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Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1–10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. jRCTs041180030. Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . 12/01/2018.

Background Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for. Alk rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with. Ret rearranged NSCLC. Methods This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naive patients treated with the RD of alectinib. Results Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naive patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. Conclusions Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.

IntroductionFamilial hypercholesterolaemia (FH) is an autosomal dominant inherited genetic disease that has an extremely elevated cardiovascular risk because of their significantly elevated low-density lipoprotein (LDL) cholesterol. Nutritional intervention is needed in improving LDL cholesterol control in patients with FH but requires a considerable burden in manpower. Artificial intelligence (AI)-supported and mobile-supported nutritional intervention using this technique may be an alternative approach to traditional nutritional counselling in person. This study aims to test the hypothesis that AI-supported nutritional counselling is more effective in reducing LDL cholesterol than the in-person, face-to-face method in terms of improving LDL cholesterol control in patients with FH.Methods and analysisThis is a single-centre, unblinded, cross-over, randomised controlled study comparing the efficacy of AI-supported automated nutrition therapy with that of conventional human nutrition counselling in patients with FH. Patients with FH are recruited and randomly assigned to AI-supported nutrition counselling (n=30) and to face-to face nutrition counselling (n=30). We are using an Asken, a mobile application that has been specially modified for this study so that it follows the recommendations by the Japan Atherosclerosis Society. We started patient recruitment on 1 September 2020, and is scheduled to continue until 31 December 2022.Ethics and disseminationThis study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. The study protocol was approved by the Institutional Review Board of Kanazawa University on 13 April 2020 (IRB no. 2623-3); all recruited patients are required to provide written informed consent. We will disseminate the final results at international conferences and in a peer-reviewed journal.Trial registration numberUMIN000040198.

Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dosePatients received 666 MBq/kg ofWe enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dosejRCTs041180030.Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 .12/01/2018.

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC.

Backgrounds and aims Structural dynamics of basement membrane components remained to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of hepatocellular carcinoma (HCC) expressing laminin γ2 monomer (LG2m), a previously unrecognized basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined if elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). Approach and results In HCC cell lines, LG2m was expressed in alpha-fetoprotein-negative cluster of differentiation 90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by alpha-fetoprotein. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff: 30pg/ml). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff: 60pg/ml). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P Conclusions LG2m is a novel predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is a HCC risk in CHC patients who have achieved SVR.

During a fracture toughness test on a welded joint, a pop-in accompanied by a load drop may occur prior to final rupture. The currently used standards for conditions to determine whether pop-ins are insignificant vary, and are not prescribed based on adequate physical grounds. Moreover, these standards can be too severe in considering the occurrence of pop-ins as equivalent to a fatal rupture in welded structures. Research to formulate reasonable conditions to assess pop-ins is important to determine whether it is necessary to remake or repair the relevant welded structure. This study reports fracture toughness tests on specimens with pop-ins caused by brittle cracks featuring arrest behavior. The results were simulated through finite element analysis by using a nodal release method, which was implemented when a pop-in occurred owing to split formation, to determine whether the pop-in was significant. From analytical results based on a load mode featuring bending and tension, it was found that the crack opening stress distribution under the bending mode at a load drop of 8% or less was larger than or almost equal to that under the tensile mode. Therefore, if the opening of a brittle crack is arrested during three-point bending fracture toughness tests, it would also be arrested in the welded structures under tensile load. In other words, the results showed that such a pop-in could be regarded as insignificant.

Background Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed. Objective The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis. Methods Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction. Results Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020. Conclusions Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device. Trial Registration UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q International Registered Report Identifier (IRRID) DERR1-10.2196/17904

Submitting data compliant with the Clinical Data Interchange Standards Consortium (CDISC) standards is mandatory for new drug applications (NDAs). The standards set by CDISC are widely adopted in the pharmaceutical business world. Introduction of CDISC standards in academia can be necessary to reduce labor, resolve the shortage of data managers in academia, and gain new knowledge through standardized data accumulation. However, the introduction of CDISC standards has not progressed in communities within the academia that do not apply for NDAs. Therefore, herein, we created study data tabulation model (SDTM)-compliant datasets within the academia, without outsourcing, to reduce costs associated with investigator-initiated clinical trials. First, we input data from paper case report forms (CRFs) into an electronic data capture system with minimal function for paper CRFs, "Ptosh," which is compatible with SDTM. Then, we developed a generic program to convert data exported from Ptosh into fully SDTM-compliant datasets. The consistency was then verified with an SDTM validator, Pinnacle21 Community V3.0.1 (P21C). This resulted in generation of SDTM datasets, resolving all "Rejects" in P21C, thereby achieving the required quality level. Although Ptosh directly exports data in SDTM format, manual mapping of items on CRFs to SDTM variables prepared in Ptosh is necessary. SDTM mapping requires extensive knowledge and skills, and it was assumed that mapping is challenging for the staff without in-depth knowledge of CDISC standards and datasets. Therefore, for CDISC dissemination in academia, it is crucial to secure the staff, time, and funding to acquire the knowledge.

The authors have already established a new CTOD calculation formula especially focusing the effect of strain hardening exponent. On the other hand, there is the demand of the conversion to J integral in order to assessment. The relationship between CTOD and J has been discussed for many years. It can be said that ISO 15653 and ASTM E1820 include the latest forms which express that relationship. These conversion equations include some coefficients calculated by numerical analyses where the validation to actual condition around the crack tip may still be insufficient. One problem is the fact that the current relationships include the a0/W term even in the SSY condition where mechanical field should be independent with the shape of the specimen. In this study, the CTOD-J relationship is redefined by using CTOD calculation results obtained by the authors’ previous reports. As a conclusion, except under very small a0/W conditions, the relationship factor, m is simple, constant and independent of a0/W, YR and the deformation level. It was also found that same m can be applied with the coefficient for obtaining CTOD from K introduced by the authors. This is convincing considering that the J integral, by definition, corresponds to the energy release rate, G in the SSY condition.

In the fracture toughness tests of multipass welds of thick steel plates, the fatigue precrack front initiating from a machined notch root frequently be non-uniform affected by the welding residual stress distribution. Reverse bending before fatigue precracking could be an effective measure of residual stress modification. However, the effect of reverse bending is not well understood from the viewpoint of the variation of the residual stress distribution at the notch root. Therefore, the transition of the welding residual stress throughout the multipass welding, notch machining, and reverse bending processes is calculated using a numerical simulation model developed in this study. The compressive plastic deformation at the notch root caused by the reverse bending and successive tensile loading during unloading are the major mechanisms of residual stress modification by reverse bending. A flattened residual stress distribution along the thickness can be achieved if the reverse bending condition is properly controlled.

BACKGROUND Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed. OBJECTIVE The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis. METHODS Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction. RESULTS Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020. CONCLUSIONS Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device. CLINICALTRIAL UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q INTERNATIONAL REGISTERED REPORT DERR1-10.2196/17904

Refractory pheochromocytoma and paraganglioma (PPGL) have a poor prognosis and the treatment strategy remains to be established. This multi-institutional phase I study was performed to determine the safety, dose-limiting toxicity (DLT), and efficacy of [131I]-meta-iodobenzylguanidine (131I-mIBG) therapy for refractory PPGLs. Twenty patients with refractory PPGL were enrolled in this study. We administered fixed doses of 131I-mIBG to all patients, delivering a second and third course of 131I-mIBG to eight and three patients, respectively. During the 20 weeks after 131I-mIBG injection, the authors surveyed the adverse events in accordance with the Common Terminology Criteria for Adverse Events. All patients experienced adverse events and adverse reactions, but none experienced a grade 4 adverse event. Twelve weeks after 131I-mIBG injection, examinations for the evaluation of therapeutic effects was performed in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST). The best overall response rates (based on RECIST categories) were 10% (complete response), 65% (stable disease), 15% (progressive disease), and 10% (not all evaluated). The efficacy and safety of 131I-mIBG therapy was shown in patients with refractory PPGL, and DLT was observed in neither single nor repeated 131I-mIBG therapy, indicating a tolerability for 131I-mIBG therapy.

Objective Pheochromocytoma and paraganglioma (PPGLs) are rare neuroendocrine tumors derived from the adrenal medulla or extra-adrenal paraganglioma from extra-adrenal chromaffin tissue. Although malignant PPGLs has miserable prognosis, the treatment strategy remains to be established. An internal radiation therapy using [131I]meta-iodobenzylguanidine (131I-mIBG) called MIBG therapy has been attempted as one of the systemic treatment of malignant PPGLs. The aim of this study is therefore to evaluate the safety and the efficacy of MIBG therapy for refractory PPGLs. Methods Patients with refractory PPGLs will be enrolled in this study. The total number of patients for registration is 20. The patients receive a fixed dose of 7,400 MBq of 131I-mIBG. Adverse events are surveyed during 20 weeks after 131I-mIBG injection and all severe adverse events will be documented and reported in detail in accordance with the Common Terminology Criteria for Adverse Events (CTCAE). Examination and imaging diagnosis are performed in 12 weeks after 131I-mIBG injection for the evaluation of therapeutic effect in accordance with the Response Evaluation in Solid Tumours (RECIST). Conclusion The current study is the first multi-institutional prospective study of MIBG therapy and thereby will play a significant role in improving the patients' prognosis of refractory PPGLs. J. Med. Invest. 64: 205-209, August, 2017.

Background The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. Methods/design RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naive patients. Conclusion This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

This paper presents a method for estimating the condition for the brittle fracture limit of a welded joint with an embedded flaw in the heat-affected zone (HAZ) based on the Weibull stress criterion. A welded joint with an embedded flaw generated by cold cracking was subjected to a wide plate (WP) tension test, and a welded joint with a fatigue crack was subjected to three-point bending (3PB) tests; both tests were conducted at −30 °C. Brittle fractures occurred in all specimens, and the microstructure of the fracture initiation point for the WP specimen in the coarse-grained HAZ (CGHAZ) was upper bainite with M-A constituents. The critical Weibull stress distribution of the CGHAZ was calculated by finite element analyses for the 3PB specimens. The predicted fracture load and global displacement of the WP specimen at the brittle fracture obtained by the critical Weibull stress distribution were in agreement with experimental results from the WP tensile test. This confirmed that the brittle fracture limit of a welded joint with an embedded flaw could be predicted from the Weibull stress criterion.

A full-scale gas burst test was conducted to confirm the behavior of unstable ductile crack propagation and arrest and to confirm the required toughness value to prevent unstable ductile fracture under an ultrahigh pressure of 18 MPa. A full-scale test was conducted at the Spadeadam test site in the UK for unburied pipes. The test pipes used in this test were of API 5L Grade L450 with outer diameter of 610 mm and thickness of 17.5 mm. The toughness of the test pipes increased away from the center, where an explosive charge was placed across the top of the girth weld for crack initiation. The gas used in the test consisted of ∼89% methane and other heavy hydrocarbon gas components, and the test temperature was 0 °C. A gas circulation loop was constructed to ensure that a homogeneous gas mixture and temperature were achieved throughout the test rig. In addition to dynamically measuring the ductile crack velocity and decompression behavior of the rich gas, as has often been done in previous burst tests, the circumferential distribution of the decompression behavior was measured using circumferentially placed pressure transducers. Furthermore, the fracture strain near the propagating crack was measured. The initiated unstable ductile crack was arrested in the third pipe. From the material properties of the test pipes in which the unstable ductile crack was arrested, the required Charpy absorbed energy and DWTT absorbed energy to prevent unstable ductile fracture in unburied pipes were obtained. In addition, the above data can be useful for validating numerical models that evaluate the propagation/arrest of unstable ductile fracture. The required Charpy and DWTT absorbed energy values obtained in this test were compared with those predicted by the Battelle Two-Curve Method (BTCM). As noted in previous studies, it was confirmed that the BTCM underestimates the required Charpy absorbed energy and requires a certain correction factor for precise evaluation, whereas the DWTT absorbed energy predicted by BTCM was consistent with the experimental result.

In this study, the effects of crack configuration and welding residual stress on the Weibull stress for high strength steel plate with embedded crack were investigated by conducting FEM analysis. Firstly, high strength wide steel plates (length: 200 mm, width: 200 mm, thickness: 25 mm) having an embedded crack which has height 6 or 9 mm, length 40 mm, depth 2 ~ 9.5 mm were created using iso-parametric elements with eight nodes. The welding residual stress of K-groove welded joint made by 780 MPa class steel was introduced around the embedded crack, and then these models were tensioned along the vertical direction to the crack surface. Finally, CTOD, overall strain, the Weibull stress and crack opening stress (local stress near the crack tip which is parallel to crack surface) were obtained in all cases. CTOD was calculated by tangential method. The Weibull stress of embedded crack without welding residual stress which has the same crack height and length as previously mentioned was found to have increased with decreasing crack depth at the same CTOD level, this means plastic constraint of shallow embedded crack was higher than one of deep embedded crack. The Weibull stress of shallow crack model with crack depth 2 mm at the same over all strain was bigger than the other cases caused by high crack driving force and plastic constraint. Based on the Weibull stress criterion, it can be found that the brittle fracture limit of embedded crack decrease with decreasing crack depth in all strain region. The Weibull stress of embedded crack with welding residual stress at the same CTOD level was higher than that with welding residual stress. This tendency was same as the relationship between the Weibull stress and over all strain before overall strain reaches yield strain. After yield strain, the Weibull stresses were almost same between embedded crack with and without welding residual stress. It can be found that the welding residual stress decrease the brittle fracture limit of embedded crack before overall strain reaches yield strain based on the Weibull stress criterion.

Prevention of cleavage fracture is one of the most significant problems in securing the structural integrity of welded structures. To simulate the fracture behavior and plastic constraint condition of structural components, wide-plate tensile tests have been conducted for experimental fracture assessments. Artificial surface flaws, through-wall flaws, and fatigue pre-cracks are generally applied. Embedded flaws from cold cracking should be considered in an integrity assessment of a structure. Nevertheless, experimental fracture evaluations based on wide-plate tensile tests using welded joints with embedded flaws from cold cracking have never been conducted, because a method for intentionally preparing a welded joint with a cold-cracking embedded flaw has not been established yet. In this study, we develop a means of manufacturing joints with cold cracking embedded flaws, based on the y-groove cracking test, and perform a series of cracking tests. We determine that deeper flaws crack more stably with more heat and more diffusible hydrogen. In addition, no relationship is apparent between the welding conditions (heat input/diffusible hydrogen), and the relative position of the embedded flaw to the fusion line in the cross-section. Accordingly, we establish a technique for intentionally and stably preparing a welded joint with a cold-cracking embedded flaw of sufficient height. We perform a wide-plate tensile test for the welded joint with the embedded flaw using the established technique to evaluate the fracture load and fracture behavior. The embedded flaw is found to be nearly rectangular and near the fusion line in the heat-affected zone. A fracture-origin survey of the wide-plate tensile specimen reveals that the cleavage fracture occurred from a local brittle zone at the tip of the introduced embedded flaw. Consequently, it is confirmed that this test meets the requirements for application to an evaluation on the significance of defects. Finally, we perform fracture evaluation by comparing the fracture stress with allowable stress and verify the applicability of the evaluation method using a failure assessment diagram (FAD) of the cold-cracking embedded flaw. The fracture load is found to be higher than the allowable stress; therefore, fracture will not occur even if similar embedded flaws exist in the structures. Furthermore, we confirm that a BS7910-based FAD evaluation can be applied to cold-cracking embedded flaws with a specific safety margin. Although the load observed in the embedded flaw near the cross-section exceeds the plastic collapse load, the fracture load estimated by the FAD evaluation is less than the plastic collapse load. This difference can be explained by an appropriate correction of critical crack-tip opening displacement and through-thickness residual stress distribution.

The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC.RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients.This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

A constraint loss correction procedure using the Weibull stress criterion is specified in ISO 27306. However, this standard is applicable only to structural steel components with defects, not to welded joints. Therefore, we propose a method for estimating the brittle fracture limit of a weld with a notch in the heat-affected zone (HAZ) and residual stress based on the Weibull stress criterion. Three-point bending (3PB) tests and wide-plate (WP) tension tests of HAZ-notched welds made of 780-MPa class high-strength steel were conducted at −40 °C. The minimum critical crack tip opening displacement (CTOD) of the WP specimen fracturing at the coarse-grained region of the HAZ (CGHAZ) was approximately four times that of the 3PB specimen. Then, the effects of specimen geometry, residual stress, crack-front shape, and HAZ microstructure classification on the Weibull stress were investigated by using a finite element analysis (FEA). The results of these analyses showed that the specimen geometry, the welding residual stress, and HAZ microstructure affect the Weibull stress of HAZ-notched welds as crack driving force. Based on above results, the CTOD–Weibull stress curves for 3PB and WP specimens fracturing at CGHAZ were calculated by using an FEA. It was confirmed that the brittle fracture limit of an HAZ-notched weld with residual stress could be predicted from the Weibull stress criterion because predicted critical CTOD of WP specimens obtained by Weibull stress included experimental critical CTOD of WP specimens.

Mutual- and self-diffusion coefficients of a semiflexible polymer, cellulose tris(phenyl carbamate) (CTC), in tetrahydrofuran were measured by dynamic light scattering and pulsed field gradient NMR, respectively, as functions of the polymer concentration and molecular weight. The mutual-diffusion coefficient after elimination of the effects of thermodynamic force and solvent back flow agrees with the self-diffusion coefficient for a low molecular weight CTC fraction with the number of Kuhn's statistical segments N = 1.8 up to high concentrations, but they disagree for a higher molecular weight CTC fraction with N = 4.7 at the highest concentration investigated. The mutual diffusion coefficients for CTC fractions with N ranging from 1.8 to 10.6 after elimination of the above two effects were also compared with the fuzzy cylinder theory for the self-diffusion coefficient. Disagreements start at lower concentration for larger N, which form in a contrast with good agreements for a more stiff polymer, poly(n-hexyl isocyanate), previously studied.

This paper presents a method for estimating the brittle fracture limit of a weld with a notch in the heat-affected zone (HAZ) and residual stress based on the Weibull stress criterion. A constraint loss correction procedure using the Weibull stress criterion is specified in ISO 27306. However, this standard is applicable only to structural steel components with defects, not to welded joints. Therefore, we conducted fracture tests and finite element analyses to propose a new evaluation method for welded structural components. In this study, three-point bending (3PB) tests and wide-plate (WP) tension tests of HAZ-notched welds made of 780-MPa-class high-strength steel were conducted at −40°C. Brittle fractures occurred in the HAZ regions of all the specimens, and the critical crack tip opening displacement (CTOD) values obtained in the 3PB and WP tests were approximately 0.02–0.07 mm and 0.08–0.11 mm, respectively. The minimum critical CTOD of the WP specimen fracturing at the coarse-grained region of the HAZ (CGHAZ) was approximately four times that of the 3PB specimen. These results confirmed that the difference of specimen geometry affects the brittle fracture resistance of a HAZ-notched weld with residual stress. Hence, the assessment of the brittle fracture limit of a welded structural component with a defect obtained by the fracture toughness of a 3PB specimen would be excessively conservative. The effects of specimen geometry, residual stress, crack-front shape and HAZ microstructure classification on the Weibull stress were investigated to clarify the difference of experimental critical CTOD for 3PB and WP by using a finite element analysis. The results of this analysis showed that the Weibull stress of WP specimen was larger than one of 3PB specimen in all CTOD region due to difference of geometry. The welding residual stress increased the Weibull stress only for WP. Compressive residual stress and crack front shape for 3PB specimen did not affect the Weibull stress. The difference of HAZ microstructure distribution for same welded joint affects the Weibull stress for 3PB and WP specimens. Finally, it was confirmed that the brittle fracture limit of a HAZ-notched weld with residual stress could be predicted from the Weibull stress criterion because critical CTOD of WP specimens predicted by critical CTOD of 3PB specimens fracturing at the CGHAZ included critical CTOD of WP specimens obtained by experiments.

カルシウム, ストロソチウム及びバリウムアルコキシドは臭化オクチル,臭化ヘキシル及び塩化ベソジルのようなハロゲン化第一級アルキルとDMSO-アルコール(1/1)溶媒中,70-100℃ で反応し,s72-94%の収率で第一級エーテルが得られた.次に二つの反応点を有するエチレングリコール及び-2-プロピン-1-オールのアルカリ土類金属塩と塩化ベンジルとの反芯では一置換体のみが選択的に与えられた.アルカリ金属塩の反応では一置換体の他に二置換体が副生するのに比べて対照的な結果である.一方アルカリ土類金属フェノキシド及びナフチルオキシドは第一級アルキル化物とDMSO中で反応しアリールアルキルエーテルが高収率で得られた.さらにヨウ化イソプロピル,臭化イソプロピル,メタンスルポソ酸イソプロビル,ヨウ化 s-ブチル及びメタンスルホソ酸 s-ブチルとの反応により第二級アルキルアリールエーテルが56-71%の収率で得られた.従来のアルカリ金属塩と第二級アルキル化物との反応ではエーテルの収率は20-30%に過ぎなかった.したがってアルカリ土類金属塩はアルカリ金属塩に比べて明らかに反応性,選択性が大きい.特にCa塩はSr塩及びBa塩よりも反応性は小さいが,安全性と緬格の点からも有機合成に有用である.

Plastic strains were measured near a propagating ductile crack in drop-weight tear tests (DWTT). Plastic work evaluated from the plastic strains agreed with crack propagation energy evaluated from dynamic load versus displacement curve. Furthermore, plastic strains were measured near a propagating ductile crack in a full-scale burst tested pipes. Plastic work of the burst pipe was found to be much larger than that of the DWTT. Values of the plastic work of the DWTT and the burst pipe were plotted against crack velocity to construct crack resistance curve. Reason to the increased crack resistance with crack velocity was understood as a dependence of plastic strain distribution on crack velocity by elasto-plastic dymanic finite element analysis.Copyright © 2012 by ASME

Full-scale burst test of X65 UOE linepipe, with 559mm outer diameter and 13.5mm wall thickness, pressurized at 16MPa by hydrogen gas was conducted. A 735mm long crack was introduced by explosive shaped charge over circumferential weld. The cracks were initiated and propagated in the both directions. The propagated crack lengths were 600mm and 270mm. J integral resistance curves were obtained from drop-weight as well as quasi static tests for the tested pipe material which was subjected to hydrogen charging. The tested steel showed little change in the resistance curves under realistic charging condition. Numerical simulation model of dynamic crack propagation, coupled with gas decompression behavior considering gas escape from opened crack, showed that an initiated crack was arrested at shorter distance in hydrogen gas pipelines than in methane gas pipelines, primarily due to earlier gas decompression in the former. The present results, together with the earlier full-scale burst tests conducted by the authors, demonstrated that hydrogen gas pipelines can be operated safely by using modern high-strength and high-toughness steel linepipes.

A new model of unstable ductile crack propagation and arrest of pressurized gas pipeline is presented. The model couples pipe deformation and fracture with gas decompression. The model also takes account of backfill effect. Pipe deformation and pressure changes are obtained by solving one-dimensional differential equations. Validity of the model was checked by comparing with published full-scale burst test data. The model can predict history of crack velocity and arrest crack length with fairly good accuracy. The model can be applied to wide ranges of gases, pipe grades and pipe sizes because it does not rely on parameter adjustment by experimental data sets but is based on physical assumptions.Copyright © 2010 by ASME

Burst tests of line pipes containing high-pressure hydrogen and methane gas were conducted. The pipes tested were X65 ERW pipes with 267mm outer diameter and 6mm wall thickness. Applied pressures were 12 and 15MPa. A 300mm long crack was initiated by a shaped charge. Unstable shear fracture propagated at velocity of approximately 200m/s and then arrested. It was demonstrated that the arrested crack lengths were shorter in the hydrogen gas burst tests than methane gas burst tests. Pressure measurement indicated that decompression wave in hydrogen gas propagated faster than that in methane gas. This is the primary reason to the shorter arrested crack lengths for the hydrogen gas burst tests. The test results are discussed based on numerical analyses of gas decompression behaviors.Copyright © 2008 by ASME

The effort of this study is to develop a damage model for simulating large ductile crack extension accompanied by a flat and a slant surface observed in the hydrostatic full-scale tests up to rupture for API X80 line pipes with an axial through-wall notch. A small and thin specimen with a shallow through-thickness notch having a large ligament (sub-sized Charpy V-notch (Sub-CVN) specimen subjected to 3-point bending) is used for a fundamental verification study. The Sub-CVN specimen provided the similar macroscopic process as well as micro-mechanism for ductile cracking, where a flat-to-slant fracture transition accompanied by a transition from an equi-axed dimple mode to a shear-slip mode fracture is presented. On the basis of the observed mechanism of ductile crack growth, a numerical ductile damage model for predicting the large ductile crack growth resistance is proposed taking into account an effect of the Lode parameter on ductile fracture into the present damage model proposed by authors. The crucial consideration is that the damage parameters to be identified can be correlated to the material properties. In this model, the shear-dominated stress state is assumed to advance the acceleration of damage evolution due to a shear localization mechanism at lower damage level even at the same stress triaxiality condition, so that the critical damage fraction dependent on the Lode parameter is phenomenologically employed in this model. The modified damage model reproduces the same ductile crack profile together with the same micro-mechanisms for forming the chevron-shaped flat surface as those observed in the experiment. The possibility to reproduce the flat-to-slant fracture transition is also demonstrated by the simulation.