Giant cell tumor of bone (GCTB) is a rare primary bone tumor, characterized by osteoclast-like giant cells that express receptor activator of nuclear factor-kappa B (RANK), and stromal cells that ...express RANK ligand (RANKL), a key mediator of osteoclast activation. A RANKL-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with GCTB.
Seventeen patients with GCTB were enrolled. Patients were treated with denosumab at 120 mg every 4 weeks, with a loading dose of 120 mg on days 8 and 15. To evaluate efficacy, objective tumor response was evaluated prospectively by an independent imaging facility on the basis of prespecified criteria.
The proportion of patients with an objective tumor response was 88% based on best response using any tumor response criteria. The proportion of patients with an objective tumor response using individual response criteria was 35% based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 82% based on the modified European Organization for Research and Treatment of Cancer (EORTC) criteria, and 71% based on inverse Choi criteria. The median time of study treatment was 13.1 months.
The findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.
Aims
To test the hypothesis that 1‐h plasma glucose in an oral glucose tolerance test is a better predictor of the development of diabetes than 2‐h plasma glucose, independently of indices of insulin ...secretion or action in Japanese adults.
Methods
A historical cohort study was conducted in 1445 Japanese workers who did not have diabetes. The association between 1‐h plasma glucose and the development of Type 2 diabetes was analysed.
Results
Overall, 95 of the study participants developed Type 2 diabetes during a mean follow‐up of 4.5 years. The area under the receiver‐operating characteristic curve for 1‐h plasma glucose for future diabetes 0.88 (95% CI 0.84–0.91) was greater than that for 2‐h plasma glucose 0.79 (95% CI 0.74–0.84), and for insulinogenic 0.73 (95% CI 0.68–0.78) and disposition indices 0.79 (95% CI 0.74–0.84); P < 0.05. Compared with the first quartile, the hazard ratio for future diabetes in the fourth quartile of 1‐h plasma glucose was 42.5 95% CI 5.7–315.2 (P < 0.05) and the hazard ratio in the fourth quartile of 2‐h plasma glucose was 4.4 95% CI 1.8–10.8 (P < 0.05), after adjustments for covariates including fasting plasma glucose. The significance of the elevated hazard ratio in the fourth quartile of 1‐h plasma glucose was maintained after adjustments for 2‐h plasma glucose, insulinogenic index or disposition index, whereas the elevation of the hazard ratio in the fourth quartile of 2‐h plasma glucose was diminished and was no longer significant after adjustments for 1‐h plasma glucose.
Conclusions
One‐hour plasma glucose had a greater association with the future development of Type 2 diabetes than did 2‐h plasma glucose, independently of oral glucose tolerance test‐derived indices of insulin action in a Japanese population.
What's new?
The study confirmed the superior predictive ability of 1‐h plasma glucose to that of 2‐h plasma glucose with regard to the development of diabetes and that this finding can be generalized to an Asian population.
The association between 1‐h plasma glucose and the future development of diabetes was independent of indices of insulin secretion or action as assessed by insulinogenic index or disposition index.
The results of receiver‐operating characteristic curve analysis showed that the predictive ability of indices of insulin secretion or action were not superior to that of sampling plasma glucose at 1 h.
The tri-smectite(S)–corrensite(Co)–chlorite(C) series minerals from two epithermal deposits show a discontinuous stepwise sequence of different mixed-layering of chlorite and smectite layers, and ...there are differences in the mode of occurrence of the two deposits. The Al/Si ratios and Fe/(Fe + Mg) ratios of the S–Co–C minerals vary closely related to mixed-layering and mode of occurrence. The S–Co–C minerals as a product of direct precipitation from ascending hydrothermal solutions may reflect fluid chemistry that originated in water–rock interaction at deeper strata. The differences in mixed-layering of the S–Co–C series minerals may be related to different thermal and redox conditions affected by fluid mixing and boiling, and to kinetic factor such as time length of hydrothermal activity that affected vein formation. The corrensite and Co–C minerals as a product of hydrothermal alteration involving dissolution, re-precipitation, and crystallization, may undergo smectite-to-chlorite transformation in epithermal systems. The transformation and distribution of corrensite and Co–C minerals in the host rocks around vein areas may have been controlled by thermal conditions related to fluid mixing and water/rock ratios. In addition, the corrensite and Co–C minerals with high Fe/(Fe + Mg) ratios may be affected by the host rock. The factors influencing the conversion of the S–Co–C series minerals may be similar in both ore veins and host rocks. However, it is emphasized that fluid/rock ratios may be a major factor influencing the conversion of the S–Co–S series minerals in host rocks. Additionally, the time length of hydrothermal activity that affected vein formation may be an important factor influencing the conversion of the S–Co–C series minerals in ore veins.
Quantitative susceptibility mapping is useful for assessing iron deposition in the substantia nigra of patients with Parkinson disease. We aimed to determine whether quantitative susceptibility ...mapping is useful for assessing the lateral asymmetry and spatial difference in iron deposits in the substantia nigra of patients with Parkinson disease.
Our study population comprised 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls. They underwent 3T MR imaging by using a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility mapping, we measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both hemibrains. To identify the more and less affected hemibrains in patients with Parkinson disease, we assessed the severity of movement symptoms for each hemibrain by using the Unified Parkinson's Disease Rating Scale.
In the posterior substantia nigra of patients with Parkinson disease, the mean susceptibility value was significantly higher in the more than the less affected hemibrain substantia nigra (P < .05). This value was significantly higher in both the more and less affected hemibrains of patients with Parkinson disease than in controls (P < .05). Asymmetry of the mean susceptibility values was significantly greater for patients than controls (P < .05). Receiver operating characteristic analysis showed that quantitative susceptibility mapping of the posterior substantia nigra in the more affected hemibrain provided the highest power for discriminating patients with Parkinson disease from the controls.
Quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease.
Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.
To examine the results of genetic testing for ...early-onset AF.
This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.
Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.
Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.
Among 1293 participants (934 72.2% male; median interquartile range age at enrollment, 56 48-61 years; median interquartile range age at AF diagnosis, 50 41-56 years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 16.8%; 95% CI, 10.0%-23.6%) and lowest after the age of 60 years (8 of 112 7.1%; 95% CI, 2.4%-11.9%). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).
In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone ...disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
Although the clinical importance of cortical microinfarcts has become well-recognized recently, the evolution of cortical microinfarcts on MR imaging is not fully understood. The aim of this study ...was to examine the temporal changes in acute cortical microinfarcts using susceptibility-weighted imaging and conventional MR imaging.
Patients with acute infarcts located in the cortical and/or juxtacortical region measuring ≤10 mm in axial diameter based on diffusion-weighted imaging who had a follow-up 3T MR imaging were retrospectively included in the study. All lesions did not show hypointensity on initial T2*WI. For cortical and/or juxtacortical microinfarcts detected on initial DWI, 2 neuroradiologists evaluated the follow-up MR imaging (T2WI, FLAIR, T2*WI, and SWI) and assessed lesion signal intensities and locations (cortical microinfarcts or microinfarcts with juxtacortical white matter involvement).
On initial DWI, 2 radiologists observed 180 cortical and/or juxtacortical microinfarcts in 35 MR imaging examinations in 25 patients; on follow-up, the neuroradiologists identified 29 cortical microinfarcts (16%) on T2WI, 9 (5%) on FLAIR, 4 (2%) on T2*, and 97 (54%) on SWI. All cortical microinfarcts detected with any follow-up MR imaging showed hyperintensity on T2WI/FLAIR and/or hypointensity on T2*WI and SWI.
SWI revealed conversion (paramagnetic susceptibility changes) of acute cortical microinfarcts, suggesting that a substantial number of cortical microinfarcts may contain hemorrhagic components.
Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage ...colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.
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