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Background: We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211 At-meta-astatobenzylguanidine ( 211 At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement., Methods: We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance., Results: We investigated the new formalism's performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [ 211 At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [ 211 At]MABG., Conclusions: The RAP dose conversion method renovated by the new formalism was able to estimate the [ 211 At]MABG absorbed dose using a similar pharmacokinetics, such as [ 131 I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy., (© 2021. The Author(s).)

Gadolinium deposition in the brain has been observed in areas rich in iron, such as the dentate nucleus of the cerebellum. We investigated the role of Fe 2+ in the effect of gadolinium-based contrast agents (GBCA) on thyroid hormone-mediated Purkinje cell dendritogenesis in a cerebellar primary culture. The study comprises the control group, Fe 2+ group, GBCA groups (gadopentetate group or gadobutrol group), and GBCA+Fe 2+ groups. Immunocytochemistry was performed with an anti-calbindin-28K (anti-CaBP28k) antibody, and the nucleus was stained with 4',6-diamidino-2-phenylindole (DAPI). The number of Purkinje cells and their arborization were evaluated with an analysis of variance with a post-hoc test. The number of Purkinje cells was similar to the control groups among all treated groups. There were no significant differences in dendrite arborization between the Fe 2+ group and the control groups. The dendrite arborization was augmented in the gadopentetate and the gadobutrol groups when compared to the control group ( p < 0.01, respectively). Fe 2+ significantly increased the effect of gadopentetate on dendrite arborization ( p < 0.01) but did not increase the effect of gadobutrol. These findings suggested that the chelate thermodynamic stability and Fe 2+ may play important roles in attenuating the effect of GBCAs on the thyroid hormone-mediated dendritogenesis of Purkinje cells in in vitro settings.

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64 Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) ( 64 Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64 Cu-ATSM uptake both in vitro and in vivo. High RBE/ 64 Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/ 64 Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/ 64 Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/ 64 Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64 Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64 Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or in a PTEC-specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Objectives: This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response., Methods: We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1st dose and after the 2nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses., Results: Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 - 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1774 participants who received the 2nd dose with a median titer of 2060.0 U/mL (IQR 1250.0 - 2650.0). Immunosuppressive medication (p < 0.001), age (p < 0.001), time from 2nd dose to sample collection (p < 0.001), glucocorticoids (p = 0.020), and drinking alcohol (p = 0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p < 0.001), female (p < 0.001), time between 2 doses (p < 0.001), and medication for allergy (p = 0.024) were identified as factors predicting higher serum antibody titers., Conclusions: Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 ( 211 At)-labeled amino acid derivative, 2- 211 At-astato-α-methyl-L-phenylalanine (2- 211 At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2- 211 At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2- 211 At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2- 211 At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2- 211 At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2- 211 At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2- 211 At-AAMP by increasing its accumulation in tumors.

Aim: Pulmonary hypertension (PH) and chronic kidney disease (CKD) are interdependent for their development and exacerbation. We evaluated the effect of PH on CKD progression in patients with connective tissue disease (CTD)-associated PH., Methods: We reviewed consecutive patients with CTD who were diagnosed with PH with right heart catheter (RHC) examinations in our hospital. Patients were divided into 2 groups according to the use of vasodilators: monotherapy or combination therapy. We further divided the patients with combination therapy into early and non-early combination groups. Early combination was defined as the addition of the second vasodilator within 1 month after starting the first drug. The clinical course of hemodynamics and CKD progression were compared., Results: Thirty-eight patients were included in the analysis: 10 were treated with monotherapy and 28 with combination therapy (14 with early and 14 with non-early). At baseline, patients who received combination therapy had a significantly higher mean pulmonary arterial pressure with RHC and a higher right ventricular systolic pressure (RVSP) with echocardiography (P = .04) and showed a greater improvement in RVSP after treatment than those who underwent monotherapy. The incidence of CKD progression was significantly lower in patients who received combination therapy than in those who received monotherapy (P = .05). Among patients who received combination therapy, the early combination group had a lower incidence of CKD progression than the non-early combination group (P = .03)., Conclusions: Early combination therapy is associated with a lower incidence of CKD progression in patients with CTD-associated PH., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

A risk management plan (RMP) has an important role in assuring the optimal benefit-risk balance of a drug throughout its life cycle. However, no clear standards have been established for differentiating risk classification between "important identified risks" and "important potential risks". This study was a review and descriptive analysis for Japanese RMPs with a focus on antineoplastic agents to identify effective factors to discriminate an important identified risk from an important potential risk. Analysis based on 51 RMPs, reporting 310 important identified risks and 72 important potential risks, revealed significant associations between selection of the risk classification and several factors, including severe cases, actual cases in the Japanese population, availability of confirmatory trial data, and incidence of adverse events. Trend of the association was also found for discontinuation cases and immune-oncology agents [IO (drug type)]. These results suggest that consideration of these factors may be useful for coherent risk classification in creating a RMP., (© 2021. The Drug Information Association, Inc.)

We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.

Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids., Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis., Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019., Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70)., Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections., Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04)., Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months., Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease. Methods: We retrospectively evaluated patients with connective tissue disease and available serum magnesium data who visited Keio University Hospital in 2019. Patients were divided into two groups: those with (serum magnesium < 1.8 mg/dl) and those without hypomagnesemia; their rates of hospitalization for severe infection and cumulative renal deterioration were compared. Patients' fractions of lymphocytes and natural killer and dendritic cell subsets, as measured by fluorescence-activated cell sorting (FACS) analysis, were also compared. Results: Among 284 patients, hypomagnesemia was detected in 63 (22.2%). Multivariate analysis revealed that the use of proton pump inhibitors [odds ratio (OR), 1.48; p = 0.01] and tacrolimus (OR, 6.14; p < 0.01) was independently associated with hypomagnesemia. In addition, the renal deterioration rate was significantly higher in tacrolimus and/or proton pump inhibitor users with hypomagnesemia ( p = 0.01). The hospitalization rate for severe infection was also higher in patients with hypomagnesemia ( p = 0.04). FACS analysis showed lower CD8+ T cell, CD19+ B cell, natural killer cell, and dendritic cell counts in patients with hypomagnesemia ( p = 0.03, p = 0.02, p = 0.02, and p = 0.03, respectively). Conclusion: The use of tacrolimus and proton pump inhibitors may be associated with hypomagnesemia and lead to poor renal outcomes and severe infection in patients with connective tissue disease., Competing Interests: Authors NS, HT, and KC were employed by the company Mitsubishi Tanabe Pharma Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hanaoka, Kikuchi, Kaneko, Seki, Tsujimoto, Chiba and Takeuchi.)

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Pretargeting radioimmunotherapy (PRIT) is a promising approach that can reduce long-time retention of blood radioactivity and consequently reduce hematotoxicity. Among the PRIT strategies, the combination of biotin-conjugated mAb and radiolabeled streptavidin (StAv) is a simple and convenient method because of its ease of preparation. This study performed three-step (3-step) PRIT using the sequential injection of (1) biotinylated bevacizumab (Bt-BV), (2) avidin, and (3) radiolabeled StAv for the treatment of triple-negative breast cancer (TNBC)., Methods: Four biodistribution studies were performed using 111 In in tumor-bearing mice to optimize each step of our PRIT methods. Further, a therapeutic study was performed with optimized 3-step PRIT using 90 Y-labeled StAv., Results: Based on the biodistribution studies, the protein dose of Bt-BV and avidin was optimized to 100 μg and 10 molar equivalent of BV, respectively. Succinylation of StAv significantly decreased the kidney accumulation level (with succinylation (6.96 ± 0.91) vs without succinylation (20.60 ± 1.47) at 1 h after injection, p < 0.0001) with little effect on the tumor accumulation level. In the therapeutic study, tumor growth was significantly suppressed in treatment groups with optimized 3-step PRIT using 90 Y-labeled succinylated StAv compared to that of the no-treatment group (p < 0.05)., Conclusions: The 3-step PRIT strategy of this study achieved fast blood clearance and low kidney uptake with little effect on the tumor accumulation level, and a certain degree of therapeutic effect was consequently observed. These results indicated that the pretargeting treatment of the current study may be effective for human TNBC treatment.

Objectives: Molecular imaging constitutes a promising technique for the early detection of rheumatoid arthritis (RA). Macrophages and hypoxia play significant roles in inflamed synovium. In the present study, we evaluated the efficacy of radiopharmaceuticals that target macrophage mannose receptors ( 99m Tc-labeled mannosylated dextran or 99m Tc(CO) 3 -DCM20) and hypoxia (copper(II) diacetyl-di(N 4 -methylthiosemicarbazone) or Cu-ATSM) for the early detection of RA in collagen-induced arthritis (CIA) mice models., Methods: CIA model was developed in DBA/1 mice, and the clinical score for arthritis was visually assessed on a regular basis. Two biodistribution studies were performed in a paired-labeled format using 2-deoxy-2- 18 F-fluoro-D-glucose ( 18 F-FDG) as a reference: (1) 99m Tc(CO) 3 -DCM20 with 18 F-FDG and (2) 67 Cu-ATSM with 18 F-FDG., Results: The accumulation levels of 99m Tc(CO) 3 -DCM20 and 67 Cu-ATSM in forepaws, hindpaws, and knee joints of CIA mice were significantly higher than that of control mice. In contrast, 18 F-FDG uptake in hindpaws and knee joints showed no significant difference between CIA and control mice. The radioactivity levels of 99m Tc(CO) 3 -DCM20 and 67 Cu-ATSM were significantly correlated with the clinical scores for the paws., Conclusion: These results suggest the potential usefulness of 99m Tc(CO) 3 -DCM20 and radiolabeled Cu-ATSM for the imaging and early detection of RA.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used incretin-based therapy for the treatment of type 2 diabetes. We investigated the cardioprotective effect of a DPP-4 inhibitor, vildagliptin (vilda), on myocardial metabolism and cardiac performance under pressure overload. Mice were treated with either vehicle or vilda, followed by transverse aortic constriction (TAC). After 3 weeks of TAC, cardiac hypertrophy and impairment of systolic function were attenuated in vilda-treated mice. Pressure-volume analysis showed that vilda treatment significantly improved left-ventricular contractile efficiency in TAC heart. Myocardial energy substrate analysis showed that vilda treatment significantly increased glucose uptake as well as fatty acid uptake. Fibroblast growth factor 21 (FGF21), a peptide involved in the regulation of energy metabolism, increased in TAC heart and was further increased by vilda treatment. FGF21 was strongly expressed in cardiac fibroblasts than in cardiomyocytes in mouse heart after TAC with vilda treatment. Vilda treatment markedly induced FGF21 expression in human cardiac fibroblasts through a sirtuin (Sirt) 1-mediated pathway, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism and exert vilda-mediated beneficial effects in stressed heart. Vilda induced a metabolic regulator, FGF21 expression in cardiac fibroblasts via Sirt1, and increased contractile efficiency in murine pressure-overloaded heart.

Objective: We aimed to estimate in vivo 211 At-labeled meta-benzylguanidine ( 211 At-MABG) absorbed doses by the two dose conversion methods, using 131 I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works., Methods: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211 At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131 I to that of 211 At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g., Results: Virtual experiments showed that 211 At-MABG and 131 I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211 At-MABG dose. Simulated 211 At-MABG doses from 131 I-MIBG using the RAP method were in agreement with those from 211 At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data., Conclusions: The present RAP dose conversion method could estimate 211 At-MABG absorbed doses from the pharmacokinetics of 131 I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

Diabetes is an independent risk factor for the development of heart failure. Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. We studied whether reduced FA uptake in the heart is protective against streptozotocin (STZ)-induced diabetic cardiomyopathy by using mice doubly deficient in fatty acid binding protein 4 (FABP4) and FABP5 (DKO mice). Cardiac contractile dysfunction was aggravated 8 weeks after STZ treatment in DKO mice. Although compensatory glucose uptake was not reduced in DKO-STZ hearts, total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. Tracer analysis with 13 C 6 -glucose revealed that accelerated glycolysis in DKO hearts was strongly suppressed by STZ treatment. Levels of ceramides, cardiotoxic lipids, were similarly elevated by STZ treatment. These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Thus, enhanced FA uptake in diabetic hearts seems to be a compensatory response to reduced energy supply from glucose, and therefore, limited FA use could be detrimental to cardiac contractile dysfunction due to energy insufficiency.

The high and persistent renal radioactivity levels after injection of radiolabeled low-molecular-weight polypeptides constitute a significant problem for their diagnostic and therapeutic applications, especially when they are labeled with metallic radionuclides. To improve the renal radioactivity levels of technetium-99m ( 99m Tc)-labeled Fab fragments, a mercaptoacetyltriglycine (MAG 3 )-based new bifunctional chelating agent with a cleavable glycyl-phenylalanyl-lysine (GFK) linkage, MAG 3 -GFK-suc-TFP, was designed, synthesized, and evaluated. 99m Tc-labeled Fab was obtained by reacting MAG 3 -GFK-Fab conjugate with 99m Tc-glucarate. The GFK linkage remained stable in plasma but was cleaved by enzymes on the renal brush border membrane. The comparative biodistribution studies with indium-111 ( 111 In)-labeled Fab using SCN-CHX-A″-DTPA showed that while both radiolabeled Fabs exhibited similar elimination rates from the blood, [ 99m Tc]Tc-MAG 3 -GFK-Fab registered much lower renal radioactivity levels from 30 min post-injection onward due to the release and subsequent urinary excretion of [ 99m Tc]Tc-MAG 3 -Gly. However, [ 99m Tc]Tc-MAG 3 -GFK-Fab showed an increase in the intestinal radioactivity levels with the time that was not observed with 111 In-labeled Fab. The analysis of the intestinal contents suggested the redistribution of [ 99m Tc]Tc-MAG 3 -Gly to the intestine. The retrospective comparison of [ 99m Tc]Tc-MAG 3 -GFK-Fab with the radiolabeled Fabs so far prepared under the identical concept suggested that some portion of [ 99m Tc]Tc-MAG 3 -Gly was generated after the coated vesicle formation and they were excreted into the blood, and subsequently redistributed in the intestine via hepatobiliary excretion. In conclusion, MAG 3 -GFK-suc-TFP provided 99m Tc-labeled Fabs that exhibit low renal radioactivity shortly after injection by the post-labeling procedure. The present study indicated that, contrary to our earlier proposal, the generation of the radiometabolites would proceed not only during the internalization process of the parental antibody fragments but also after coated vesicle formation. This study also showed that the intracellular behaviors of radiometabolites played crucial roles in the elimination rates and the routes of the radioactivity from the kidney.

Introduction: Targeted α-radionuclide therapy has attracted attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, we prepared an LAT1-selective α-radionuclide-labeled amino acid analog, 2-[ 211 At]astato-α-methyl-L-phenylalanine (2-[ 211 At]AAMP), and evaluated its potential as a therapeutic agent., Methods: 2-[ 211 At]AAMP was prepared from the stannyl precursor. Stability of 2-[ 211 At]AAMP was evaluated both in vitro and in vivo. In vitro studies using an LAT1-expressing human ovarian cancer cell line, SKOV3, were performed to evaluate cellular uptake and cytotoxicity of 2-[ 211 At]AAMP. Biodistribution and therapeutic studies in SKOV3-bearing mice were performed after intravenous injection of 2-[ 211 At]AAMP., Results: 2-[ 211 At]AAMP was stable in murine plasma in vitro and excreted intact into urine. Cellular uptake of 2-[ 211 At]AAMP was inhibited by treatment with an LAT1-selective inhibitor. After 24 h incubation, 2-[ 211 At]AAMP suppressed clonogenic growth at 10 kBq/ml, and induced cell death and DNA double-strand breaks at 25 kBq/ml. When injected into mice, 2-[ 211 At]AAMP exhibited peak accumulation in the tumor at 30 min postinjection, and radioactivity levels in the tumor were retained up to 60 min. The majority of the radioactivity was rapidly eliminated from the body into urine in an intact form immediately after injection. 2-[ 211 At]AAMP significantly improved the survival of mice (P < 0.05) without serious side effects., Conclusion: 2-[ 211 At]AAMP showed α-radiation-dependent cellular growth inhibition after it was taken up via LAT1. In addition, 2-[ 211 At]AAMP had a beneficial effect on survival in vivo. These findings suggest that 2-[ 211 At]AAMP would be useful for the treatment of LAT1-positive cancer., Advances in Knowledge and Implications for Patient Care: This is the first report of an LAT1-targeting radiopharmaceutical for α-radionuclide therapy; this agent would be applicable for the treatment of various types of cancer., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Revisions of drug package inserts (PIs) may be made immediately after approval or after considerable clinical experience; however, it is unclear whether there is a relationship between the characteristics of these safety measures and the period since drug approval. Here, we analyzed 209 cases of safety measures (revisions of the PIs) taken in Japan over 5 years (FY2014 to FY2018). The median, minimum, and maximum period from approval date in Japan to PI revision date was 6.29 years (interquartile range 2.68-15.53 years), 0.16 years, and 59.69 years, respectively. The cases were classified into four groups depending on types of adverse reaction and therapeutic category in relation to the national approval date and international birth date, resulting in the grouping together of particular adverse reactions and therapeutic drugs. For example, "Hepatobiliary disorders", "Blood and lymphatic system disorders", "Respiratory, thoracic and mediastinal disorders", "Antineoplastics", "Chemotherapeutics", and "Other agents affecting metabolism" were associated with the group of safety measures taken early after approval of a drug soon after the international birth date, suggesting that careful attention at an earlier stage after approval is necessary for these adverse reactions and drugs. Understanding such features of PI revisions makes pharmacovigilance planning more appropriate, contributing to the implementation of rapid and proper safety measures after drug approval.

A 46-year-old man with Klinefelter syndrome (KS) presented with obliterative phlebitis of the lower legs with a deteriorated renal function, and elevated serum alkaline phosphatase and ataxia levels. Examinations demonstrated tubulointerstitial nephritis, obliterative phlebitis and lymphadenopathy with IgG4+ plasma cell infiltrate and sclerosing cholangitis. Although the serological profile and central nerve system involvement were compatible for systemic lupus erythematosus (SLE), a definite diagnosis of SLE was difficult to make. IgG4-related disease (IgG4-RD) with KS was finally diagnosed, and high dose prednisolone with intravenous cyclophosphamide was initiated and thereafter the patient demonstrated a prompt improvement. This is the first known case demonstrating overlapping IgG4-RD with lupus-like serological and neurological features in a patient with KS, thus highlighting the pathogenic role with the genomic background for IgG4-RD and SLE.

The development of gene therapy products has been expanding globally, and among them, the recombinant adeno-associated virus (rAAV) vector is one of the most promising vectors for gene transfer. For efficient and rapid development of the manufacturing process and quality control strategy, the quality by design (QbD) approach can be as effective for gene therapy products as it is for gene recombinant proteins, which have been developed for decades. However, prior available knowledge required for the QbD approach is limited in the field of gene therapy. Here, we comprehensively review rAAV study results that can form the basis of QbD-based development and propose a critical quality attribute identification method suitable for gene therapy development. As a case study for rAAV, we propose a series of practical development steps, including a quality target product profile (QTPP) setting, identification of critical quality attributes (CQAs), repetitive risk assessment associated with process optimization, design space (DS) establishment, and control strategy using the QbD method. Our case study, which was based on publicly available literature, is a basic model that can be augmented by unique data pertaining to specific products. An improvement in rAAV development is expected using this model as the first step., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The cognitive function of nursing home (NH) residents with cognitive impairment (CI) tends to decline over time. An effective multimodal non-pharmacological intervention (MNPI) strategy is needed to improve the cognitive function of NH residents with CI.The aim of this study was to clarify the cognitive function characteristics of NH residents with CI in whom a non-pharmacological intervention (NPI) can be implemented, consisting of MNPI using a Bayesian analysis, and to incorporate suggestions to make the MNPI strategy as effective as possible.This study had a cross-sectional design. The 61 subjects were selected from the residents of 5 NHs, of whom 90.16% were female, and the mean (standard deviation) age was 87.20 ± 6.90. Analyses were performed using a hierarchical Bayesian model, and the global and specific cognitive functions as assessed by the Japanese version of the Neurobehavioral Cognitive Status Examination were the response variables. Three types of NPI (cognitive enhancement NPI, physical NPI, psychological and psychosocial NPI), and activities of daily living (ADL), as assessed by the Barthel index, were the explanatory variables.Cognitive enhancement NPI was revealed to have no association with any cognitive function. Physical NPI was negatively associated with orientation [OR 0.31 (95% credible interval (95% CI) -2.33, -0.10)], comprehension [OR 0.16 (95% CI -2.78, -0.95)] and naming [OR 0.49 (95% CI -1.47, -0.02)]. Psychological and psychosocial NPI was positively associated with comprehension [OR 3.67 (95% CI 0.52, 2.13)]. Barthel index was positively associated with total Japanese version of the Neurobehavioral Cognitive Status Examination [OR 1.74 (95% CI 0.08, 2.12)], comprehension [OR 3.49 (95% CI 0.45, 4.67)], repetition [OR 10.07 (95% CI 0.53, 9.01)], naming [OR 2.24 (95% CI 0.07, 3.20)], and calculations [OR 18.82 (95% CI 2.71, 9.40)].The implementation of MNPI should be preceded by cognitive enhancement NPI and physical NPI. Providing ADL enhancing NPI in response to cognitive improvement may be an effective strategy. Providing cognitive enhancement NPI, physical NPI, psychological, and psychosocial NPI, as well as ADL-enhancing NPI at the same time, is also an effective strategy for subjects with mild dementia who are considered to have relatively high cognitive functions.

L-2-[ 18 F]fluoro-alpha-methylphenylalanine (2-[ 18 F]FAMP) is a promising amino acid tracer for positron emission tomography (PET) imaging, yet the low production yield of direct electrophilic radiofluorination with [ 18 F]F 2 necessitates further optimization of the radiolabeling process. This paper describes a two-step preparation method for L-2-[ 18 F]fluoro-alpha-methylphenylalanine (2-[ 18 F]FAMP) starting from [ 18 F]fluoride. The (Mesityl)(L-alpha-methylphenylalanine)-2-iodonium tetrafluoroborate precursors with various protecting groups were prepared. The copper-mediated 18 F-fluorination of the iodonium salt precursors successfully produced 2-[ 18 F]FAMP. The highest radio chemical conversion of 57.6% was noted with N-Piv-protected (mesityl)(aryl)iodonium salt in the presence of 5 equivalent of Cu (OTf) 2 . Subsequent deprotection with 57% hydrogen iodide produced 2-[ 18 F]FAMP within 120 min in 21.4 ± 11.7% overall radiochemical yield with >95% radiochemical purity and an enantiomeric excess >99%. The obtained 2-[ 18 F]FAMP showed comparable biodistribution profiles in normal mice with that of the carrier-added 2-[ 18 F]FAMP. These results indicate that usefulness of copper mediated 18 F-fluorination for the production of 2-[ 18 F]FAMP, which would facilitate clinical translation of the promising tumor specific amino acid tracer. Individual facilities could adopt either production method based on radioactivity demand and equipment availability., (© 2020 John Wiley & Sons, Ltd.)

Introduction: Secondary lymphoedema of the extremities is an important quality-of-life issue for patients who were treated for their malignancies. Indocyanine green (ICG) fluorescent lymphography may be helpful for assessing lymphoedema and for planning lymphaticovenular anastomosis (LVA). The objective of the present clinical trial is to confirm whether or not ICG fluorescent lymphography using the near-infrared monitoring camera is useful for assessing the indication for LVA, for the identification of the lymphatic vessels before the conduct of LVA, and for the confirmation of the patency of the anastomosis site during surgery., Methods and Analysis: This trial is a phase III, multicentre, single-arm, open-label clinical trial to assess the efficacy and safety of ICG fluorescent lymphography when assessing and treating lymphoedema of patients with secondary lymphoedema who are under consideration for LVA. The primary endpoint is the identification rate of the lymphatic vessels at the incision site based on ICG fluorescent lymphograms obtained before surgery. The secondary endpoints are 1) the sensitivity and specificity of dermal back flow determined by ICG fluorescent lymphography as compared with 99m Tc lymphoscintigraphy-one of the standard diagnostic methods and 2) the usefulness of ICG fluorescent lymphography when confirming the patency of the anastomosis site after LVA., Ethics and Dissemination: The protocol for the study was approved by the Institutional Review Board of each institution. The trial was filed for and registered at the Pharmaceuticals and Medical Devices Agency in Japan. The trial is currently on-going and is scheduled to end in June 2020., Trial Registration Number: jRCT2031190064; Pre-results., Competing Interests: The present clinical trial plans to be conducted under funding from Hamamatsu Photonics K.K. The possibility that conflict of interest occurs with respect to the conduct of the clinical trial and its outcomes should be controlled appropriately based on the conflict of interest management policies of each medical institution., (© 2020 The Authors.)

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-β was upregulated in progressive disease cases., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Although 2- 18 F-fluoro-2-deoxy-glucose ( 18 F-FDG) has established roles in the diagnosis of a variety of cancers, it has limited value in the detection of primary/recurrent lesions in the bladder, mainly because of interference by the pooled radioactivity in the urine. Our previous study revealed promising properties of L- and D-2- 18 F-α-methyl-phenylalanine (2- 18 F-FAMP) as radiotracers; i.e., their rapid blood clearance and low renal accumulation. In the present study we evaluated the utility of L- and D-2- 18 F-FAMP for imaging bladder cancer in a mouse model., Methods: We used the human bladder cancer cell line HT1376 to prepare a bladder cancer xenograft model in mice bearing both orthotopic and subcutaneous tumors. Biodistribution and PET imaging studies were performed at 1 and 3 h after injection of L-2- 18 F-FAMP or D-2- 18 F-FAMP. 18 F-FDG was used as a control., Results: At 1 h after injection, greater accumulations of both L-2- 18 F-FAMP and D-2- 18 F-FAMP were observed in the orthotopic tumors compared to 18 F-FDG. The orthotopic tumor-to-muscle ratio of D-2- 18 F-FAMP was significantly higher than that of 18 F-FDG (p < 0.01), because of the rapid blood clearance of D-2- 18 F-FAMP. L-2- 18 F-FAMP showed the highest subcutaneous tumor-to-muscle ratio (p < 0.01) due to its high subcutaneous tumor uptake. Compared to L-2- 18 F-FAMP, D-2- 18 F-FAMP exhibited faster clearance and lower kidney accumulation. In the PET imaging studies, L- and D-2- 18 F-FAMP both clearly visualized the orthotopic bladder tumors at 1 h after injection., Conclusion: Our study showed that L-2- 18 F-FAMP and D-2- 18 F-FAMP have the potential to detect bladder cancer.

Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis. Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated. Results: Ten patients were enrolled. A significantly higher AUC 0-12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without ( p  = .03). All the patients with high MPA-AUC 0-12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0-12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01-1.45, p  = .02). Conclusion: The high AUC 0-12 of MPA at the early phase of induction therapy may predict good renal response.

Background: Foxp3 is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4 + Foxp3 + T cells. This study aimed to examine the phenotype and function of circulating CD4 + Foxp3 + T cells in patients with systemic lupus erythematosus (SLE)., Methods: We enrolled 47 patients with SLE, 31 with organ-specific autoimmune diseases (15 with multiple sclerosis and 16 with primary immune thrombocytopenia), and 19 healthy subjects. Peripheral blood mononuclear cells were used to evaluate the proportion and phenotype of CD4 + Foxp3 + cells using multicolor flow cytometry, the status of the Treg-specific demethylated region (TSDR) of the foxp3 gene by methylation-specific polymerase chain reaction, and the immunoregulatory function of CD4 + CD25 + cells by allogeneic mixed lymphocyte reaction. Immunohistochemistry of renal biopsy specimens obtained from 6 patients with lupus nephritis and 5 with IgA nephropathy was conducted to detect IL-17A-expressing CD4 + Foxp3 + cells., Results: CD4 + Foxp3 + T cells were increased in SLE patients compared with organ-specific autoimmune disease controls or healthy controls. Circulating CD4 + Foxp3 + T cells were correlated with the disease activity of SLE. The increased CD4 + Foxp3 + T cells in active SLE patients were mainly derived from thymus-derived Treg (tTreg) cells, as determined by a demethylated TSDR status, and represented a unique phenotype, upregulated expression of CD49d, CD161, and IL-17A, with immunosuppressive ability comparable to that of healthy controls. Finally, CD4 + Foxp3 + IL-17A + cells were infiltrated into the renal biopsy specimens of patients with active lupus nephritis., Conclusions: A unique tTreg subset with dichotomic immunoregulatory and T helper 17 phenotypes is increased in the circulation of SLE patients and may be involved in the pathogenic process of SLE.

Background: Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC., Methods: Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan., Results: Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs., Conclusions: The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy., Trial Registration Number: UMIN000007321., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission., Methods and Analysis: A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility - sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years., Ethics and Dissemination: The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association's Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal., Trial Registration Number: Japan Registry of Clinical Trials (jRCT2031190065)., Competing Interests: Competing interests: HH has received personal fees from Torii Yakuhin, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome., Methods: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period., Results: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events., Conclusion: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123., (© 2019 Japan Geriatrics Society.)

Objectives: Adult-onset Still's disease (AOSD) is an inflammatory disorder characterised by sustained fevers, arthritis, and skin involvement. Interstitial lung disease (ILD) is a rare manifestation, and its clinical characteristics have yet to be determined., Methods: We sought to examine the clinical characteristics of AOSD-associated ILD. We retrospectively investigated 78 patients diagnosed as AOSD. ILD was diagnosed based on chest high-resolution computed tomography (HRCT). Clinical characteristics were compared between patients with and without ILD. Relapse was defined as sustained fevers, re-emergence of arthritis, and skin involvement after remission. We further investigated the pathological features of ILD on available samples., Results: Patients with ILD, found in 9 of 78 (11.5 %), had older age of onset (mean age 62.6) than those without ILD (mean age 38.8) (p<0.01). The 3-year survival rates were comparable between patients with ILD (92.5%) and those without ILD (88.9%) (p=0.23). Patients with ILD had a higher cumulative rate of haemophagocytic syndrome (HPS) and relapse than those without (p<0.0001 and p=0.009, respectively). Chest HRCT showed marked thickening of the interlobular septa, the bronchovascular bundles, or the visceral pleura in all cases. There was no honeycomb or volume loss. Pulmonary pathological findings revealed marked thickening of the visceral pleura and the interlobular septa., Conclusions: Patients with ILD might have higher risks for HPS and relapse. Careful observation and appropriate therapeutic intervention might be needed.

Backgrounds: Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels., Methods: The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111 In- or 64 Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting., Results: We found that tumors with high EGFR expression had significantly higher [ 111 In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [ 111 In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [ 64 Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [ 64 Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors., Conclusion: Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.

Objective: Early detection plays a role in the prognosis of melanoma, the most aggressive skin cancer. 64 Cu- and 68 Ga-labeled alpha-melanocyte-stimulating hormone (α-MSH) analogs targeting the melanocortin-1 receptor are promising positron emission tomography (PET) tracers for detecting melanoma, and the use of 18 F-labeling will further contribute to the detectability and availability. However, the high radiochemistry demand related to the conventional 18 F-labeling methods has restricted the development of 18 F-labeled α-MSH analogs. A recently developed radiofluorination method using aluminum-fluoride (Al 18 F) offers a simple, efficient, and time-saving labeling procedure compared to the conventional 18 F-labeling methods. Herein, we sought to establish a simple preparation method for an 18 F-labeled α-MSH analog using Al 18 F, and we examined its potential for the early detection of melanoma., Methods: A 1,4,7-triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated α-MSH analog (NOTA-GGNle-CycMSH hex ) was prepared by the Fmoc solid-phase strategy. NOTA-GGNle-CycMSH hex was labeled with Al 18 F by heating at 105 °C using a microwave synthesizer for 15 min. Biodistribution study was conducted on B16/F10-luc melanoma-bearing mice at 30 min, 1 h and 3 h after injection of Al 18 F-NOTA-GGNle-CycMSH hex . PET imaging was conducted on melanoma-bearing mice at 1 h post-injection. One day prior to the PET imaging, bioluminescence imaging was also performed., Results: Al 18 F-NOTA-GGNle-CycMSH hex was readily prepared with a high radiochemical yield (94.0 ± 2.8%). The biodistribution study showed a high accumulation of Al 18 F-NOTA-GGNle-CycMSH hex in the tumor at 30 min and 1 h post-injection (6.69 ± 1.49 and 7.70 ± 1.71%ID/g, respectively). The tumor-to-blood ratio increased with time: 3.46 ± 0.89, 12.67 ± 1.29, and 35.27 ± 9.12 at 30 min, 1 h, and 3 h post-injection, respectively. In the PET imaging, Al 18 F-NOTA-GGNle-CycMSH hex clearly visualized the tumors and depicted very small tumors (< 3 mm)., Conclusions: We successfully prepared Al 18 F-NOTA-GGNle-CycMSH hex in a simple and efficient manner. Al 18 F-NOTA-GGNle-CycMSH hex showed high tumor accumulation and clearly visualized very small tumors in melanoma-bearing mice. These findings suggest that Al 18 F-NOTA-GGNle-CycMSH hex will be a promising PET tracer for melanoma imaging at an earlier stage.

Objective: To study maintenance therapy after achievement of the lowest possible disease activity in systemic lupus erythematosus (SLE) without major organ manifestations., Methods: We retrospectively evaluated patients with SLE who visited our hospital from Jan 2015 to Feb 2018 and were taking prednisolone (PSL) < 10 mg/day. After excluding those with neuropsychiatric SLE or severe lupus nephritis, patients were divided into four groups according to their maintenance monotherapy treatment, namely, prednisolone (PSL), immunosuppressant (IS), hydroxychloroquine (HCQ), and no drugs. The groups were then compared with regard to cumulative flare rate and changes in SLE Disease Activity Index (SLEDAI)., Results: There were 47 patients on PSL, 10 on IS, 5 on HCQ, and 11 on no drugs. Flare rate was higher in the no drug group, and no patients with the IS or HCQ group experienced a flare (p = 0.003). A reduction in SLEDAI was only seen in the IS and HCQ groups (p = 0.05 and p = 0.03, respectively). There were no differences in adverse events among groups during the study period., Conclusions: Our results suggest that the cessation of all drugs is associated with disease flare for SLE patients without major organ manifestations. IS or HCQ monotherapy might be a reasonable maintenance strategy comparing with steroid monotherapy. Key Point • Immunosuppressant or hydroxychloroquine monotherapy appears to be a reasonable maintenance strategy.

To evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes on improving the visual functions of patients with retinitis pigmentosa (RP), twenty eyes of 10 patients with RP underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) 6 times at 2 week intervals. All patients were stimulated bilaterally with 1.0 mA pulses. The primary endpoint was safety, and the secondary endpoints were the changes in the best-corrected visual acuity (BCVA), visual fields determined by the Humphrey field analyzer (HFA) 10-2 and Goldmann perimetry, and answers to the Visual Function Questionnaire-25. All of the 10 enrolled patients completed the study according to the protocol. No adverse events related to the treatments were reported during the follow-up examinations. The mean BCVA and Early Treatment Diabetic Retinopathy Study visual acuity were significantly improved after the TdES (P = 0.0078 and P = 0.001, respectively). The mean deviation of the HFA 10-2 was also significantly improved (P = 0.0076). We conclude that TdES with skin electrode is a safe therapeutic option and should be considered as a treatment option for patients with RP.

Positron emission tomography (PET) imaging with 18 F-labeled α-methyl-substituted amino acids exerts significant influence on differential diagnosis of malignant tumors and tumor-like lesions. Exclusive uptake via L-type amino acid transporter 1 (LAT1), a tumor-specific transporter, accounts for their excellent tumor specificity and low background accumulation. However, further refinement and optimization in their tumor accumulation and pharmacokinetics are sorely needed. To address these issues, we newly designed 18 F-labeled α-methyl-phenylalanine ( 18 F-FAMP) regioisomers (2-, 3-, or 4- 18 F-FAMP) and stereoisomers (L- or D-form), and we comprehensively evaluated their potential as tumor-imaging agents. 18 F-FAMPs were prepared from α-methyl phenylalanine by electrophilic radiofluorination and purified by reversed-phase HPLC. In biodistribution studies on normal mice, L-2- 18 F-FAMP and the three D- 18 F-FAMPs showed faster blood clearance and lower renal accumulation than L-3- 18 F-FAMP or L-4- 18 F-FAMP. In LS180 human colorectal cancer cell line xenograft mice, L-2- 18 F-FAMP exhibited significantly higher tumor accumulation than the D- 18 F-FAMPs or a clinically relevant tracer, L-3- 18 F-α-methyl-tyrosine ( 18 F-FAMT) ( p < 0.05). The renal accumulation levels of L-2- 18 F-FAMP were significantly lower than that of 18 F-FAMT ( p < 0.01). LAT-1 specificity of L-2- 18 F-FAMP was validated in the cellular uptake studies. The PET imaging with L-2- 18 F-FAMP clearly visualized the tumor as early as 1 h after injection, and the high tumor accumulation level was retained for 3 h. These findings suggest that L-2- 18 F-FAMP constitutes a potential PET tracer for tumor-specific imaging.

Objective: To investigate the role of transporter proteins in gadolinium (Gd) distribution and retention in the brain after one high-dose injection of Gd-based contrast agent (GBCA)., Methods and Materials: 30 ddY mice were randomly divided into three treatment groups to be intravenously injected with either Gadodiamide (linear GBCA), Gadobutrol (macrocyclic GBCA), or Gadoterate (macrocyclic GBCA) at a dose of 5 mmol/kg, while five mice in the control group received 250 µL saline. Five minutes (5 min) and ten days (10d) post-injection, the cerebrospinal fluid (CSF), choroid plexus (CP), and meninges and associated vasculature (MAV) were collected. The brain was then dissected to obtain the olfactory bulb, cerebral cortex, hippocampus, cerebellum, and brainstem. Proteins were extracted and separated by a size-exclusion high-performance liquid chromatography (SEC) system, and Gd concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS)., Results: 5 m post-injection, the Gadodiamide group had the highest Gd concentration, while Gadoterate had the lowest Gd concentration in all parts of the brain ( p < .05). Gd concentration was highest in the cerebrospinal fluid (CSF) of the Gadodiamide group (578.4 ± 135.3 nmol), while Gd concentration was highest in MAV in the Gadobutrol group (379.7 ± 75.4 nmol) at 5 min post-injection. At 10d, in spite of the significant decrease of Gd from all GBCAs ( p < 0.01), retained Gd from Gadodiamide was detected all over the brain in several molecules that varied in size. Gd from Gadobutrol detected in the olfactory bulb (8.7 ± 4.5 nmol) was significantly higher than in other parts of the brain. Although most Gd from Gadobutrol was found in molecules similar in size to Gadobutrol, it was also found in several protein molecules of molecular size larger than the contrast agents. Only a small amount of Gd from Gadoterate was found in the brain., Conclusion: GBCAs may be able to pass through intact brain barriers, and the chemical structures of GBCAs may affect the penetration capability of Gd into the brain. Retained Gd in the brain tissue from Gadodiamide and Gadobutrol may be bound to some organic molecules, including proteins., Advances in Knowledge: Intact GBCA are able to penetrate a series of brain barrier immediately after administration regardless the type of the chelate. Gd may be bound with macromolecules that may cause Gd retention in the brain.

Aim: This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients., Methods: We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using 99m thallium ( 99m Tl) and 123 I-β-methyl-P-iodophenyl-pentadecanoic acid ( 123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of 123 I-BMIPP from that of 99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing 99m Tl and 123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis., Results: Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases., Conclusions: Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

We investigated impacts of increased generic drug use on spontaneous adverse event reports (SAERs), because SAERs have been a major source of data for drug safety assessment at the postmarket stage. Reporting proportion of SAERs for the generic drugs was consistently and significantly lower than that for the original branded drugs. The reporting proportion targeting for 55 active product ingredients, which had the longest follow-up period after generic drug marketed, gradually decreased for the original branded drugs and increased for the generic drugs. However, these transitions did not parallel the changes in market share over the same period. These results suggest that the reporting proportion of SAERs for generic drugs may not keep pace with growth in market share. When generic drugs account for the majority of market share, utilization of multiple sources of information and data, in addition to SAERs, may be a key to assuring drug safety at the postmarket stage., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Objective: This study investigates the presence or absence of reminiscence experiences in older adults when using aromas. Focusing on 40 scents familiar to Japanese people, our objective was to determine points of caution for aroma selection and use in reminiscence therapy. Materials and Methods: The participants were 118 community-dwelling older adults aged 65 years and older. They were asked about the experience of recalling the past in response to stimuli of 40 aromas on the Japanese version of the University of Pennsylvania Smell Identification Test (UPSIT-J). In addition, an olfactory visual analog scale (VAS) was used to evaluate olfactory function. Furthermore, a questionnaire-based survey was administered instead of asking participants to actually smell the odorants in the UPSIT-J. Results: At least 70% of the participants experienced recalling the past triggered by 16 aromas including sandalwood and yuzu fruit. Furthermore, 15 of the scents demonstrated a significant association with age, gender, and olfactory function. Conclusion: These results suggest the importance of considering method, age, and gender when selecting olfactory stimuli. In addition, frequently recalled aromas might evoke reminiscence in older adults.

Background: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy., Methods: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period., Results: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days)., Conclusions: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD., (© 2019 Japan Pediatric Society.)

Objective Hydroxychloroquine (HCQ) was not approved in Japan until 2015, and its therapeutic potential has not been explored in depth. We evaluated the additional therapeutic effect of HCQ in Japanese patients with systemic lupus erythematosus (SLE) on maintenance therapy. Methods Patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/day were retrospectively evaluated. All patients were divided into three groups according to their maintenance treatment regimen: PSL + immunosuppressant, PSL alone, and no treatment. We compared the changes in the SLE disease activity index (SLEDAI), PSL dose, and cumulative flare rate between patients who were and were not treated with HCQ. Results Among the 165 patients evaluated, 35 (21.2%) were treated with HCQ. The mean period of observation did not differ markedly between patients who did and did not receive HCQ (p=0.3). The SLEDAI and PSL dose were significantly reduced in patients who received HCQ, regardless of their background treatment regimen. The cumulative flare rate was lower in patients who received HCQ than in those who did not in the PSL + immunosuppressant and no maintenance treatment groups (p=0.03 and 0.05, respectively). Conclusion The addition of HCQ reduced the disease activity and allowed PSL dose reduction, regardless of background treatment, in Japanese patients with SLE.

Administration of four once-weekly doses of 375 mg/m 2 rituximab (RTX) is commonly used as remission induction therapy for ANCA-associated vasculitis (AAV). Low-dose RTX has been recently shown to produce closely similar results to conventional treatments in other autoimmune diseases. However, the therapeutic potential of this approach in AAV remains largely unknown. Here, we analyzed the efficacy and tolerability of high- and low-dose regimens of RTX in patients with AAV. We retrospectively examined AAV patients who met the classification algorithm of Watts et al. from 2006 to 2016. Patients were divided into high- (HD) and low-dose (LD) RTX groups. HD-RTX was the original regimen while LD-RTX consisted of two once-weekly doses of 375 mg/m 2 . Cumulative complete remission (CR) rates for 1 year were compared, and serial changes in peripheral B cell counts and serious adverse events were monitored. Apart from a higher percentage of elderly patients in the LD group (p < 0.01), the 17 patients with HD-RTX and 11 patients with LD-RTX showed no significant differences in clinical characteristics, including Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), and the initial dose of glucocorticoid. On 1-year observation, cumulative CR rates did not significantly differ (p = 0.20). Further, peripheral B cell counts and incidence of serious adverse events also did not differ. Cumulative CR rate did not significantly differ between LD and HD groups. Further study is warranted to confirm these results.

Objective: Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To simultaneously detect not only primary cancer but also bone metastases, this study aimed to develop a positron emission tomography probe using generator-produced nuclide Gallium-68 (T 1/2 = 68 min), in which a carrier for primary cancer, a carrier for bone metastases lesions, and a stable gallium complex are introduced into the one molecule. Based on this strategy, the somatostatin receptor-targeted peptide, [Tyr 3 ]-octreotate (TATE), aspartic acid peptide (D n ) with high binding affinity for hydroxyapatite, and Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a stable gallium complex were selected. The novel complexes, Ga-DOTA-D n -TATE (n = 0, 2, 5, 8, or 11), were designed, synthesized, and evaluated. The radiogallium complexes were prepared using the easy-to-handle radioisotope 67 Ga due to relatively long half-life., Methods: The radiogallium complex precursor DOTA-D n -TATE was synthesized by the Fmoc-based solid-phase method and by the air oxidation method to form the disulfide bond. [ 67 Ga]Ga-DOTA-D n -TATE was synthesized by reacting DOTA-D n -TATE and 67 Ga. Hydroxyapatite binding assays, in vitro cellular uptake experiments in AR42J tumor cells, in biodistribution experiments in AR42J tumor-bearing mice, were performed using [ 67 Ga]Ga-DOTA-D n -TATE., Results: The radiochemical purities of [ 67 Ga]Ga-DOTA-D n -TATE were > 96.0%. In in vitro and in vivo experiments, [ 67 Ga]Ga-DOTA-D 11 -TATE had a high affinity for hydroxyapatite and highly accumulated in bone. However, the uptake of [ 67 Ga]Ga-DOTA-D 11 -TATE into somatostatin receptor-positive AR42J cells was lower than that of [ 67 Ga]Ga-DOTA-TATE, and the accumulation of [ 67 Ga]Ga-DOTA-D 11 -TATE in tumor was significantly low., Conclusion: Ga-DOTA-D 11 -TATE may not be recognized by somatostatin receptor by the introduction of D 11 , and the charge adjustment may be important for somatostatin receptor-positive cell uptake.

Background: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities., Methods: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174., Findings: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78)., Interpretation: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG., Funding: Japan Agency for Medical Research and Development (grant CCT-B-2503)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To assess for any additive value of hydroxychloroquine (HCQ) in Japanese patients with systemic lupus erythematosus (SLE) depending on calcineurin inhibitors (CNIs)., Methods: We retrospectively evaluated patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/d and one immunosuppressant (IS). Patients were divided into two groups depending on HCQ use and the groups were compared for changes in SLE Disease Activity Index (SLEDAI), prednisolone (PSL) dose, and cumulative flare rate between patients who were treated and not treated with CNI., Results: Among the 103 patients evaluated, 19 (18.4%) were treated with HCQ. On analysis of all patients, SLEDAI, PSL doses, and cumulative flare rate were significantly reduced in patients who received HCQ compared to those who did not (P = 0.04, P = 0.01, and P = 0.03, respectively). Regarding IS use, we found less additive therapeutic effect in CNI users than in users of other ISs in terms of reduction in SLEDAI and PSL dose (P = 0.05 and P < 0.01, respectively)., Conclusions: The addition of HCQ reduced disease activity, PSL dose, and flares in Japanese SLE patients but conferred less additive clinical efficacy when added to CNIs., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)