWP that is measured by the combination of LA function and volume before ablation was a better predictor of the successful ablation compared with LA function and volume separately. The ePCWP estimated by STE is useful to predict the successful ablation in paroxysmal AF, and could be useful to improve candidate selection for AF ablation.