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Volumetric‐modulated arc therapy (VMAT) requires highly accurate control of multileaf collimator (MLC) movement, rotation speed of linear accelerator gantry, and monitor units during irradiation. Pretreatment validation and monitoring of these factors during irradiation are necessary for appropriate VMAT treatment. Recently, a gantry mounted transmission detector “Delta4 Discover® (D4D)” was developed to detect errors in delivering doses and dose distribution immediately after treatment. In this study, the performance of D4D was evaluated. Simulation plans, in which the MLC position was displaced by 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 mm from the clinically used original plans, were created for ten patients who received VMAT treatment for prostate cancer. Dose deviation (DD), distance‐to‐agreement (DTA), and gamma index analysis (GA) for each plan were evaluated by D4D. These results were compared to the results (DD, DTA and GA) measured by Delta4 Phantom + (D4P). We compared the deviations between the planned and measured values of the MLC stop positions A‐side and B‐side in five clinical cases of prostate VMAT during treatment and measured the GA values. For D4D, when the acceptable errors for DD, DTA, and GA were determined to be ≤3%, ≤2 mm, and ≤3%/2 mm, respectively, the minimum detectable errors in the MLC position were 2.0, 1.5, and 1.5 mm based on DD, DTA, and GA respectively. The corresponding minimum detectable MLC position errors were 2.0, 1.0, and 1.5 mm, respectively, for D4P. The deviation between the planned and measured position of MLC stopping point of prostate VMAT during treatment was stable at an average of −0.09 ± 0.05 mm, and all GA values were above 99.86%. In terms of delivering doses and dose distribution of VMAT, error detectability of D4D was comparable to that of D4P. The transmission‐type detector “D4D” is thus suitable for detecting delivery errors during irradiation.

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase β (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase β, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase β. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase β and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC0-24 and Cmax for JR-051 over agalsidase β were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase β to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase β in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.

Pabinafusp alfa is a fusion protein comprising a humanized anti-human transferrin receptor (TfR) antibody and human iduronate-2-sulfatase. It was developed as a novel modality to target central nervous system-related symptoms observed in patients with mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome). As the fusion protein contains an entire IgG1 molecule that binds TfR, there may be specific safety concerns, such as unexpected cellular toxicity due to its effector functions or its ability to inhibit iron metabolism, in addition to general safety concerns. Here, we present the comprehensive results of a nonclinical safety assessment of pabinafusp alfa. Pabinafusp alfa did not exhibit effector functions, as assessed by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity studies in TfR-expressing hematopoietic cells. Repeat-dose toxicity studies in cynomolgus monkeys showed that pabinafusp alfa did not induce any significant toxicological changes at doses up to 30 mg/kg/week upon intravenous administration for up to 26 weeks. Interaction of transferrin with TfR was not inhibited by pabinafusp alfa, suggesting that the effect of pabinafusp alfa on the physiological iron transport system is minimal, which was confirmed by toxicity studies in cynomolgus monkeys. These findings suggest that pabinafusp alfa is expected to be safe for long-term use in individuals with MPS II.

Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.

Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.

Purpose: Compared with the general population, a poorer quality of bone-implant osseointegration occurs and at a higher failure rate in patients with type 2 diabetes mellitus. The aim of this study was to analyze the effects of local injection of nerve growth factor at the bone-implant interface after implantation in type 2 diabetic rats. Materials and Methods: Goto-Kakizaki (GK) rats (n = 30) were used as a model of type 2 diabetes mellitus, and Wistar rats were used as a control (n = 15). GK rats were assigned randomly into two groups (n = 15/group): the diabetes mellitus group (saline only) and the nerve growth factor group (received nerve growth factor treatment). One titanium implant was placed in each rat's left tibia. Immediately postoperatively, nerve growth factor group rats were injected with nerve growth factor (0.4 μg/ day) intramuscularly around the implant, daily for 7 days. Diabetes mellitus and control group rats received normal saline in an identical manner. Rats were sacrificed at 2, 4, and 8 weeks following implant surgery. Results: Traditional light and confocal laser scanning microscopy were used on nondecalcified sections to investigate fluorochrome labeling changes and histologic features of bone adjoining the implants. Bone-toimplant contact and bone volume percentage in the diabetes mellitus group were significantly less than in the control and nerve growth factor groups, with no statistically significant differences between the control and nerve growth factor groups. Confocal laser scanning microscopy showed a significant increase in marked bone around the nerve growth factor group implant at 4 weeks (P < .01) and 8 weeks (P < .05) compared with the diabetes mellitus group. Conclusion: This study showed that local injection of nerve growth factor could improve implant-bone osseointegration in diabetic rats and may have important clinical implications.

Purpose We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. Patients and Methods Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. Results Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). Conclusion We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

Fabry disease (FD) is an X-linked lysosomal storage disease. It is caused by deficiency of the enzyme α-galactosidase A (α-Gal A), which leads to excessive deposition of neutral glycosphingolipids, especially globotriaosylceramide (GL-3), in cells throughout the body. Progressive accumulation of GL-3 causes life-threatening complications in several tissues and organs, including the vasculature, heart, and kidney. Currently available enzyme replacement therapy for FD employs recombinant α-Gal A in two formulations, namely agalsidase alfa and agalsidase beta. Here, we evaluated JR-051 as a biosimilar to agalsidase beta in a non-clinical study. JR-051 was shown to have identical primary and similar higher-order structures to agalsidase beta. Mannose-6-phosphate content was higher in JR-051 than in agalsidase beta, which probably accounts for a slightly better uptake into fibroblasts in vitro. In spite of these differences in in vitro biological features, pharmacokinetic profiles of the two compounds in mice, rats, and monkeys were similar. The ability to reduce GL-3 accumulation in the kidney, heart, skin, liver, spleen, and plasma of Gla-knockout mice, a model of FD, was not different between JR-051 and agalsidase beta. Furthermore, we identified no safety concerns regarding JR-051 in a 13-week evaluation using cynomolgus monkeys. These findings indicate that JR-051 is similar to agalsidase beta in terms of physicochemical and biological properties.

Among the industries with safety issues, we have chosen the following seven areas and conducted a comparative study: automobile traffic, air traffic, earthquake-resistancy, nuclear power, healthcare, pharmaceutical products, and food products. We have focused on the four aspects, namely 1) systems for collecting and providing accident, incident and safety-related information, 2) national, industrial, academic and international role-taking and cooperation in standard-setting and testing, and 3) systems for the relief of the victims. The method for designing safety-related institutions shall be established by analyzing the similarities and differences among the legal system for each area from such perspectives as the social and industrial structures as well as the risk characteristics. Language: ja

We prospectively studied the results of distal release, performed between February 1989 and December 1994 for the treatment of a contracture of the deltoid muscle, in forty patients (forty-nine shoulders). Forty-seven contractures (in thirty-eight patients) developed after multiple intramuscular injections of various medications. The two remaining contractures (in two patients) were congenital. The average age at the onset of the symptoms was thirty-two years (range, birth to fifty-eight years). The primary symptoms included pain around the neck and the shoulder girdle, dimpling of the skin, a palpable fibrous band, winging of the scapula, difficulty in combing the hair or reaching the contralateral side of the body for grooming, and inability to bring the arm adjacent to the body. The average age at the time of the operation was thirty-nine years (range, fifteen to sixty-three years). The average duration of follow-up was three years and eleven months (range, two years to six years and six months). After the distal release of the contracture, but on the same day, the patients started a physical-therapy program. Postoperatively, the pain, dimpling of the skin, palpable fibrous band, and winging of the scapula resolved in forty-eight shoulders (thirty-nine patients). Six patients (six shoulders) no longer had difficulty in combing the hair or adducting the shoulder. There were no infections or neuromuscular complications. Forty-seven (96 per cent) of the forty-nine shoulders (thirty-eight of the forty patients) had a good clinical result, and two shoulders (two patients) had a poor result. Anterosuperior subluxation of the humeral head, noted on preoperative radiographs of twenty-three shoulders (eighteen patients), was not present postoperatively. Drooping of the acromion, seen in six patients (six shoulders) in whom the contracture had developed before they were sixteen years old, improved postoperatively in five shoulders (five patients). Rotation of the scapula, seen in five shoulders (five patients), resolved after release of the contracture in all five. There were no clinical or radiographic signs of osteoarthrosis due to long-term anterior translation of the shoulder joint in the four patients (six shoulders) who had had the contracture for at least twenty years (average, twenty-three years; maximum, twenty-seven years).

Synovial chondromatosis is an unusual monoarticular condition of the synovial membrane of the joint and may occasionally involve the bursae and tendon sheaths. 5' 7. 9, 11, 12 Although the disease most often affects the knee, elbow, or hip joints, other joints such as the wrist, ankle, shoulder, and the small joints of the hand may be involved. The condition usually presents as dull aching pain and crepitation in the involved joint. Diagnosis is frequently delayed until numerous loose bodies accumulate, which are demonstrated on roentgenographs. We report a case of synovial chondromatosis in the subacromial bursa of the right shoulder of a 46-year-old housewife. The major symptoms were crepitation of the right shoulder during movement in all directions for 4 years and painful discomfort for 6 months. No history of trauma was reported. Prolonged existence of the loose bodies caused rupture of the rotator cuff. Unusual multiple slitlike tears were noted during the operation. Anterior acromioplasty, total removal of the loose bodies, partial bursectomy, and rotator cuff repair rendered the patient free of symptoms. CASE REPORT A 46-year-old housewife was seen because of progressive painful discomfort that had been in her right shoulder for 4 years. In the beginning she reported a sound unaccompanied by pain in her right shoulder during movement. Painful discomfort developed 6 months before presentation. The pain

The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro . Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis , including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo . Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB.

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I kr blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.

A 70-year-old man presented with acute massive pulmonary embolism (PE). His clinical condition deteriorated despite regular heparin and thrombolytic agent treatment, and he eventually developed cardiogenic shock. A thrombus originating from the inferior vena cava was detected and acute-on-chronic embolization resulted, with an unusual clinical course. Aggressive catheter thrombectomy with pigtail rotation failed to fragment the organized thrombus, but it was successfully removed by a 3-loop snare device combined with guiding catheter under percutaneous cardiopulmonary support.

An arthroscopic and histological investigation of patellar chondropathy in adolescents was performed in 98 knees of 83 patients who were classified into three clinical types of patellofemoral disorder. These were the anterior knee pain syndrome, idiopathic chondropathy, and unstable patella. Histological findings suggested little evidence of progression to high-grade chondropathy in the patients with anterior knee pain syndrome, and this may account for the resolution of clinical symptoms in this group. Even in patients with high-grade lesions in the idiopathic chondropathy and unstable patella groups, histological observations indicated that these lesions could heal either by intrinsic (fibrous metaplasia of chondrocytes and regeneration of matrix) or extrinsic repair. Chondropathy in adolescents may be similar to the early changes of osteoarthritis of the knee. However, chondropathy shows far more potential for repair by the synovium and/or the cartilage itself than does osteoarthritis.

Randomized comparative study was conducted with periarthritis scapulohumeralis to determine the efficacy, safety, and usefulness of SPH using 2.5ml of 1% SPH solution (S) or of 0.01% SPH solution (P) for intra-articular, intra-subacromial bursa or intrabiceps tendon sheath injection five times continuously in weekly intervals.1) Total number of patients examined was 152 (S: 76, P: 76). Among those patients, 139 (S: 67, P: 72) were adopted for the analysis of final global improvement and usefulness, and 150 (5: 74, P: 76) for analysis of general safety.2) With respect to final global improvement, the effective rate (more than “moderately improved”) of S group was 70.2% (47/67), and 36.1% (26/72) for P group.S group was significantly superior to P group.3) With respect to overall safety, incidence of side effects was 2.7% (2/74) for S group, 2.6% (2/76) for P group, and no significant difference was observed between S and P groups.4) With respect to usefulness, the rate of usefulness (more than “moderately useful”) of S group was 68.7% (46/67), and 38.9% (28/72) for P group.S group was significantly superior to P group.5) As for the change of global improvement and of patient's impression, S group was significantly superior to P group.As for improvement on symptoms, S group was significantly superior to P group in “rest pain, ” “pain under movement, ” “motion of washing face, ” “motion of arranging hair, ” “tying a string behind one's back, ” “put the hand on the opposite side of shoulder” and S group tended to be superior in “oppressive pain.” On the other hand, as for the range of motion, both S and P groups were equally improved, and no significant difference was observed between the two groups, but S group was superior in the rate of improvement. High effectiveness of SPH was proved in patients whose duration of symptoms is within one year and global severity is slight to moderate.With pespect to injection site, S group was superior to P group, both in subacromial bursa and biceps tendon sheath, and S group tended to be superior in glenohumeral joint.6) As an adverse side effect, slight to moderate local pain after injection of drugs was noted in 4 patients (S: 2, P: 2).No abnormality caused by the drugs was found in laboratory test values.In conclusion, SPH is considered to be useful in the treatment of periarthritis scapu-lohumeralis.