VALIDATION OF MONTE CARLO DOSE CALCULATION FOR PAEDIATRIC CT EXAMINATIONS USING TUBE CURRENT MODULATION BASED ON IN-PHANTOM DOSIMETRY.

The aim of this study is to estimate tube current modulation (TCM) profiles in paediatric computed tomography (CT) examinations with a TCM scheme (Volume-EC) and evaluate the estimation accuracy of TCM profiles. Another aim is to validate organ doses calculated using Monte Carlo-based CT dosimetry software and estimated TCM profiles by comparing them with those measured using 5-year-old and 10-year-old anthropomorphic phantoms and radio-photoluminescence glass dosemeters. Dose calculations were performed by inputting detailed descriptions of a CT scanner, scan parameters and CT images of the phantoms into the software. Organ doses were evaluated from the calculated dose distribution images. Average relative differences (RDs) between the estimated and actual TCM profiles ranged from -3.6 to 5.6%. RDs between the calculated and measured organ doses ranged from -4.2 to 13.0% and -18.1 to 4.9% for 5-year-old and 10-year-old phantoms, respectively. These results validate dose calculations for paediatric CT scans using TCM.

Organ Dose Evaluations Based on Monte Carlo Simulation for CT Examinations Using Tube Current Modulation.

The aims of this study were to estimate tube current values for each X-ray projection angle used in adult chest computed tomography (CT) and abdomen-pelvis CT examinations with tube current modulation (TCM) and to validate organ doses determined using Monte Carlo (MC) simulations through comparisons with the doses measured using in-phantom dosimetry. For dose simulations, dose distribution images were obtained by inputting the geometry of a CT scanner, scan parameters including estimated TCM curves and CT images of an adult anthropomorphic phantom into MC simulation software. Organ doses were then determined from the dose distribution images. For dose measurements, organ doses were evaluated using radio-photoluminescence glass dosemeters located at various organ positions within the phantom. Relative differences between the simulated and measured organ doses were -2.5 to 11.0% and -1.5 to 10.5% for organs in chest and abdomen-pelvis CT scan ranges, respectively. Thus, the simulated and measured doses agreed well.

DEVELOPMENT OF AGE-SPECIFIC JAPANESE PHYSICAL PHANTOMS FOR DOSE EVALUATION IN INFANT CT EXAMINATIONS.

Secondary to the previous development of age-specific Japanese head phantoms, the authors designed Japanese torso phantoms for dose assessment in infant computed tomography (CT) examinations and completed a Japanese 3-y-old head-torso phantom. For design of age-specific torso phantoms (0, 0.5, 1 and 3 y old), anatomical structures were measured from CT images of Japanese infant patients. From the CT morphometry, it was found that rib cages of Japanese infants were smaller than those in Europeans and Americans. Radiophotoluminescence glass dosemeters were used for dose measurement of a 3-y-old head-torso phantom. To examine the validity of the developed phantom, organ and effective doses by the in-phantom dosimetry system were compared with simulation values in a web-based CT dose calculation system (WAZA-ARI). The differences in doses between the two systems were <20 % at the doses of organs within scan regions and effective doses in head, chest and abdominopelvic CT examinations.

HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia.

We previously found that tyrosine kinase 2 (TYK2) signaling through its downstream effector phospho-STAT1 acts to upregulate BCL2, which in turn mediates aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we show that pharmacologic inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein levels were not affected by AUY922 treatment, but phospho-STAT1 (Tyr-701) levels rapidly became undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression was downregulated after AUY922 treatment, and although this effect was necessary for AUY922-induced apoptosis, it was not sufficient because many T-ALL cell lines were resistant to ABT-199, a specific inhibitor of BCL2. Unlike ABT-199, AUY922 also upregulated the proapoptotic proteins BIM and BAD, whose increased expression was required for AUY922-induced apoptosis. Thus, the potent cytotoxicity of AUY922 involves the synergistic combination of BCL2 downregulation coupled with upregulation of the proapoptotic proteins BIM and BAD. This two-pronged assault on the mitochondrial apoptotic machinery identifies HSP90 inhibitors as promising drugs for targeting the TYK2-mediated prosurvival signaling axis in T-ALL cells.

Optimised paediatric CT dose at a tertiary children's hospital in Japan: a 4-y single-centre analysis.

Since diagnostic reference levels (DRLs) for children are not currently established in Japan, the authors determined local DRLs for the full range of paediatric CT examinations in a single tertiary care children's hospital. A retrospective review of 4801 CT performance records for paediatric patients (<15 y old) who had undergone CT examinations from 2008 to 2011 was conducted. The most frequent examinations were of the head (52 %), followed by cardiac (15 %), temporal bone (9 %), abdomen (7 %), chest (6 %) and others (11 %). Approximately one-third of children received two or more CT scans. The authors' investigation showed that mean CTDIvol and DLP for head, chest and abdomen increased as a function of age. Benchmarking of the results showed that CTDIvol, DLP and effective dose for chest and abdomen examinations in this hospital were below average, whereas those for the head tended to be at or slightly above average of established DRL values from five countries. The results suggest that CT examinations as performed in a tertiary children's hospital in Japan are well optimised.

Evaluation of organ doses in adult and paediatric CT examinations based on Monte Carlo simulations and in-phantom dosimetry.

The aim of this study was to validate the computed tomography dose index (CTDI) and organ doses evaluated by Monte Carlo simulations through comparisons with doses evaluated by in-phantom dosimetry. Organ doses were measured with radio-photoluminescence glass dosemeter (RGD) set at various organ positions within adult and 1-y-old anthropomorphic phantoms. For the dose simulations, the X-ray spectrum and bow-tie filter shape of a CT scanner were estimated and 3D voxelised data of the CTDI and anthropomorphic phantoms from the acquired CT images were derived. Organ dose simulations and measurements were performed with chest and abdomen-pelvis CT examination scan parameters. Relative differences between the simulated and measured doses were within 5 % for the volume CTDI and 13 % for organ doses for organs within the scan range in adult and paediatric CT examinations. The simulation results were considered to be in good agreement with the measured doses.

Efficacy of Mitiglinide Combined with Dapagliflozin in Streptozotocin-nicotinamide-induced Type 2 Diabetic Rats and in Zucker Fatty Rats.

The efficacy of the combination of the rapid-acting insulin secretagogue mitiglinide and the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was explored in streptozotocin-nicotinamide-induced type 2 diabetic (STZ-NA) rats and in Zucker fatty (ZF) rats. The STZ-NA rats were prepared at 8 weeks of age. At 9 weeks of age, the combination study was conducted by oral glucose tolerance test (OGTT). At 13 weeks of age, ZF rats were dosed orally with dapagliflozin once daily up to the 22(nd) day. At days 15 and 22, the combination study was conducted by OGTT. In 2 different animal models, plasma glucose levels were strongly suppressed by the combination of mitiglinide and dapagliflozin as compared with either drug alone. The urinary glucose excretion was drastically elevated in the dapagliflozin group, but the combination with mitiglinide suppressed it about 50%. In STZ-NA rats, the plasma insulin secretion by the combination of both drugs was about at the same level as in the mitiglinide group. In ZF rats, the plasma insulin secretion by the combination of both drugs was less than mitiglinide group. Thus, in 2 different animal models, the combination of mitiglinide and dapagliflozin showed stronger antihyperglycemic action accompanied by less insulin secretion than mitiglinide alone, and reduced the urinary glucose excretion as compared with dapagliflozin used alone. These results indicate that the combination of mitiglinide and dapagliflozin can be a promising combination for the treatment of diabetic patients.

Development of age-specific Japanese head phantoms for dose evaluation in paediatric head CT examinations.

In this study, the authors developed age-specific physical head phantoms simulating the physique of Japanese children for dose evaluation in paediatric head computed tomography (CT) examinations. Anatomical structures at 99 places in 0-, 0.5-, 1- and 3-y-old Japanese patients were measured using DICOM viewer software from CT images, and the head phantom of each age was designed. For trial manufacture, a 3-y-old head phantom consisting of acrylic resin and gypsum was produced by machine processing. Radiation doses for the head phantom were measured with radiophotoluminescence glass dosemeters and Si-pin photodiode dosemeters. To investigate whether the phantom shape was suitable for dose evaluation, organ doses in the same scan protocol were compared between the 3-y-old head and commercially available anthropomorphic phantoms having approximately the same head size. The doses of organs in both phantoms were equivalent. The authors' designed paediatric head phantom will be useful for dose evaluation in paediatric head CT examinations.

Long-time correlation in non-Markovian dephasing of an exciton-phonon system in InAs quantum dots.

We have observed a time-correlated frequency fluctuation in non-Markovian dephasing of excitons in InAs quantum dots using a six-wave mixing technique. In this measurement, the arrival times of the excitation pulses were controlled to eliminate the influence of Markovian dephasing and to measure the pure non-Markovian behavior. The experimental result shows that the time correlation of the frequency fluctuation due to exciton-phonon interactions was maintained in the quantum dots for over 10 ps. This long-time correlation is caused by the modification of the phonon coupling distribution.

BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia.

Allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for chronic myeloid leukemia and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia, and the graft-vs-leukemia (GVL) effect can eradicate residual leukemia after allo-SCT. Ph(+) leukemia cells frequently express death-inducing receptors (DR4 and DR5) for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the cytotoxic ligands expressed on cytotoxic T cells and natural killer cells mediating the GVL effect. Here we demonstrate that imatinib specifically downregulated DR4 and DR5 expression in cell lines and clinical samples of Ph(+) leukemia. Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) and short hairpin RNA against bcr-abl also downregulated DR4 and DR5 expression in Ph(+) leukemia cells, and transfection of bcr-abl into a Ph(-) leukemia cell line induced DR4 and DR5 expression, which was abrogated by imatinib treatment. Accordingly, Ph(+) leukemia cells that had been pretreated with imatinib showed resistance to the pro-apoptotic activity of recombinant human soluble TRAIL. These observations demonstrate that BCR-ABL is critically involved in the leukemia-specific expression of DR4 and DR5 and in the susceptibility of Ph(+) leukemia to TRAIL-mediated anti-leukemic activity, providing new insight into the mechanisms of the tumor-specific cytotoxic activities of TRAIL.

Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.

t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.

Evaluation of organ doses in CT examinations with an infant anthropomorphic phantom.

The aim of this study is to evaluate organ doses in infant CT examinations with multi-detector row CT scanners. Radiation doses were measured with radiophotoluminescence glass dosemeters set in various organ positions within a 1-y-old child anthropomorphic phantom and organ doses were evaluated from the measurement values. Doses for tissues or organs within the scan range were 28-36 mGy in an infant head CT, 3-11 mGy in a chest CT, 5-11 mGy in an abdominal-pelvic CT and 2-14 mGy in a cardiac CT. The doses varied by the differences in the types of CT scanners and scan parameters used at each medical facility. Compared with those for children of various ages, the doses in an infant CT protocol were found to be similar to or slightly smaller than those in a paediatric CT for 5- or 6-y-old children.

Dose measurement for medical staff with glass dosemeters and thermoluminescence dosemeters during 125I brachytherapy for prostate cancer.

Photoluminescence glass dosemeters (PLDs) and thermoluminescence dosemeters (TLDs) are commonly used as a personal monitoring dosemeter. PLDs and TLDs were used for surface dose monitoring of medical staff involved in (125)I brachytherapy for prostate cancer because these dosemeters have a wide dose-response linearity and high sensitivity for low photon energy. Surface doses measured with PLDs agreed with those with TLDs within ∼20 % except for a few cases. Surface doses at a surgeon's left hand and arm were higher than those at the other measuring points. A surgeon received a maximum dose of 650 µGy at the back of left hand. Surface doses to an assistant were <100 µGy. Surface doses to a nurse, a radiologist, an anaesthesiologist and a radiological technologist were <10 µGy. The occupational exposure to a surgeon could be reduced by the adjustment of fluoroscopic parameters and the use of lead gloves.

Successful tandem (autologous-cord blood) SCT in advanced neuroblastomas with highly amplified MYCN.

Although autologous tandem hematopoietic SCT has improved the prognosis of patients with advanced high-risk neuroblastoma, the results remain unsatisfactory. In an attempt to induce the graft-versus-tumor effect, we performed autologous PBSCT followed by allogeneic cord blood transplantation in three consecutive advanced neuroblastoma cases with marked BM infiltration and high MYCN amplification. Severe acute complications did not occur in any patient and they have maintained disease-free survival for 37-60 months. This strategy appears to be feasible and effective for the treatment of extremely high-risk neuroblastoma cases.

Palmitate induces apoptosis in Schwann cells via both ceramide-dependent and independent pathways.

Peripheral neuropathy has been reported to prevail in obese or pre-diabetic individuals, yet its etiology remains unknown. Palmitate, a saturated fatty acid increased in obesity and diabetes, is known to induce apoptosis in multiple types of cells and this effect may be mediated by ceramide, a member of the sphingolipid family. To clarify whether de novo ceramide synthesis from palmitate contributes to apoptosis of Schwann cells, we cultured immortalized mouse Schwann cells (IMS) and rat primary Schwann cells with palmitate, a ceramide analogue C2-ceramide as well as inhibitors of the de novo ceramide synthesis (myriocin and fumonisin B1). Apoptosis of IMS detected by nuclear staining and cell membrane inversion was significantly increased by incubation with palmitate for 48 h in a dose-dependent fashion. This enhanced apoptosis was partially but significantly suppressed by myriocin and fumonisin B1. Western blot analysis and immunostaining revealed that palmitate clearly activated caspase-3 in IMS. Unexpectedly, the ceramide synthesis inhibitors failed to suppress the palmitate-induced caspase-3 activation in spite of complete restoration in ceramide accumulation. The results seemed relevant to the observations that C2-ceramide did not activate caspase-3 while provoking apoptosis with a clear dose-dependency. In agreement, the pro-apoptotic action of C2-ceramide was not attenuated by caspase inhibitors that partially suppressed palmitate-induced apoptosis. These results in IMS were well reproducible in rat primary Schwann cells, indicating that the observed phenomena are not specific to the cell line. Collectively, we have reached a conclusion that palmitate induces apoptosis in Schwann cells via both a ceramide-mediated, caspase-3-independent pathway and ceramide-independent, caspase-3-dependent pathways. Given the fact that palmitate and ceramide are increased in obese or pre-diabetic subjects, these lipids may be implicated in the pathogenesis of peripheral neuropathy observed in these disorders.

Rectal duplication cyst successfully treated by laparoscopic total mesorectal excision using the prolapsing technique.

Congenital alimentary tract duplication is a rare disease. It most frequently occurs in the ileum, with the rectum being the rarest site. Herein, we report a 38-year-old woman who was referred to our hospital because of severe anal pain. On digital examination, a smooth, round, rubbery mass was palpable; it was located 5 cm from the anal verge in the posterior rectal wall. A CT scan demonstrated a 5-cm cystic lesion located anterior to the sacrum that was displacing the rectum anteriorly. Spontaneous remission of the tumor was evident; however, after 5 months of follow-up, the patient experienced the same severe anal pain. MRI demonstrated a recurrent cystic lesion. To prevent further complications and to confirm or deny malignancy, laparoscopic total mesorectal excision using the prolapsing technique was performed. Pathologically, the cystic lesion was diagnosed as a rectal duplication cyst. This is the first report of a rectal duplication cyst successfully treated by laparoscopic total mesorectal excision.

Radiation dose evaluation in 64-slice CT examinations with adult and paediatric anthropomorphic phantoms.

The objective of this study was to evaluate the organ dose and effective dose to patients undergoing routine adult and paediatric CT examinations with 64-slice CT scanners and to compare the doses with those from 4-, 8- and 16-multislice CT scanners. Patient doses were measured with small (<7 mm wide) silicon photodiode dosemeters (34 in total), which were implanted at various tissue and organ positions within adult and 6-year-old child anthropomorphic phantoms. Output signals from photodiode dosemeters were read on a personal computer, from which organ and effective doses were computed. For the adult phantom, organ doses (for organs within the scan range) and effective doses were 8-35 mGy and 7-18 mSv, respectively, for chest CT, and 12-33 mGy and 10-21 mSv, respectively, for abdominopelvic CT. For the paediatric phantom, organ and effective doses were 4-17 mGy and 3-7 mSv, respectively, for chest CT, and 5-14 mGy and 3-9 mSv, respectively, for abdominopelvic CT. Doses to organs at the boundaries of the scan length were higher for 64-slice CT scanners using large beam widths and/or a large pitch because of the larger extent of over-ranging. The CT dose index (CTDI(vol)), dose-length product (DLP) and the effective dose values using 64-slice CT for the adult and paediatric phantoms were the same as those obtained using 4-, 8- and 16-slice CT. Conversion factors of DLP to the effective dose by International Commission on Radiological Protection 103 were 0.024 mSvmGy(-1)cm(-1) and 0.019 mSvmGy(-1)cm(-1) for adult chest and abdominopelvic CT scans, respectively.

Carbon-ion radiotherapy: clinical aspects and related dosimetry.

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

Little impact of donor/recipient major mismatch for neutrophil-specific antigen NA2 on neutrophil recovery after allogeneic SCT.

The Fcgamma receptor IIIb (FcgammaRIIIb), a receptor for the Fcgamma region of IgG, is specifically expressed on neutrophils. It has two allelic polymorphisms, NA1 and NA2, which are highly immunogenic and act as targets in alloimmune or autoimmune neutropenia. Thus, neutrophil antigens (NA) compatibility of donor/recipient pairs might be expected to affect the engraftment of neutrophils after allogeneic SCT (allo-SCT). Here, the impact of NA compatibility of 17 patients and their donors undergoing allo-SCT with a myeloablative regimen was determined. Leukocyte depletion filters were used for all transfusions before and post-SCT; most patients received G-CSF after transplant. Major mismatches for NA1 and NA2 were present in 1 and 7 patient/donor pairs, respectively. These eight patients receiving NA major-mismatched allo-SCT were compared with nine patients who received NA compatible allo-SCT. Engraftment of neutrophils and the incidence of post-engraftment neutropenia were found to be identical in the two groups. Despite the limitations in statistical power because of the small number of patients analyzed, these observations suggest that the major mismatching for NA2 antigen has little impact on the engraftment of neutrophils after myeloablative allo-SCT, at least in patients transfused using leukocyte depletion filters and receiving G-CSF after transplantation.