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Purpose This study evaluated the risk of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer who received denosumab or zoledronic acid (ZA) for treating bone metastasis. Methods The medical records of patients were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. The primary endpoint was a comparison of the risk of developing MRONJ between the denosumab and ZA groups. Propensity score matching was used to control for baseline differences between patient characteristics and compare outcomes for both groups. Results Among the 799 patients enrolled, 58 (7.3%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the ZA group (9.6% [39/406] vs. 4.8% [19/393], p = 0.009). Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.65–5.25; p p p = 0.016). Conclusion The results of this study suggest that denosumab poses a significant risk for developing MRONJ in patients treated for bone metastasis, and thus these patients require close monitoring.

Purpose Switch from zoledronic acid (ZA) to denosumab may increase the risk of medication-related osteonecrosis of the jaw (MRONJ) owing to the additive effect of denosumab on the jawbone and residual ZA activities. We evaluated the risk of developing MRONJ in patients who received ZA, denosumab, or ZA-to-denosumab for the treatment of bone metastases. Methods The medical charts of patients with cancer who received denosumab or ZA for bone metastases were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. Primary endpoint was the evaluation of the risk of developing MRONJ in the ZA-to-denosumab group. Secondary endpoints were probability of MRONJ and the relationship between risk factors and the time to the development of MRONJ. Results Among the 795 patients included in this study, 65 (8.2%) developed MRONJ. The incidence of MRONJ was significantly higher in the ZA-to-denosumab group than in the ZA group [7/43 (16.3%) vs. 19/350 (5.4%), p = 0.007]. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment [hazard ratio (HR), 2.41; 95% confidence interval (CI), 1.37–4.39; p = 0.002], ZA-to-denosumab treatment (HR, 4.36; 95% CI, 1.63–10.54, p = 0.005), tooth extraction after starting ZA or denosumab (HR, 4.86; 95% CI, 2.75–8.36; p p = 0.030) were significant risk factors for MRONJ. Conclusion Our results suggest that switching from ZA to denosumab significantly increases the risk for developing MRONJ in patients with bone metastases.

Background and Aims Serum phosphorus is an important factor associated with mortality and cardiovascular disease in dialysis patients as well as in non-dialysis patients with chronic kidney disease (CKD) and healthy individuals. One observational study reported that elevated phosphorus is a risk factor for end-stage renal disease and is linked to reduced renal function, even within the normal range. Although the mechanism is unknown, an excessive load of phosphorus to the kidney is presumed to cause renal damage via phosphorus-containing nanoparticles. In this study, we examined the association between phosphorus excretion per nephron and the prognosis of CKD. Method A single-center, retrospective cohort study was conducted in 276 patients with CKD category G3 to G5 who were admitted to our hospital and received an inpatient educational program on CKD between June 2016 and November 2019 and who could be followed up for at least 1 year or started on dialysis within 1 year after hospitalization. Phosphorus excretion per nephron was defined as daily phosphorus excretion divided by creatinine clearance (Ccr), and its association with the annual rate of decline in estimated glomerular filtration rate (eGFR) was investigated for each CKD category. For statistical analysis, multiple regression analysis was performed using the following covariates: age, sex, presence/absence of diabetes mellitus, mean arterial blood pressure, amount of daily urine protein, serum phosphorus level, and use of a renin-angiotensin system inhibitor. Results There were 108 patients with CKD G3, 106 patients with CKD G4, and 62 patients with CKD G5. Daily phosphorus excretion was 442 mg in G3, 350 mg in G4, and 350 mg in G5 patients. Phosphorus excretion per nephron was 8.4 mg/Ccr in G3, 14.0 mg/Ccr in G4, and 24.2 mg/Ccr in G5 patients. It increased with the progression of renal damage. In G4 patients, phosphorus excretion per nephron was significantly negatively correlated with the rate of decline in eGFR (p = 0.004); however, no correlation was found between the two in G3 and G5 patients (p = 0.09 and p = 0.16, respectively). Multiple regression analysis showed that phosphorus excretion per nephron was not a significant worsening factor for renal function in G3, G4, and G5 patients (p = 0.09, p = 0.36, and p = 0.41, respectively). On the other hand, serum phosphorus level was a significant worsening factor for renal function in G3 and G5 patients (p = 0.03 and p = 0.01, respectively). Conclusion No association was found between phosphorus excretion per nephron and the rate of the subsequent decline in renal function.

Background and Aims Serum magnesium levels are an important factor associated with vital prognosis, cardiovascular disease, and vascular calcification in hemodialysis patients. Moreover, low serum magnesium levels are reportedly associated with an increased risk of hip fractures. Previously we reported that mean magnesium level during the first 3 years of hemodialysis was associated with all-cause mortality in ERA-EDTA 2018. Here, we investigated whether mean magnesium level during the first 3 years of hemodialysis can predict fracture risk. Method A retrospective cohort study was conducted in 283 patients who started hemodialysis at our hospital between March 2004 and the present and who could be followed for at least 3 years or had a fracture within 3 years. To assess the association between mean serum magnesium level during 3 years after the start of hemodialysis or until fracture and fracture risk, a multivariate analysis was performed using the Cox proportional hazard model with factors related to fractures as covariates, with all fractures such as hip fracture and spinal compression fracture as the outcome. Results The mean follow-up period was 6.1 years, and the mean age of patients was 64 years, with women accounting for 31%. Of all 283 patients, 62 developed fractures. A univariate analysis of factors associated with fractures revealed that high serum magnesium level was a significant fracture suppressor (hazard ratio [HR]: 0.31 [0.12–0.73]). Multivariate analysis conducted with significant factors in univariate analysis (mean serum albumin level, serum phosphorus level, hemoglobin level, C-reactive protein level, age, history of heart disease, history of bone fractures, and use or nonuse of phosphate binder during the 3 years) as the covariates revealed that the serum magnesium level was not significantly associated with bone fractures (HR: 0.95 [0.33–2.78]), whereas, old age, history of fractures, low albumin level, high CRP level, and nonuse of phosphate binder were significantly associated with fractures. Conclusion Serum magnesium levels during 3 years after the initiation of hemodialysis did not predict the risk of subsequent fractures, whereas a high level of inflammatory response, malnutrition, and nonuse of phosphate binder did.

Background and Aims In the treatment of idiopathic focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome, the remission of proteinuria is considered to be an important goal. The partial remission of proteinuria improves renal survival, whereas it may progressively reduce the renal function. A study searched for a novel partial remission more accurately reflecting the long-term renal outcome. The goal of proteinuria reduction for improving the renal prognosis remains to be clarified. We examined factors associated with the long-term renal outcome of idiopathic FSGS. Method Of 148 patients with FSGS diagnosed based on kidney biopsy between 1981 and 2018, a retrospective cohort study was conducted involving 33 who had undergone immunosuppressive therapy for nephrotic syndrome, and had been followed-up for ≥1 year, excluding those with secondary FSGS. We examined the renal prognosis, regarding a 50% decrease in the estimated glomerular filtration rate (eGFR) as an outcome. We calculated the rate of decrease in the urinary protein level 4 and 8 months after the start of treatment, and estimated the rate of decrease associated with renal hypofunction using ROC analysis. Based on the results of ROC analysis, Cox’s proportional hazard analysis was performed using factors contributing to renal hypofunction as covariates. Results Concerning the background of the 33 patients, the mean follow-up period was 11.4 years, and there were 24 males. The mean age was 49.8 years, and the mean blood pressure was 100.5 mmHg. The mean urinary protein level, albumin (Alb) level, eGFR, and total cholesterol (TCho) level were 7.4 g/day, 2.1 g/dL, 44.3 mL/min/1.73 m2, and 369 mg/dL, respectively. Corticosteroid therapy was selected in 21 patients, whereas it was combined with steroid pulse therapy in 12. The daily dose of prednisolone was 37.3 mg. On ROC analysis, the rate of decrease in the urinary protein level after 4 months was 83.1% (AUC: 0.74, sensitivity: 0.80, specificity: 0.74), and that after 8 months was 85.7% (AUC: 0.78, sensitivity: 0.90, specificity: 0.65). Cox’s proportional hazard analysis, in which the data were adjusted with the sex, blood pressure, urinary protein level at the start of treatment, Alb level, eGFR, and treatment methods, showed that the rate of decrease in the urinary protein level after 4 months was significantly correlated with renal hypofunction: after 4 months: hazard ratio, 0.19 (95%CI: 0.04-0.77); p=0.0202; after 8 months: hazard ratio, 0.34 (95%CI: 0.05-1.37); p=0.1359. Conclusion In the treatment of idiopathic FSGS with nephrotic syndrome, the rate of decrease in the urinary protein level 4 months after the start of treatment was correlated with the long-term renal outcome.

Demands for large-scale lithium-ion batteries for electric vehicles and grids have increased in order to reduce CO2 emissions in consideration of the global environment. To improve the reliability for practical large-scale batteries, further improvements in safety, rate capability, and cycle life are required. One of the unique behaviors taking place in lithium-ion battery composite electrodes is an inhomogeneous reaction of active materials.1 Since the heterogeneous reaction behavior induces overcharge and degradation of local active materials, the homogeneous charge-discharge reaction should be required. Ouvrard et al. reported that an inhomogeneous electrode reaction was caused during the charge-discharge process in LiFePO4 lithium-ion battery cathode, which was detected by using X-ray absorption spectroscopy.2 The study concluded that the ionic and electronic connectivity influenced by applied pressure is a crucial parameter for reaction distribution in composite electrodes. In this study, we examine the commercially utilized composite electrodes where enough electronic conduction path is formed. We compare the electrochemical characteristics using the commercial electrodes with self-made composite electrodes prepared in the laboratory and then measured the reaction distribution by imaging XAS. Two types of composite electrodes using LiFePO4 as the active material were used, and their thickness and mass loading were almost similar. Two electrode cells were assembled using 1 M LiFP6 in a solvent mixture of ethylene carbonate (EC) and ethyl metal carbonate (EMC) at a volume ratio of 3:7, and lithium counter electrode. Charge-discharge measurements were performed with an upper limit voltage of 3.6 V and a lower limit voltage of 2.0 V at rates of 0.1, 0.2, 0.5, 1.0, 2.0, 5.0, 10, 20, 30, 40 and 50 C. Imaging XAS measurements were performed at beamline BL-4 in Ritsumeikan University SR Center. Fe K-edge XAS was measured in a transmission mode using a two-dimensional detector. As a result of the discharge rate capability test, the capacity retention of 5 C was 92% for the commercial electrode and 5.4% for the self-made electrode, compared with the discharge capacity at 0.1 C, and the self-made electrode showed a remarkable decrease in capacity at high rates. The imaging XAS of the commercial electrodes implies a lack of inhomogeneous reaction after discharging at 5C. The previous reports have shown that the reaction in the planar direction of LiFePO4 proceeds from island-shaped points.3 We assume that the commercial composite electrodes are developed to be improved ionic and electronic connectivity. Reference: J. Liu, M. Kunz, K. Chen, N. Tamura, J. Richardson, J. Phys. Chem. Lett., 1, 2120-2123 (2010). G. Ouvrard, M. Zerrouki, P. Soudan, B. Lestrez, C. Masquelier, M. Morcrette, S. Hamelet, S. Belin, A. M. Flank, F. Baudelet, J. Power Sources, 229, 16-21 (2013). M. Katayama, K. Sumiwaka, R. Miyahara, H. Yamashige, H. Arai, Y. Uchimoto, T. Ohta, Y. Inada, Z. Ogumi, J. Power Sources, 269, 994-999 (2014).

Background Palbociclb is an orally available selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that is indicated for patients with hormone receptor-positive HER2-negative advanced or recurrent breast cancer with 3 weeks on/1 week off schedule. Previous report showed that elevated serum creatinine (Scr) was only 2.0% in frequency for all grade, without cases of grade 3 or more. Anecdotal episode of declined eGFR (implying elevated Scr) seems to be more frequent in daily clinical practice; however, the actual frequency of declined eGFR and its impact on severe toxicity has not been determined yet. Objective To investigate the frequency of declined eGFR in patients treated with palbociclib and to determine the association between declined eGFR and severe toxicity. Methods Consecutive patients treated with palbociclib at National Cancer Center Hospital East between December 1 2017 and May 31 2018 were retrospectively investigated. Patient characteristics, eGFR at cycle 1 day1 (C1D1) and C1D15, C2D1, C2D15, and C3D1 of palbociclib, grade 4 neutropenia, treatment discontinuation or interruption caused by toxicity were retrieved from medical records. The frequency of declined eGFR and its correlation with severe toxicity were analyzed. Results A total of 42 patients were included. Median age was 65 years (range 43-80), and 41 cases were female. Median eGFR at the start of palbociclib was 76 mL/min/1.73m2, which declined 12.5 in median (range 3.0-39.0) on C1D15. At C2D1, eGFR was recovered (change in median -3 mL/min/1.73m2; range -17.0 - +19.0). Declined eGFR was not correlated significantly with either grade 4 neutropenia or treatment discontinuation. Conclusions While eGFR was declined by median of 12.5 mL/min/1.73m2 with palbociclib administration on C1D15, eGFR recovered to the baseline by drug interruption. Declined eGFR was not correlated with severe toxicity such as grade 4 neutropenia or toxicities leading to treatment discontinuation.

Revolver discovered in the Triticeae plant is a novel class of transposon-like gene and a major component of the large cereal genome. An 89 bp segment of Revolver that is enriched in the genome of rye was isolated by deleting the DNA sequences common to rye and wheat. The entire structure of Revolver was determined by using rye genomic clones, which were screened by the 89 bp probe. Revolver consists of 2929-3041 bp with an inverted repeated sequence on each end and is dispersed through all seven chromosomes of the rye genome. Revolver is transcriptionally active, and the isolated full-length cDNA (726 bp) reveals that Revolver harbors a single gene consisting of three exons (342, 88, and 296 bp) and two introns (750 and 1237 bp), and encodes 139 amino acid residues of protein, which shows similarity to some transcriptional regulators. Revolver variants ranging from 2665 to 4269 bp, in which 5' regions were destructed, indicate structural diversities around the first exon. Revolver does not share identity with any known class I or class II autonomous transposable elements of any living species. DNA blot analysis of Triticeae plants shows that Revolver has existed since the diploid progenitor of wheat, and has been amplified or lost in several species during the evolution of the Triticeae.