Publications by authors named "Koji Ono"

258 Publications

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.

J Med Chem 2021 Mar 25;64(5):2501-2520. Epub 2021 Feb 25.

Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals Company Ltd., Cambridge, Massachusetts 02139, United States.

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01491DOI Listing
March 2021

[Proposal for Reduction Measures of Eye Lens Exposure Based on Actual Exposure Management in Radiation-exposed Medical Staff].

Nihon Hoshasen Gijutsu Gakkai Zasshi 2021 ;77(2):160-171

Higashigaoka Faculty of Nursing · Postgraduate School of Nursing, Tokyo Healthcare University.

Purpose: To investigate the actual condition of the crystalline lens equivalent dose and effective dose according to the type of job and the type of duties in a medical institution. We also sought to clarify effective exposure reduction strategies.

Methods: Equivalent crystalline lens doses, effective doses, job type, and duties for 8656 persons · year were obtained from 17 medical facilities. We analyzed the relationship between the effective dose and the crystalline lens equivalent dose in uniform exposure control and non-uniform exposure control conditions. Exposure data were obtained for 13 unique job types and duties.

Results: The ratio of the lens equivalent dose to the effective dose of non-uniform exposure managers was 2 to 6 times and varied depending on the occupation. The percentage of persons whose annual lens equivalent dose exceeded 20 mSv was 4.75% for medical doctors, 1.17% for nurses, and 0.24% for radiological technologists. Highly exposed tasks included doctors in cardiology and gastroenterology performing angiography and endoscopy, nurses in endoscopy, and radiological technologists in radiography and CT examinations.

Conclusion: Thorough unequal exposure control for operations with high crystalline lens exposure, radiation protection education, and effective use of proper personal protective equipment such as the use of radiation protection glasses may reduce lens exposure levels.
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http://dx.doi.org/10.6009/jjrt.2021_JSRT_77.2.160DOI Listing
February 2021

BNCT for primary synovial sarcoma.

Appl Radiat Isot 2021 Mar 29;169:109407. Epub 2020 Dec 29.

Department of Pathology, Hyogo Cancer Center, Japan.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.
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http://dx.doi.org/10.1016/j.apradiso.2020.109407DOI Listing
March 2021

Antifungal drugs-low-susceptibility in Aspergillus flavus isolated from a captively reared Okinawa rail (Hypotaenidia okinawae).

J Vet Med Sci 2021 Jan 13;83(1):28-30. Epub 2020 Nov 13.

Yambaru Wildlife Conservation Center, Ministry of the Environment, 1-15-15 Higawa, Naha, Okinawa 900-0022, Japan.

A four-month old female Okinawa rail (Hypotaenidia okinawae) presented with respiratory distress. Despite antifungal treatment with voriconazole (VRZ), micafungin (MCF), and itraconazole (ITZ), respiratory distress did not improve and the bird died 167 days after initiating treatment. Necropsy revealed multifocal pyogranulomatous necrotic nodular lesions with numerous whitish-green fungal hyphae in the left air sac. Aspergillus flavus was isolated from the left air sac lesion. Antifungal susceptibility tests indicated that the isolate showed low susceptibility to amphotericin B (AMB), fluconazole (FLZ), VRZ and MCF.
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http://dx.doi.org/10.1292/jvms.20-0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870398PMC
January 2021

Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan (B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial.

Radiother Oncol 2021 Feb 11;155:182-187. Epub 2020 Nov 11.

Southern Tohoku BNCT Research Center, Koriyama, Japan; Department of Radiation Oncology, Southern Tohoku General Hospital, Koriyama, Japan.

Background And Purpose: Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (B) for recurrent or locally advanced head and neck cancer.

Materials And Methods: In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS).

Results: Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4-76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%).

Conclusion: These data suggest that BNCT using C-BENS with borofalan (B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.
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http://dx.doi.org/10.1016/j.radonc.2020.11.001DOI Listing
February 2021

Boron neutron capture therapy for clear cell sarcoma.

Appl Radiat Isot 2020 Dec 3;166:109324. Epub 2020 Aug 3.

Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10- 2 Tomogaoka, Suma-ku, Kobe, 654-0142, Japan.

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS.
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http://dx.doi.org/10.1016/j.apradiso.2020.109324DOI Listing
December 2020

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

J Radiol Prot 2020 Aug 6. Epub 2020 Aug 6.

Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, FRANCE.

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.
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http://dx.doi.org/10.1088/1361-6498/abacffDOI Listing
August 2020

Boron neutron capture therapy for malignant brain tumors.

J Neurooncol 2020 Aug 16;149(1):1-11. Epub 2020 Jul 16.

Kansai BNCT Medical Center, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.

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 (B) 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 B-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.
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http://dx.doi.org/10.1007/s11060-020-03586-6DOI Listing
August 2020

Synthesis and Evaluation of Dodecaboranethiol Containing Kojic Acid (KA-BSH) as a Novel Agent for Boron Neutron Capture Therapy.

Cells 2020 06 25;9(6). Epub 2020 Jun 25.

Research Center of Boron Neutron Capture Therapy, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai 599-8531, Japan.

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (B) to produce high-linear energy transfer (LET) alpha particles and recoiling Li nuclei (B [n, alpha] Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of B to tumor cells, with only small amounts of B to normal tissues. To develop practical materials utilizing B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel B carrier on cytotoxicity, B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. The tumor boron concentrations showed the highest concentrations at 1 h after the termination of administration. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute (KURRI) with KA-BSH. Median survival times (MSTs) of untreated and irradiated control rats were 29.5 and 30.5 days, respectively, while animals that received KA-BSH, followed by neutron irradiation, had an MST of 36.0 days ( = 0.0027, 0.0053). Based on these findings, further studies are warranted in using KA-BSH as a new B compound for malignant glioma.
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http://dx.doi.org/10.3390/cells9061551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349888PMC
June 2020

An attempt to improve the therapeutic effect of boron neutron capture therapy using commonly employed 10B-carriers based on analytical studies on the correlation among quiescent tumor cell characteristics, tumor heterogeneity and cancer stemness.

J Radiat Res 2020 Nov;61(6):876-885

Kansai BNCT Medical Center, Osaka Medical College, Japan.

Based on our previously published reports concerning the response of quiescent (Q) tumor cell populations to boron neutron capture therapy (BNCT), the heterogeneous microdistribution of 10B in tumors, which is influenced by the tumor microenvironment and the characteristics of the 10B delivery carriers, has been shown to limit the therapeutic effect of BNCT on local tumors. It was also clarified that the characteristics of 10B-carriers for BNCT and the type of combined treatment in BNCT can also affect the potential for distant lung metastases from treated local tumors. We reviewed the findings concerning the response of Q tumor cell populations to BNCT, mainly focusing on reports we have published so far, and we identified the mode of BNCT that currently offers the best therapeutic gain from the viewpoint of both controlling local tumor and suppressing the potential for distant lung metastasis. In addition, based on the finding that oxygenated Q tumor cells showed a large capacity to recover from DNA damage after cancer therapy, the interrelationship among the characteristics in Q tumor cell populations, tumor heterogeneity and cancer stemness was also discussed.
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http://dx.doi.org/10.1093/jrr/rraa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674684PMC
November 2020

Boron neutron capture therapy for head and neck cancer: Relevance of nuclear-cytoplasmic volume ratio and anti-tumor effect. -A preliminary report.

Appl Radiat Isot 2020 Sep 20;163:109212. Epub 2020 May 20.

Kansai BNCT Medical Center and Department of Otolaryngology Head and Neck Surgery, Osaka Medical College, Takatsuki, Japan.

BNCT is a type of particle beam radiation therapy that utilizes an α particle and 7Li nucleus generated when a thermal neutron is captured by a 10B nucleus involved in the boron compound that has been taken up into tumor tissue selectively. In this report, the relevance of N/C ratio of tumor cell and anti-tumor effect for BNCT clinical cases of head and neck cancer were verified. Examination of pre-irradiated tumor histopathological specimens of 9 BNCT treated head and neck cancer patients (4 CR patients, 5 non-CR patients) was performed. The statistically significant difference between the CR group and the non-CR group was examined for the physical dose was multiplied by the absolute biological effectiveness (ABE) value determined from the patient's tumor specific N/C ratio. Analysis showed the mean tumor dose could not distinguish between CR and non-CR groups. However, the ABE dose could clearly distinguish between the CR group and the non-CR group (p = 0.0250). The N/C ratio of tumor cell can influence the anti-tumor effect of BNCT for HNC.
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http://dx.doi.org/10.1016/j.apradiso.2020.109212DOI Listing
September 2020

Single-dose toxicity study by intra-arterial injection of BSH entrapped water-in-oil-in-water emulsion for boron neutron capture therapy to hepatocellular carcinoma.

Appl Radiat Isot 2020 Sep 13;163:109202. Epub 2020 May 13.

Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan; Cooperative Unit of Medicine & Engineering, The University of Tokyo Hospital, Tokyo, 113-8655, Japan.

We developed a mixing medical device by attaching Shirasu porous glass Millipore membrane to prepare water-in-oil-in-water (WOW) emulsion in a shorter time to be applied as B-entrapped WOW emulsion for hepatocellular carcinoma (HCC) treatment. Single-dose toxicity studies by intra-arterial injection of BSH-entrapped WOW were performed in rabbits and pig, and no side effects were observed. We hope to proceed to the preclinical and clinical studies for further evaluation of B compound as multidisciplinary treatments for HCC.
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http://dx.doi.org/10.1016/j.apradiso.2020.109202DOI Listing
September 2020

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.

Radiat Environ Biophys 2020 08 18;59(3):407-414. Epub 2020 Jun 18.

Oita University of Nursing and Hearth Sciences, 2944-9 Megusuno, Oita, Oita, 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.
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http://dx.doi.org/10.1007/s00411-020-00857-8DOI Listing
August 2020

Reevaluation of CBE value of BPA for hepatocytes.

Appl Radiat Isot 2020 Jul 2;161:109159. Epub 2020 Apr 2.

Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science Kyoto University (KURNS), 2 Asashiro-Nishi, Kumatori-cho, Osaka, 590-0494, Japan. Electronic address:

The compound biological effectiveness (CBE) value of boronophenylalanine (BPA) for hepatocytes was experimentally determined for the purpose of boron neutron capture therapy (BNCT) for liver tumors. In this study, the critical reevaluation of previous value was performed. In previous experimental studies, the contribution of β component of dose was ignored in the response curve to X-ray. X-ray dose cell survival curves were estimated by combining the α/β values obtained in the ordinary micronucleus (MN) assay with the curve of MN-negative cell fraction (MN(-)F) to dose. This curve was compared to the boron neutron capture reaction (BNCR) dose curve. As a result, the CBE value was 4 at doses close to 0 Gy, decreasing to about 1.0 at doses close to 4.5 Gy. The new value is smaller than the previous value 4.2. This indicates that the bioequivalent dose to normal liver is lower than previously expected. Therefore, higher doses can be given to the tumor.
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http://dx.doi.org/10.1016/j.apradiso.2020.109159DOI Listing
July 2020

Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.

J Med Chem 2020 03 16;63(6):3215-3226. Epub 2020 Mar 16.

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound () led to bromobenzothiophene () with potent inhibitory activity against DHPS. X-ray crystallographic analysis of complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01979DOI Listing
March 2020

Japanese population dose from natural radiation.

J Radiol Prot 2020 Sep;40(3):R99-R140

Ad hoc Committee of Japanese Population Dose Estimation of Japan Health Physics Society, Yoshimatsu Buid. 3F, 3-7-2 Shimbashi, Minato-ku, Tokyo 105-0004, Japan. Department of Radiation Physics and Chemistry, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.

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.
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http://dx.doi.org/10.1088/1361-6498/ab73b1DOI Listing
September 2020

Relationships among pulmonary capillary wedge pressure, dry weight and natriuretic peptide in patients undergoing hemodialysis: a three-dimensional speckle tracking echocardiography study.

J Echocardiogr 2020 09 29;18(3):160-168. Epub 2020 Jan 29.

Department of Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan.

Background: Although the evaluation of fluid status in hemodialysis (HD) patients is useful, relationship among pulmonary capillary wedge pressure (PCWP), dry body weight (DW) and natriuretic peptide has not been elucidated. In addition, there has been no objective marker for instantaneously monitoring hemodynamic improvement in response to HD. We previously reported that PCWP and time constant of left ventricular pressure decline (Tau) can be noninvasively estimated (ePCWP and eTau) by speckle tracking echocardiography (STE). The aim of this study was to elucidate the relationship among ePCWP, eTau, DW and natriuretic peptide in patients undergoing HD.

Methods: We measured ePCWP and body weight (BW) by STE in 81 patients and ANP and BNP by blood examination in 31 patients just before and after HD during sinus rhythm.

Results: The ePCWP decreased after HD, and this was associated with reductions in ln ANP, eTau and BW (r = 0.523, 0.271 and 0.814, respectively, p < 0.05). The % change in ePCWP was not correlated with the % change in ln BNP (p = 0.47). The change in ePCWP had a stronger correlation with the % change in BW than the change in any other parameters.

Conclusions: The ePCWP is more sensitive to estimate the change in BW during HD than any other parameters such as ANP and BNP. These results indicated that a substantial amount of excess fluid can be assessed real-time by STE using ePCWP.
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http://dx.doi.org/10.1007/s12574-020-00461-1DOI Listing
September 2020

Double superior venae cavae with absence of the coronary sinus and anomalies of the azygos venous system.

Anat Sci Int 2020 Jun 10;95(3):420-424. Epub 2020 Jan 10.

Department of Anatomy, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.

The superior vena cava is formed during the fetal period by the development of anastomoses between the right and left anterior cardinal veins, and the regression of the central part of the left anterior cardinal vein. The persistence of this part of the left anterior cardinal vein causes the formation of a left superior vena cava, which is a rare anomaly in cadaver dissection. We report the case of a persistent left superior vena cava with a normal right superior vena cava in a 95-year-old male cadaver, which was discovered during anatomical dissection for medical students at Kawasaki Medical School in 2016. The left superior vena cava was formed by the confluence of the left internal jugular and left subclavian veins and terminated in the right atrium via what would normally be the coronary sinus. The right and left superior venae cavae received intercostal veins via a right and left azygos vein, respectively. However, the right azygos vein was shorter than the normal azygos vein and received only the second to fifth intercostal veins, whereas the left azygos vein received the fifth to eleventh left intercostal veins and the sixth to eleventh right intercostal veins. We consider that the anomalies of the azygos venous system were the result of regression of right supracardinal vein and the persistence of the left supracardinal vein during development. An awareness of such variations of major thoracic veins is important for the interpretation of unusual CT images.
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http://dx.doi.org/10.1007/s12565-020-00524-4DOI Listing
June 2020

Angular dependence of shielding effect of radiation protective eyewear for radiation protection of crystalline lens.

Radiol Phys Technol 2019 Dec 15;12(4):401-408. Epub 2019 Oct 15.

Faculty of Nursing, Tokyo Healthcare University, Tokyo, Japan.

Radiation protective (RP) eyewear effectively protects crystalline lenses from radiation exposure. A drawback of RP eyewear is the angular dependence of the shielding effect, which results from the design of the eyewear. In this study, 21 models of RP eyewear with different designs and lead equivalences were assessed. Each piece of RP eyewear was hung on a Styrofoam phantom that imitated the head, and a 0.125-cc ionization chamber dosimeter was placed at the position of the crystalline lens. The differences in angular dependence of the shielding effect were evaluated by changing the irradiation angle, and parameters that improved the angular dependence of the shielding effect-sufficient lead equivalence, large coverage design, and minimum gap between the crystalline lens and the RP eyewear-were identified. Thus, the findings highlight the importance of selecting RP eyewear according to the angular distribution and the nature of radiation exposure in the workplace for radiation workers.
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http://dx.doi.org/10.1007/s12194-019-00538-2DOI Listing
December 2019

Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential.

Int J Radiat Biol 2019 12 23;95(12):1708-1717. Epub 2019 Sep 23.

Kansai BNCT Medical Center, Osaka Medical College, Osaka, Japan.

To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a B-carrier (-boronophenylalanine-B (BPA) or sodium mercaptoundecahydrododecaborate-B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT. BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.
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http://dx.doi.org/10.1080/09553002.2019.1666214DOI Listing
December 2019

PROPOSAL FOR LOCAL DIAGNOSTIC REFERENCE LEVELS IN GENERAL RADIOGRAPHY IN JAPAN.

Radiat Prot Dosimetry 2019 Dec;187(3):338-344

Department of Radiological Technology, Toyota Kosei Hospital, Toyota, Japan.

The present study aimed to propose local diagnostic reference levels (DRLs) formulated by calculating entrance surface doses for general radiography at 20 facilities of Aichi prefecture in Japan, by comparing these values with DRLs established in Japan in 2015 (DRLs 2015) and assessing radiation dose differences among facilities. X-ray outputs (half-value layer and air kerma) of each facility were measured with a non-invasive type of detector. The results were employed to formulate local DRLs based on the 75th percentiles of dose distributions. These local DRLs were lower than the DRLs 2015 for all examinations. If proposed local DRLs from other 46 prefectures can be collected, this paper can be used to benefit the next effort to draft better DRL for Japan.
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http://dx.doi.org/10.1093/rpd/ncz172DOI Listing
December 2019

Effect of Intravesical Bacilli Calmette-Guerin Therapy After Second Transurethral Resection in Stage Ta T1 High-Grade Bladder Cancer.

Yonago Acta Med 2019 Jun 20;62(2):191-197. Epub 2019 Jun 20.

Division of Urology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.

Background: To evaluate the efficacy of Bacilli Calmette-Guerin (BCG) induction instillation therapy after second transurethral resection (TUR) in stage Ta T1 high-grade bladder cancer.

Methods: We performed a retrospective analysis of 49 consecutive new onset Ta T1 high-grade bladder cancer patients treated with second TUR at our affiliated institutions. Residual cancer rate, intravesical recurrence-free survival (RFS), and risk factors related to RFS were evaluated by univariate and multivariate Cox proportional hazard model analyses.

Results: Thirty-one patients received BCG therapy after the second TUR (BCG group), and 18 patients were treated with second TUR alone (no BCG group). There were statistically significant differences in the RFS rates between the two groups, ( = 0.037). BCG therapy was the only factor predictive of intravesical recurrence after second TUR in both univariate and multivariate analyses. After the second TUR, BCG therapy significantly decreased intravesical recurrence in the patients with residual tumors ( = 0.014). However, there was no significant difference in intravesical recurrence in the patients with no residual tumors between the two groups ( = 0.359).

Conclusion: BCG therapy after second TUR significantly decreased intravesical recurrence of residual tumors found at the second TUR.
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http://dx.doi.org/10.33160/yam.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584257PMC
June 2019

Effects of Status of Tumor Cells and Combined Treatment With Mild Hyperthermia, Wortmannin or Caffeine on Recovery From Radiation-Induced Damage.

World J Oncol 2019 Jun 29;10(3):132-141. Epub 2019 Jun 29.

Kansai BNCT Medical Center, Osaka Medical College, 2-7 Daigaku-machi Takatsuki, Osaka 569-8686, Japan.

Background: The aim of the study was to examine the dependency of status and the usefulness of mild hyperthermia (MHT) as an inhibitor of recovery from radiation-induced damage, referring to the response of quiescent (Q) tumor cell population.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/) or with neo vector (SAS/) were injected subcutaneously into left hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received high dose-rate γ-ray irradiation (HDR) immediately followed by localized MHT (40 °C for 2 h), or caffeine or wortmannin administration, or low dose-rate γ-ray irradiation simultaneously with localized MHT or caffeine or wortmannin administration. Nine hours after the start of irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells) was determined using immunofluorescence staining for BrdU.

Results: SAS/ tumor cells, especially intratumor Q cell populations, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q tumor cells within SAS/ tumors that showed little recovery capacity. The recovery from radiation-induced damage was thought to be a dependent event. In both total and Q tumor cells within SAS/ tumors, especially the latter, MHT efficiently suppressed the reduction in sensitivity caused by leaving an interval between HDR irradiation and the assay and decreasing the irradiation dose-rate, as well as the combination with wortmannin administration.

Conclusions: From the viewpoint of solid tumor control as a whole, including intratumor Q-cell control, non-toxic MHT is useful for suppressing the recovery from radiation-induced damage, as well as wortmannin treatment combined with γ-ray irradiation.
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http://dx.doi.org/10.14740/wjon1203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615912PMC
June 2019

Left Ventricular Torsion in Hypertension and Hypertensive Heart Failure - 3-Dimensional Speckle Tracking Echocardiography Assessment.

Circ Rep 2019 Feb 2;1(2):78-86. Epub 2019 Feb 2.

Department of Cardiology, Gifu University Graduate School of Medicine Gifu Japan.

Left ventricular (LV) torsion by contraction of inner and outer oblique muscles contributes to EF. Outer muscle plays a predominant role in torsion. We evaluated the impact of LV remodeling by hypertension (HTN) on torsion using 3-dimensional speckle tracking echocardiography (3D-STE). LV strain, strain rate during systole (SR-S) and torsion at endocardium, mid-wall and epicardium were assessed on 3D-STE in 53 controls and 186 HTN patients. Torsion was defined as the difference between apical and basal rotation divided by long axis length. LVEF and strain, SR-S and torsion in all 3 layers in HTN without LV hypertrophy (LVH) were similar to those in controls. LV longitudinal strain at endocardium in HTN with LVH decreased, whereas LVEF was similar to that in controls and, which was associated with increased torsion at epicardium. Reduced LVEF in hypertensive HF was associated with reduced strain, SR-S and torsion in all layers and with LV dilation. On multivariate analysis, epicardial torsion was an independent determinant of LVEF. At epicardial torsion cut-off 0.41, the sensitivity and specificity for the identification of HFrEF were 88% and 68%. Torsion on 3D-STE may represent a compensatory mechanism to maintain LVEF despite reduced endocardial function, suggesting that the deterioration of torsion caused by insult to outer muscle and dilation may lead to HFrEF.
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http://dx.doi.org/10.1253/circrep.CR-19-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890276PMC
February 2019

Effect of a change in reactor power on response of murine solid tumors in vivo, referring to impact on quiescent tumor cell population.

Int J Radiat Biol 2019 05 8;95(5):635-645. Epub 2019 Jan 8.

c Particle Radiation Oncology Center , Institute for Integrated Radiation and Nuclear Science, Kyoto University , Sennan-gun , Osaka , Japan.

Purpose: To examine the effect of a change in reactor power on the response of solid tumors, referring to impact on quiescent (Q) tumor cell population.

Materials And Methods: Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) tumor cells, and were treated with boronophenylalanine-B (BPA) or sodium mercaptododecaborate-B (BSH). After reactor neutron beam irradiation at a power of 1 or 5 MW with an identical beam spectrum, cells from tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled Q and total (P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.

Results: After neutron irradiation with or without B-carrier, radio-sensitivity was reduced by decreasing reactor power in both cells, especially in Q cells and after irradiation with BPA. The values of relative and compound biological effectiveness were larger at a power of 5 MW and in Q cells than at a power of 1 MW and in total cells, respectively. The sensitivity difference between total and Q cells was widened when combined with B-carrier, especially with BPA, and through decreasing reactor power.

Conclusion: 5 MW is more advantageous than 1 MW for boron neutron capture therapy.
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http://dx.doi.org/10.1080/09553002.2019.1558300DOI Listing
May 2019

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

Radiat Environ Biophys 2019 03 24;58(1):59-67. Epub 2018 Nov 24.

Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.

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.
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http://dx.doi.org/10.1007/s00411-018-0765-2DOI Listing
March 2019

Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study.

Neurol Med Chir (Tokyo) 2018 Dec 21;58(12):487-494. Epub 2018 Nov 21.

Section for Advanced Medical Development, Cancer Center, Osaka Medical College.

Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.
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http://dx.doi.org/10.2176/nmc.oa.2018-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300692PMC
December 2018

Proposal for determining absolute biological effectiveness of boron neutron capture therapy-the effect of 10B(n,α)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size.

J Radiat Res 2019 Jan;60(1):29-36

Division of Radiation Life Science, Kyoto University, 2-Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka, Japan.

The relationship between the radiation dose delivered to a tumor and its effect is not completely predictable. Uncertainty in the estimation of the boron concentration in a tumor, variation in the radiation sensitivity of the tumor cells, and the complexity of the interactions between the four types of radiation comprising the boron neutron capture therapy (BNCT) dose contribute to this uncertainty. We reanalyzed the data of our previous papers to investigate the variation in radiosensitivity of tumor cells to the 10B(n,α)7Li dose: the dose generated by the reaction of thermal neutrons and 10B, hereafter the 'boron-neutron dose'. The radiosensitivities of five tumors (EL4, SAS/neo, SAS/mp53, SCCVII and B16-BL6 melanoma) were examined. For the combination of p-boron-L-phenylalanine (BPA: C9H12BNO4) with neutron irradiation, D0, the cell survival curve for the boron-neutron dose was the smallest for the SAS/neo, followed by the EL4, SAS/mp53, SCCVII and B16-BL6 melanoma, in that order. For the combination of mercaptoundecahydrododecaborate (BSH: Na2B12H11SH) with neutron irradiation, D0 was the smallest for the EL4, followed by the SAS/neo, B16-BL6melanoma, SAS/mp53 and SCCVII, in that order. The relationships between these D0 values and the nucleocytoplasmic ratios (Xncs) or cell size indices (Xcs) obtained by histopathological microslide image were as follows: (D0 = 0.1341Xnc-1.586, R2 = 0.9721) for all tumor types with BPA-BNCT, and D0 = 0.0122Xcs-0.1319 (R2 = 0.9795) for four tumor types (all except the B16-BL6 melanoma) with BSH-BNCT. Based on these results, we proposed a new biologically equivalent effectiveness factor: the absolute biological effectiveness (ABE) factor. The ABE factor is Gy/D0. Thus, the ABE dose is the physical dose multiplied by the ABE factor, and refers to the dose needed to decrease the cell survival rate to e-ABE dose/Gy.
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http://dx.doi.org/10.1093/jrr/rry080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373679PMC
January 2019

The Effect of Status on Radio-Sensitivity of Quiescent Tumor Cell Population Irradiated With γ-Rays at Various Dose Rates.

J Clin Med Res 2018 Nov 9;10(11):815-821. Epub 2018 Oct 9.

Kansai BNCT Collaborative Research Center, Osaka Medical College, 2-7, Daigaku-cho, Takatsuki, Osaka 569-8686, Japan.

Background: The aim of the study was to clarify the effect of status of tumor cells on radio-sensitivity of solid tumors following γ-ray irradiation at various dose rates, referring to the response of intratumor quiescent (Q) cells.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/) or with neo vector (SAS/) were injected subcutaneously into hind legs of nude mice. Tumor bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays at a high, middle or low dose rate. Immediately or 9 h after the high dose-rate irradiation (HDR, 2.5 Gy/min), or immediately after the middle (MDR, 0.039 Gy/min) or low (LDR, 0.00098 Gy/min) dose-rate irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU.

Results: Following γ-ray irradiation, SAS/ tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/ tumors that showed little repair capacity. The recovery capacities following γ-ray irradiation were greater in Q than total cell population and increased in the following order of 9 h after HDR < MDR < LDR. Thus, the difference in radio-sensitivity between the total (P + Q) and Q cells after γ-ray irradiation increased in the same order.

Conclusion: To secure controlling solid tumors as a whole, difference in sensitivity between total and Q tumor cells especially in solid tumors irrespective of status has to be suppressed as irradiation dose rate decreases, for instance, through employing combined method for enhancing the response of Q tumor cells.
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http://dx.doi.org/10.14740/jocmr3610wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188028PMC
November 2018

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).

Circ J 2018 11 16;82(12):3029-3036. Epub 2018 Oct 16.

Department of Cardiology, Gifu Prefectural General Medical Center.

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.
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http://dx.doi.org/10.1253/circj.CJ-18-0799DOI Listing
November 2018