ICRP Publication 140: Radiological Protection in Therapy with Radiopharmaceuticals.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Inferring causal structures and comparing the causal effects among calving difficulty, gestation length and calf size in Japanese Black cattle.

The objectives of this study were to infer phenotypic causal networks involving gestation length (GL) and calving difficulty (CD) for the primiparity of 1850 Japanese Black heifers, and the birth weight (BWT), withers height (WH) and chest girth (CHG) of their full blood calves, and to compare the causal effects among them. The inductive causation (IC) algorithm was employed to search for causal links among these traits; it was applied to the posterior distribution of the residual (co)variance matrix of a multiple-trait sire-maternal grand sire (MGS) model. The IC algorithm implemented with 95% and 90% highest posterior density intervals detected only one structure with links between GL and BWT (WH or CHG) and between BWT (WH or CHG) and CD, although their directions were not resolved. Therefore, a possible causal structure based on the networks obtained from the IC algorithm [GL→BWT (WH or CHG)→CD] was fitted using a structural equation model to infer causal structure coefficients between the traits. The structural coefficients of GL on BWT and of BWT on GL on the observable scale showed that an extra day of GL led to a 270-g gain in BWT, and a 1-kg increase in BWT increased the risk for dystocia by 1.1%, in the causal structure. Similarly, an increase in GL by 1 day resulted in a 2.1 (2.0)-mm growth in WH (CHG), and a 1-cm increase in WH (CHG) increased the risk of dystocia by 1.2% (0.9%). The structural equation model was also fitted to alternative causal structures, which involved the addition of a directed link from GL to CD, or GL→CD to the structures described above. The inferred structural coefficients with the alternative structures were almost the same as the corresponding ones that had GL→BWT (WH or CHG)→CD. However, the direct causal effect of the extra link from GL on CD was similar to the indirect causal effect of GL through the mediating effect of BWT (WH or CHG) on CD and significant (P<0.05). This suggest that maternal genetic effects might not be removed completely from the residual variance components in the sire-MGS model, and the application of the IC algorithm to the variances from the model could detect an incorrect structure. Nonetheless, fitting the structural equation model to the causal structure provided useful information such as the magnitude of the causal effects between the traits.

Sialyl-glycoconjugates in cholesterol-rich microdomains of P388 cells are the triggers for apoptosis induced by Rana catesbeiana oocyte ribonuclease.

SBL/RC-RNase was originally isolated from frog (Rana catesbeiana) oocytes and purified as a novel sialic acid-binding lectin (SBL) that displayed strong anti-cancer activity. SBL was later shown to be identical to a ribonuclease (RC-RNase) from oocytes of the same species. The administration of SBL/RC-RNase induced apoptosis (with nuclear condensation and DNA fragmentation) in mouse leukemia P388 cells but did not kill umbilical vein endothelial or fibroblast cells derived from normal tissues. The cytotoxic activity of SBL/RC-RNase was inhibited by desialylation of P388 cells and/or the co-presence of free bovine submaxillary mucin. FACS analysis showed that SBL/RC-RNase was incorporated into cells after attachment to cholesterol-rich microdomains. Addition of the cholesterol remover methyl-ß-cyclodextrin reduced SBL/RC-RNase-induced apoptosis. Apoptosis occurred through the caspase-3 pathway following activation of caspase-8 by SBL/RC-RNase. A heat shock cognate protein (Hsc70) and a heat shock protein (Hsp70) (each 70 kDa) on the cell membrane were shown to bind to SBL/RC-RNase by mass spectrometric and flow cytometric analyses. Quercetin, an inhibitor of Hsc70 and Hsp70, significantly reduced SBL/RC-RNase-induced apoptosis. Taken together, our findings suggest that sialyl-glycoconjugates present in cholesterol-rich microdomains form complexes with Hsc70 or Hsp70 that act as triggers for SBL/RC-RNase to induce apoptosis through a pathway involving the activation of caspase-3 and caspase-8.

Single institutional experience of the treatment of angiosarcoma of the face and scalp.

OBJECTIVE: Angiosarcoma is a rare malignant neoplasm with a poor prognosis. A retrospective study was performed to accumulate radiotherapy (RT) data. METHODS: Data from 17 patients with angiosarcoma of the face and scalp (AFS) who were treated with definitive RT between January 1999 and July 2011 were retrospectively analysed. The total radiation dose was 70 Gy, and the fractional doses were 2.0-2.5 Gy. Combined with RT, chemotherapy using docetaxel alone, recombinant interleukin-2 immunotherapy alone and both of these was performed in 10, 4 and 2 patients, respectively. Three patients underwent limited surgery before RT. RESULTS: The response rate was 82%, and the median overall survival (OS) rate was 26 months. Locoregional relapse alone, distant metastasis alone and both of these were confirmed in 4, 5 and 4 patients, respectively. Patients treated with docetaxel showed a better prognosis (p=0.0477), a distant metastasis-free rate (p=0.0063) and a better in-field control rate, although the last was not statistically significant (p=0.1645). CONCLUSION: Definitive RT combined with docetaxel chemotherapy provided an effective approach for treating AFS. ADVANCES IN KNOWLEDGE: Since patients treated with chemoradiotherpy using docetaxel showed better OS and distant metastasis-free rates than those who did not receive docetaxel, it was warranted to continue use of docetaxel. In chemoradiotherapy at a dose of 70 Gy using docetaxel, 2-year in-field control rate was 67%.

Contributions of FASN and SCD gene polymorphisms on fatty acid composition in muscle from Japanese Black cattle.

The fatty acid synthase (FASN) and stearoyl-CoA desaturase (delta-9-desaturase) (SCD) genes affect fatty acid composition. This study evaluated the contributions of polymorphisms of these genes on fatty acid composition in muscle in two different populations: 1189 and 1058 Japanese Black cattle from the Miyagi and the Yamagata populations respectively. We sampled intramuscular fat from the longissimus thoracis muscle in the Miyagi population and from the trapezius muscle in the Yamagata population. The collective contributions of FASN and SCD polymorphisms to total additive genetic variance for oleic acid were 13.46% in the Miyagi population and 16.29% in the Yamagata population and to phenotypic variance were 5.45% and 6.54% respectively. Although the individual effects of FASN and SCD polymorphisms on fatty acid composition were small, overall gene substitution may effectively improve fatty acid composition. In addition, we found that gene polymorphism contributions of fatty acids varied by population even in the same breed.

Net effect of lymphaticovenous anastomosis on volume reduction of peripheral lymphoedema after complex decongestive physiotherapy.

OBJECTIVE: The results of reported lymphaticovenous anastomoses include some effects of complex decongestive physiotherapy (CDP). The present study aimed to determine the net effect of lymphaticovenous side-to-end anastomosis (LVSEA) in patients with lower limb lymphoedema treated by preoperative CDP. DESIGN: Retrospective observational study. MATERIALS: 37 LVSEAs in 31 patients. METHODS: Volumes of the thigh and leg with oedema were compared between the time of initial examination, and before (application of CDP) and after LVSEA. The patients were divided into two groups based on the number of anastomoses and lymphoscintigraphic findings. RESULTS: Preoperative CDP resulted in a reduction of 593 ml (both leg and thigh; p < 0.001). After CDP, LVSEA (1-8 anastomoses; average of 5) reduced the volume by 109 ml (52 ml for the thigh (p = 0.01) and 57 ml for the leg (p = 0.002)). There was no significant difference in volume reduction on lymphoscintigraphy. Volume was significantly reduced (by 55 ml in the thigh, p = 0.049; 96 ml in the leg, p = 0.006) in the group that underwent 6-8, but not 1-5 LVSEAs. CONCLUSIONS: The net effect of LVSEA on volume reduction was confirmed, but was not particularly large. The need for CDP decreased in some patients postoperatively, and these patients should be considered for evaluation.

Direct impact analysis of multi-leaf collimator leaf position errors on dose distributions in volumetric modulated arc therapy: a pass rate calculation between measured planar doses with and without the position errors.

We propose a new method for analyzing the direct impact of multi-leaf collimator (MLC) leaf position errors on dose distributions in volumetric modulated arc therapy (VMAT). The technique makes use of the following processes. Systematic leaf position errors are generated by directly changing a leaf offset in a linac controller; dose distributions are measured by a two-dimensional diode array; pass rates of the dose difference between measured planar doses with and without the position errors are calculated as a function of the leaf position error. Three different treatment planning systems (TPSs) were employed to create VMAT plans for five prostate cancer cases and the pass rates were compared between the TPSs under various leaf position errors. The impact of the leaf position errors on dose distributions depended upon the final optimization result from each TPS, which was explained by the correlation between the dose error and the average leaf gap width. The presented method determines leaf position tolerances for VMAT delivery for each TPS, which may facilitate establishing a VMAT quality assurance program in a radiotherapy facility.

[Intermittent opening of a mechanical mitral valve prosthesis due to pannus formation; report of a case].

A 76-year-old woman with a history of severe mitral valve stenosis had undergone mitral valve replacement with a 27 mm St. Jude Medical (SJM) valve in 1991. Follow-up transthoracic echocardiography revealed an increase in the pressure gradient across the mitral prosthesis 16 years after the surgery. Prosthetic valve dysfunction was suspected, but transesophageal echocardiography and cineradiography failed to show mechanical valve dysfunction. Two years later, she presented with dyspnea on exertion and leg edema. Cineradiography revealed intermittent restriction of the opening of the mechanical valve leaflet approximately every 10 beats. Thus, we diagnosed intermittent prosthetic valve dysfunction and performed a reoperation. On inspection of the prosthesis, we observed semicircular pannus formation around the posterior leaflet in the ventricular side. It was considered that the pannus tissue had interfered with 1 leaflet opening of the mitral valve prosthesis, resulting in intermittent valve dysfunction. We replaced the prosthesis with a new 25 mm SJM valve. The patient was discharged after confirmation of normal prosthetic function.

Classification of lymphoscintigraphy and relevance to surgical indication for lymphaticovenous anastomosis in upper limb lymphedema.

Upper limb lymphedema that develops after breast cancer surgery causes physical discomfort and psychological distress, and it can require both conservative and surgical treatment. Lymphaticovenous anastomosis has been reported to be an effective treatment; however the disease severity criteria that define indications for this treatment remain unclear. Here, we examined lymphoscintigraphic findings in 78 patients with secondary upper limb lymphedema and classified them into 5 major types (Type I-V) and 3 subtypes (Subtype E, L, and 0). Results revealed that this classification is related to the clinical stage scale of the International Society of Lymphology. Based on intraoperative examination findings in 20 of the 78 patients, lymphatic pressure is likely to be further elevated in Type II-V cases which are characterized by the presence of dermal back flow. Therefore, lymphaticovenous anastomosis should be considered as a treatment option for lymphedema in Type II-V cases. Furthermore, there are only limited lymph vessel sites usable for lymphaticovenous anastomosis in more severe lymphedema types [Types IV and Type V (which is characterized by dermal backflow only in the hand)]. The findings in Type IV-V cases suggest that therapeutic strategies for severe upper limb lymphedema need further consideration.

[Graft harvesting in coronary artery bypass grafting].

The technique of graft harvesting during coronary artery bypass grafting (CABG) consists of 2 main components: the vessel exposure at an adequate layer and the division of branches. Recently, the ultrasonic scalpel has been used for skeletonization of arterial grafts. A hook-type tip is used for the internal thoracic artery and the radial artery graft, while a shear type tip is used for the right gastroepiploic artery graft. The ultrasonic scalpel is useful both for graft vessel exposure and for the division of branches. The cavitation phenomenon is useful for the vessel exposure, while ultrasonic protein coagulation is useful for the division of branches. In endoscopic saphenous vein graft harvesting, electrocautery scissors are used for the division of branches. Avoiding thermal damage to the graft vessel is important in the use of either device. In any graft harvesting, direct contact with the main trunk should be avoided as much as possible to prevent damage. A thorough knowledge of the anatomy of the graft vessel and the surrounding organs is necessary for graft harvesting and to avoid complications. Furthermore, an understanding of characteristics of the harvesting devices is also important.

Operation of a 500 MHz high temperature superconducting NMR: towards an NMR spectrometer operating beyond 1 GHz.

We have begun a project to develop an NMR spectrometer that operates at frequencies beyond 1 GHz (magnetic field strength in excess of 23.5 T) using a high temperature superconductor (HTS) innermost coil. As the first step, we developed a 500 MHz NMR with a Bi-2223 HTS innermost coil, which was operated in external current mode. The temporal magnetic field change of the NMR magnet after the coil charge was dominated by (i) the field fluctuation due to a DC power supply and (ii) relaxation in the screening current in the HTS tape conductor; effect (i) was stabilized by the 2H field-frequency lock system, while effect (ii) decreased with time due to relaxation of the screening current induced in the HTS coil and reached 10(-8)(0.01 ppm)/h on the 20th day after the coil charge, which was as small as the persistent current mode of the NMR magnet. The 1D (1)H NMR spectra obtained by the 500 MHz LTS/HTS magnet were nearly equivalent to those obtained by the LTS NMR magnet. The 2D-NOESY, 3D-HNCO and 3D-HNCACB spectra were achieved for ubiquitin by the 500 MHz LTS/HTS magnet; their quality was closely equivalent to that achieved by a conventional LTS NMR. Based on the results of numerical simulation, the effects of screening current-induced magnetic field changes are predicted to be harmless for the 1.03 GHz NMR magnet system.

Purification and biochemical characterization of a D-galactose binding lectin from Japanese sea hare (Aplysia kurodai) eggs.

A lectin was purified from Japanese sea hare Aplysia kurodai by lactosyl-agarose affinity chromatography. The molecular mass of the lectin was determined to be 56 and 32 kDa by SDS-PAGE under non-reducing and reducing conditions, respectively. It was found to agglutinate trypsinized and glutaraldehyde-fixed rabbit and human erythrocytes in the absence of divalent cations. The lectin exhibited stable thermo-tolerance as it retained hemagglutinating activity for 1 h even at 80 degrees C and showed stability at pH 10. By contrast, it was very sensitive at pH less than 5 and in the presence of the sulfhydryl-group preserving reagent, beta-mercaptoethanol. The hemagglutinating activity by the lectin was specifically inhibited by D-galactose, galacturonic acid, methyl-alpha- and methyl-beta-D-galactopyranoside, lactose, melibiose, and asialofetuin. The association rate constant (k(ass)) and dissociation rate constant (k(diss)) were determined for the lectin to be 4.3 x 10(5) M(-1) x sec(-1) and 2.2 x 10(-3) sec(-1), respectively, using a surface plasmon resonance biosensor. The lectin moderately inhibited cell proliferation in the P388 cell line dose dependently. Interestingly, lectin-treated cells did not show a fragmented DNA ladder as is caused by apoptosis, suggesting that the cell proliferation inhibition was caused by another unknown mechanism.

Genetic parameters for dry matter, energy and protein intake, and their relationships with performance and carcass traits in Japanese Black cattle.

Genetic parameters for feed intake and performance traits of 514 bulls and carcass traits of 22 099 of their progeny, and the relationships of measures of feed intake with performance and carcass traits were estimated. Feed intake traits were dry matter intake (DMI), concentrate intake (CONI), roughage intake, ratio of roughage intake to DMI, metabolizable energy intake (MEI) and digestible crude protein intake (DCPI). Performance traits included daily gain, metabolic weight, live weight at the end of test, dry matter conversion ratio and residual feed intake. Progeny carcass traits were carcass weight, percentage of meat yield, rib eye area (REA), subcutaneous fat, marbling score, meat colour (MCS), fat colour (FCS) and meat quality grade. All the feed intake and performance traits were moderately heritable. The heritabilities for REA and MCS were moderate, and that for FCS was low, while those for the other carcass traits were high. Selection against DMI, CONI and DCPI would reduce excessive intake of feed, but would have undesirable effects on growth and most of the carcass traits. Selection against MEI would lead to improvements in feed efficiency and growth traits. Selection against DCPI would also improve feed efficiency; however, responses in growth traits would decrease. Results indicate that selection against MEI might be better than any other measures of feed intake to improve feed efficiency with simultaneous improvement in growth and most of the carcass traits.

Quality of portal verification radiography using EC-L film in electron beam therapy.

The quality of the portal verification radiographs produced using the enhanced-contrast localisation (EC-L) Fast cassette-EC-L film (F-EC) combination and the EC-L Oncology cassette-EC-L film (O-EC) combination was investigated fundamentally and clinically. A computerised radiography (CR) system was used for comparison. In the clinic, portal verification radiographs produced for 22 patients with breast cancer were evaluated. The characteristic curves showed that the relative speed was 0.92 for the O-EC combination when the speed of the F-EC combination was defined to be 1, and that the average gradients were 4.76 and 4.35 for the F-EC combination and the O-EC combination, respectively. The smallest visible volumes of Burger's phantom were 50.3 mm(3), 60.8 mm(3) and 199.5 mm(3) for the F-EC combination, the O-EC combination and the CR system, respectively, at an energy of 9 MeV, and 68.4 mm(3), 74.2 mm(3) and 195 mm(3), respectively, at an energy of 12 MeV. In the clinic, both combinations at an energy of 6 MeV and the O-EC combination at 9 MeV showed very poor quality owing to underdensity. However the F-EC combination at an energy of 12 MeV and the O-EC combination at an energy of 15 MeV demonstrated a higher quality. When bremsstrahlung dose passing through the body is sufficient, the quality of portal verification radiography using EC-L film is appropriate for clinical use.

Demonstration of cerebellar atrophy in neuroacanthocytosis of 2 siblings.

SUMMARY: Neuroacanthocytosis is a rare hereditary disorder characterized by involuntary choreiform movements and erythrocytic acanthocytosis in the peripheral blood. Clinical manifestations of this disorder resemble those of Huntington disease (HD). Neuroimaging features of neuroacanthocytosis are atrophy and signal intensity change of the striata on MR imaging, as in HD. We report herein the cases of 2 siblings with neuroacanthocytosis showing cerebellar atrophy as well as atrophy and signal intensity changes of striata.

Genetic parameters for measures of energetic efficiency of bulls and their relationships with carcass traits of field progeny in Japanese Black cattle.

Records on 514 bulls from the sire population born from 1978 to 2004, and on 22,099 of their field progeny born from 1997 to 2003 with available pedigree information (total number = 124,458) were used to estimate genetic parameters for feed intake and energy efficiency traits of bulls and their relationships with carcass traits of field progeny. Feed intake and energetic efficiency traits were daily feed intake, TDN intake, feed conversion ratio (FCR), TDN conversion ratio (TDNCR), residual feed intake (RFI), partial efficiency of growth, relative growth rate, and Kleiber ratio. Progeny carcass traits were carcass weight (CWT), yield estimate, ribeye area, rib thickness, subcutaneous fat thickness (SFT), marbling score (MSR), meat color standard (MCS), fat color standard (FCS), and meat quality grade. All measures of feed intake and energetic efficiency were moderately heritable (ranged from 0.24 to 0.49), except for partial efficiency of growth and relative growth rate, which were high (0.58) and low (0.14), respectively. The phenotypic and genetic correlations between FCR and TDNCR were >or=0.93. Selection for Kleiber ratio will improve all of the energetic efficiency traits with no effect on feed intake measures (daily feed intake and TDN intake). The genetic correlations of FCR, TDNCR, and RFI of bulls with most of the carcass traits of their field progeny were favorable (ranged from -0.24 to -0.72), except with fat color standard (no correlation), MCS, and SFT. Positive (unfavorable) genetic correlations of MCS with FCR, TDNCR, and RFI (0.79, 0.70, and 0.51, respectively) were found. The SFT was negatively genetically correlated with FCR and TDNCR (-0.32 and -0.20, respectively); however, the genetic correlation between RFI and SFT was not significantly different from zero (r(g) = -0.08 +/- 0.12). Favorable correlated responses in CWT, yield estimate, ribeye area, rib thickness, MSR, and meat quality grade would be predicted for selection against any measure of energetic efficiency. The correlated responses in CWT and MSR of progeny were greater for selection against RFI than for selection against any other energetic efficiency trait. Results of this study indicate that RFI should be preferred over other measures of energetic efficiency to include in selection programs.

[New proximal anastomotic system in coronary artery bypass grafting].

The Heartstring proximal anastomotic system is a device designed to facilitate the creation of a clampless hand-sewn proximal anastomosis. Thirty-four patients who underwent coronary artery revascularization had 40 proximal anastomoses using the Heartstring device. There were 26 men and 8 women, with the mean age of 70 +/- 8.9 years. Thirty-one patients underwent coronary artery bypass grafting through off-pump procedures and 3 patients on-pump beating procedures. In all patients, saphenous vein grafts were anastomosed to the aorta using the Heartstring device, the median number of distal anastomoses being 2.4 +/- 0.7. Either emergent or urgent surgery was required in 14 patients (41%). Diseased aorta was found in 11 patients (32%). One patient (2.9%) died postoperatively due to ischemic necrosis of the small intestine and the colon. There was no occurrence of postoperative stroke. Of 40 saphenous vein grafts anastomosed with the Heartstring system, 39 (97.5%) were patent. The occluded saphenous vein was not considered to be device related. Our clinical experience demonstrated that the Heartstring system allow us to create clampless and reproductive hand-sewn proximal anastomosis and to decrease the incidence of neurological complication.

[Aortic root replacement in Marfan syndrome with hemophilia A].

A 34-year-old man with Marfan syndrome was admitted to our hospital for surgical treatment of aortic regurgitation due to annuloaortic ectasia. He had no history of bleeding complications. Preoperative investigation revealed a slight prolongation of an activated partial thromboplastin time, which went unnoticed. He underwent aortic root replacement with a composite valve graft. During the operation, he had excessive bleeding due to coagulopathy after the termination of cardiopulmonary bypass, and needed a large amount of blood transfusion to obtain hemostasis. Before his discharge from our hospital, he was diagnosed as mild hemophilia A because of the decline in his factor VII level. To our knowledge, there has been no published case of cardiac operations in Marfan syndrome with hemophilia A.

Influence of different pneumoperitoneal pressures on tumor cell distribution in rats.

BACKGROUND: The effect of different pneumoperitoneal pressures on tumor cell distribution was investigated. METHODS: Donryu rats were allocated to receive carbon dioxide pneumoperitoneum at 5, 10, or 15 mmHg for 60 min or to serve as a control. During the procedure, each rat was inoculated with radiolabeled ascites hepatoma cells via the portal vein (experiment 1) or femoral vein (experiment 2). In both experiments, the rats were killed 30, 60, 90, or 120 min after tumor cell inoculation, and the liver and lungs were extirpated for radioactivity count (n = 5 or 6 for each time point in each group). RESULTS: In experiment 1, the percentage of injected dose (% ID) for the liver was greater than for the other three groups 120 min after tumor cell inoculation. There were no significant differences in the %IDs of the lungs at any time point among the groups. In experiment 2, there were no significant differences in the %IDs of the liver and lungs at any time point among the groups. CONCLUSIONS: These results suggest that an elevated insufflation pressure facilitates the location of intraportally injected tumor cells in the liver, and that pulmonary location of the tumor cells may not depend on insufflation pressures in this animal model.