Prediction of High-Risk Neuroblastoma Among Neuroblastic Tumors Using Radiomics Features Derived from Magnetic Resonance Imaging: A Pilot Study.

PURPOSE: This study aimed to predict high-risk neuroblastoma among neuroblastic tumors using radiomics features extracted from MRI. MATERIALS AND METHODS: Pediatric patients (age≤18 years) diagnosed with neuroblastic tumors who had pre-treatment MR images available were enrolled from institution A from January 2010 to November 2019 (training set) and institution B from January 2016 to January 2022 (test set). Segmentation was performed with regions of interest manually drawn along tumor margins on the slice with the widest tumor area by two radiologists. First-order and texture features were extracted and intraclass correlation coefficients (ICCs) were calculated. Multivariate logistic regression (MLR) and random forest (RF) models from 10-fold cross-validation were built using these features. The trained MLR and RF models were tested in an external test set. RESULTS: Thirty-two patients (M:F=23:9, 26.0±26.7 months) were in the training set and 14 patients (M:F=10:4, 33.4±20.4 months) were in the test set with radiomics features (n=930) being extracted. For 10 of the most relevant features selected, intra- and inter-observer variability was moderate to excellent (ICCs 0.633-0.911, 0.695-0.985, respectively). The area under the receiver operating characteristic curve (AUC) was 0.94 (sensitivity 67%, specificity 91%, and accuracy 84%) for the MLR model and the average AUC was 0.83 (sensitivity 44%, specificity 87%, and accuracy 75%) for the RF model from 10-fold cross-validation. In the test set, AUCs of the MLR and RF models were 0.94 and 0.91, respectively. CONCLUSION: An MRI-based radiomics model can help predict high-risk neuroblastoma among neuroblastic tumors.

Comparison of elasticity changes in the paraspinal muscles of adolescent patients with scoliosis treated with surgery and bracing.

Scoliosis is a three-dimensional spinal deformity, and paraspinal muscles play an important role as stabilizers of the spinal curve. In this prospective study, we compared elasticity changes in the paraspinal muscles of adolescent patients with scoliosis after surgery or bracing. Elasticity was measured on the concave and convex sides of the paraspinal muscles at the apex of the curve at the beginning of treatment and 6 and 12 months after treatment. Twenty-six patients with correction surgery (n = 15) or bracing (n = 11) were included. At initial evaluation, the Cobb angle was larger in the surgery group (72.3 ± 20.2° in surgery vs. 30.6 ± 5.1° in brace, p < 0.001). The estimated mean elasticity value of the paraspinal muscles was lower in the surgery group at baseline on the convex side (15.8 vs. 22.8 kPa, p = 0.037) and 6 months on both the concave (12.1 vs. 22.7 kPa, p = 0.004) and convex (13.4 vs. 23.8 kPa, p = 0.005) sides. There was a significant stiffness decrease from baseline to 6 months on the concave side in the surgery group (5.9 kPa, p = 0.025). However, the elasticity change recovered at 12 months without significant differences between the two groups.

Contrast-Enhanced Ultrasonography for the Evaluation of Crohn's Disease in Pediatric Patients.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) of the bowel wall has been suggested as an alternative imaging modality for the follow-up of children with Crohn's disease. To demonstrate the feasibility and clinical usefulness of CEUS in the estimation of Crohn's disease activity in children with endoscopy as the reference standard. METHOD: In this prospective study, 30 pediatric patients with Crohn's disease (24 males and 6 females; median age 14 years) underwent CEUS from December 2020 to August 2021. The simple endoscopic score for Crohn's disease, pediatric Crohn's disease activity index, serologic inflammatory markers, fecal calprotectin and CEUS perfusion parameters were assessed and compared between the inactive and active group based on endoscopic findings. RESULTS: CEUS was performed successfully in all 30 patients. Two patients showed mild adverse side effects such as temporary dysosmia. The active Crohn's disease group showed higher erythrocyte sedimentation rate (mm/hr) (13.0 vs. 2.0, P = 0.003), C-reactive protein (mg/dL) (4.7 vs. 0.55, P = 0.018) and fecal calprotectin (mcg/g) (1,503 vs. 237.5, P = 0.005). Among the quantitative parameters for CEUS, the mean gradient to the peak value was higher in the active group (1.18 vs. 0.93, P = 0.034). The sensitivity and specificity of the mean gradient to the peak value for predicting active Crohn's disease was 55.6% and 83.3%, respectively, with a cut-off of 1.09 (P = 0.015). CONCLUSION: CEUS can be a safe and specific diagnostic modality for Crohn's disease activity in children. Among quantitative CEUS parameters, the mean gradient to the peak value could be used to differentiate active and inactive Crohn's disease.

Decrease of Muscle Mass in Young Patients With Neuromuscular Disease: Assessment of Sarcopenia.

BACKGROUND: Sarcopenia can be associated with the disease etiologies other than degenerative processes, such as neurologic disease including cerebral palsy, myelomeningocele, or Duchenne muscular dystrophy, even in children. Although the relationship between neurologic disease and scoliosis or ambulatory function is known, the mediators affecting scoliosis or gait function in these patients are unclear, an example might be sarcopenia. This study aimed to assess the degree of sarcopenia in young patients with neurologic diseases using computed tomography (CT), and analyze the correlation between sarcopenia and scoliosis or ambulatory function. METHODS: Pediatric and young adult patients (≤ 25 years old) who underwent whole-spine or lower-extremity CT were retrospectively included. From bilateral psoas muscle areas (PMAs) at the L3 level, the psoas muscle z-score (PMz) and psoas muscle index [PMI = PMA/(L3 height)²] were calculated. The t-test, Fisher's exact test, and logistic regression analyses were performed. RESULTS: A total of 121 patients (56 men, mean age 12.2 ± 3.7 years) were included with 79 neurologic and 42 non-neurologic diseases. Patients with neurologic diseases had lower PMz (P = 0.013) and PMI (P = 0.026) than patients without. In neurologic disease patients, severe scoliosis patients showed lower PMz (P < 0.001) and PMI (P = 0.001). Non-ambulatory patients (n = 42) showed lower BMI (ß = 0.727, P < 0.001) and PMz (ß = 0.547, P = 0.025). In non-ambulatory patients, patients with severe scoliosis also showed lower PMz (P < 0.001) and PMI (P = 0.004). CONCLUSION: Patients with neurologic diseases could have sarcopenia even in young age. Psoas muscle volume was also associated with ambulatory function in these patients. Sarcopenia was more severe in severe scoliosis patients in the non-ambulatory subgroup.

Pre- and Immediate Post-Kasai Portoenterostomy Shear Wave Elastography for Predicting Hepatic Fibrosis and Native Liver Outcomes in Patients With Biliary Atresia.

OBJECTIVE: To evaluate the feasibility of ultrasound shear wave elastography (SWE) for predicting hepatic fibrosis and native liver outcomes in patients with biliary atresia. MATERIALS AND METHODS: This prospective study included 33 consecutive patients with biliary atresia (median age, 8 weeks [interquartile range, 6-10 weeks]; male:female ratio, 15:18) from Severance Children's Hospital between May 2019 and February 2022. Preoperative (within 1 week from surgery) and immediate postoperative (on postoperative days [PODs] 3, 5, and 7) ultrasonographic findings were obtained and analyzed, including the SWE of the liver and spleen. Hepatic fibrosis, according to the METAVIR score at the time of Kasai portoenterostomy and native liver outcomes during postsurgical follow-up, were compared and correlated with imaging and laboratory findings. Poor outcomes were defined as intractable cholangitis or liver transplantation. The diagnostic performance of SWE in predicting METAVIR F3-F4 and poor hepatic outcomes was analyzed using receiver operating characteristic (ROC) analyses. RESULTS: All patients were analyzed without exclusion. Perioperative advanced hepatic fibrosis (F3-F4) was associated with older age and higher preoperative direct bilirubin and SWE values in the liver and spleen. Preoperative liver SWE showed a ROC area of 0.806 and 63.6% (7/11) sensitivity and 86.4% (19/22) specificity at a cutoff of 17.5 kPa for diagnosing F3-F4. The poor outcome group included five patients with intractable cholangitis and three undergoing liver transplantation who showed high postoperative liver SWE values. Liver SWE on PODs 3-7 showed ROC areas of 0.783-0.891 for predicting poor outcomes, and a cutoff value of 10.3 kPa for SWE on POD 3 had 100% (8/8) sensitivity and 73.9% (17/23) specificity. CONCLUSION: Preoperative liver SWE can predict advanced hepatic fibrosis, and immediate postoperative liver SWE can predict poor native liver outcomes in patients with biliary atresia.

A preoperative scoring system to predict lymph node metastasis in intrahepatic cholangiocarcinoma.

BACKGROUND: The abnormality of imaging finding of lymph node (LN) has demonstrated unsatisfactory diagnostic accuracy for pathologic lymph node metastasis (LNM). We aimed to develop and validate a simple scoring system predicting LNM in patients with intrahepatic cholangiocarcinoma (iCCA) prior to surgery based on MRI and clinical findings. METHODS: We retrospectively enrolled consecutive patients who underwent surgical resection for treatment-naïve iCCA from six institutions between January 2009 and December 2015. Patients who underwent lymph node dissection (LND) were randomly assigned to the training and validation cohorts at a 2:1 ratio, an¹ìd pathologic LN status was evaluated. Patients who did not undergo LND were assigned to the test cohort, and clinical LN status was evaluated. Using MRI and clinical findings, a preoperative LNM score was developed in the training cohort and validated in the validation and test cohorts. RESULTS: The training, validation, and test cohorts included 102, 53, and 118 patients, respectively. The preoperative LNM score consisted of serum carcinoembryonic antigen and two MRI findings (suspicious LN and bile duct invasion). The preoperative LNM score was associated with pathologic LNM in training (p < 0.001) and validation (p = 0.010) cohorts and clinical LNM in test cohort (p < 0.001). The preoperative LNM score outperformed MRI-suspicious LN alone in predicting pathologic LNM (area under the curve, 0.703 vs. 0.604, p = 0.004). The preoperative LNM score was also associated with overall survival in all cohorts (p < 0.001). CONCLUSIONS: Our preoperative LNM score was significantly associated with pathologic or clinical LNM and outperformed MRI-suspicious LN alone.

Correction: Kim et al. The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins. Toxins 2022, 14, 779.

In the original publication [...].

The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins.

The accumulation of protein-bound uremic toxins (PBUT) is associated with increased cardiovascular outcomes in patients on dialysis. However, the efficacy of PBUT removal for a medium-cutoff (MCO) membrane has not been clarified. This study was designed to assess the efficacy of PBUT clearance according to dialysis modalities. In this prospective and cross-over study, we enrolled 22 patients who received maintenance hemodiafiltration (HDF) thrice weekly from three dialysis centers. The dialysis removal of uremic toxins, including urea, beta 2-microglobulin (B2MG), lambda free light chain (λ-FLC), indoxyl sulfate (IS), and p-cresyl sulfate (pCS), was measured in the 22 patients on high-flux HD (HF-HD), post-dilution online HDF (post-OL-HDF), and MCO-HD over 3 weeks. The average convection volume in post-OL-HDF was 21.4 ± 1.8 L per session. The reduction rate (RR) of B2MG was higher in post-OL-HDF than in MCO-HD and HF-HD. The RR of λ-FLC was the highest in MCO-HD, followed by post-OL-HDF and HF-HD. The dialysate albumin was highest in MCO-HD, followed by post-OL-HDF and HF-HD. Post-dialysis plasma levels of IS and pCS were not statistically different across dialysis modalities. The total solute removal and dialytic clearance of IS and pCS were not significantly different. The clearance of IS and pCS did not differ between the HF-HD, post-OL-HDF, and MCO-HD groups.

[Diagnostic Imaging of Biliary Atresia]. / 담도폐쇄증의 영상 진단.

Biliary atresia is a rare but significant cause of neonatal cholestasis. An early and accurate diagnosis is important for proper management and prognosis. To diagnose biliary atresia, various imaging studies using ultrasonography, MRI, hepatobiliary scans, and cholangiography can be performed, although ultrasonography is more important for initial imaging studies. In this article, we review the findings of biliary atresia from various imaging modalities, including ultrasonography, MRI, hepatobiliary scans, and cholangiography. The known key imaging features include abnormal gallbladder size and shape, periportal thickening visible as a 'triangular cord' sign, invisible common bile duct, increased hepatic arterial flow, and combined anomalies. Aside from the imaging findings of biliary atresia, we also reviewed the diagnostic difficulty in the early neonatal period and the role of imaging in predicting hepatic fibrosis. We hope that this review will aid in the diagnosis of biliary atresia.

T2 Relaxation Time Changes in the Distal Femoral Condylar Cartilage of Children and Young Adults with Discoid Meniscus.

OBJECTIVE: To investigate compositional changes in the distal femoral condylar cartilage (FCC) of children and young adults with and without discoid meniscus by T2 relaxation time mapping. DESIGN: We retrospectively reviewed knee magnetic resonance images including sagittal T2 maps of distal FCC performed in patients with or without discoid meniscus. Combined meniscal pathology such as degeneration or tears was also reviewed. Regions of interest were selected, and T2 relaxation time profiles were generated according to medial and lateral and FCC and according to weight-bearing and non-weight-bearing FCC. Nonparametric comparison tests using median values were performed. RESULTS: Seventy-nine knees from 73 patients (2-20 years) including 45 knees with lateral discoid meniscus (discoid group) were studied. T2 values of FCC showed negative correlation with age in both the discoid and nondiscoid groups (P < 0.01), except for medial weight-bearing FCC. In the discoid group, T2 relaxation times of lateral weight-bearing FCC (median, 46.5 ms) were lower than those of lateral non-weight-bearing (median, 53.2 ms; P < 0.001) and medial weight-bearing (median, 50.5 ms; P = 0.012) FCC. Lateral weight-bearing FCC also showed lower T2 values than other areas in patients with meniscal pathology in the discoid group. However, T2 relaxation times did not differ between the discoid and nondiscoid groups in patients without meniscal pathology. CONCLUSIONS: Children and young adults with discoid meniscus have lower T2 relaxation times in lateral weight-bearing FCC compared with non-weight-bearing or medial FCC, suggesting compositional changes have occurred in these patients.

Attenuation Coefficient Measurement Using a High-Frequency (2-9 MHz) Convex Transducer for Children Including Fatty Liver.

We evaluated the measurement feasibility and diagnostic ability of an ultrasound-guided attenuation parameter (UGAP) using a high-frequency convex transducer in children. This retrospective study included all consecutive children who underwent abdomen ultrasonography from July to December 2020. Attenuation coefficients (ACs) of the liver were measured using both 1- to 6-MHz (AC1-6) and 2- to 9-MHz (AC2-9) probes of the LOGIQ E10 system (GE Healthcare). t-Tests and Pearson's or partial correlation analyses were performed, and AC cutoff values for diagnosing fatty liver were obtained from receiver operating characteristic curve analyses. Finally, 118 patients (M:F = 83:35, mean age: 10.2 ± 4.1 y) were evaluated, and the measurement success rate was 98.3% (116/118) for AC2-9. AC1-6 was available in children with a liver depth greater than 9 cm. The ratio of interquartile range to median of the AC2-9 was lower than that of the AC1-6 (4.3 vs. 8.5, p < 0.001). In the normal group (n = 41), the AC2-9 values were not associated with age, sex or body mass index. For the evaluation of steatosis, the AC2-9 values exhibited a positive correlation with the MR fat fraction (coefficient = 0.498, p < 0.001). The cutoff value of 0.699 dB/cm/MHz had 90.2% sensitivity and 100% specificity for diagnosing fatty liver. In conclusion, measurements of ACs using a high-frequency convex transducer are feasible even in small children, with lower measurement variability. The AC2-9 values also had good diagnostic performance for pediatric fatty liver.

Image quality assessment of pediatric chest and abdomen CT by deep learning reconstruction.

BACKGROUND: Efforts to reduce the radiation dose have continued steadily, with new reconstruction techniques. Recently, image denoising algorithms using artificial neural networks, termed deep learning reconstruction (DLR), have been applied to CT image reconstruction to overcome the drawbacks of iterative reconstruction (IR). The purpose of our study was to compare the objective and subjective image quality of DLR and IR on pediatric abdomen and chest CT images. METHODS: This retrospective study included pediatric body CT images from February 2020 to October 2020, performed on 51 patients (34 boys and 17 girls; age 1-18 years). Non-contrast chest CT (n = 16), contrast-enhanced chest CT (n = 12), and contrast-enhanced abdomen CT (n = 23) images were included. Standard 50% adaptive statistical iterative reconstruction V (ASIR-V) images were compared to images with 100% ASIR-V and DLR at medium and high strengths. Attenuation, noise, contrast to noise ratio (CNR), and signal to noise (SNR) measurements were performed. Overall image quality, artifacts, and noise were subjectively assessed by two radiologists using a four-point scale (superior, average, suboptimal, and unacceptable). A phantom scan was performed including the dose range of the clinical images used in our study, and the noise power spectrum (NPS) was calculated. Quantitative and qualitative parameters were compared using repeated-measures analysis of variance (ANOVA) with Bonferroni correction and Wilcoxon signed-rank tests. RESULTS: DLR had better CNR and SNR than 50% ASIR-V in both pediatric chest and abdomen CT images. When compared with 50% ASIR-V, high strength DLR was associated with noise reduction in non-contrast chest CT (33.0%), contrast-enhanced chest CT (39.6%), and contrast-enhanced abdomen CT (38.7%) with increases in CNR at 149.1%, 105.8%, and 53.1% respectively. The subjective assessment of overall image quality and the noise was also better on DLR images (p < 0.001). However, there was no significant difference in artifacts between reconstruction methods. From NPS analysis, DLR methods showed a pattern of reducing the magnitude of noise while maintaining the texture. CONCLUSION: Compared with 50% ASIR-V, DLR improved pediatric body CT images with significant noise reduction. However, artifacts were not improved by DLR, regardless of strength.

Whole Cigarette Smoke Condensates Induce Accumulation of Amyloid Beta Precursor Protein with Oxidative Stress in Murine Astrocytes.

Although cigarette smoking has been postulated to be a potential risk factor for Alzheimer's disease (AD), the toxic mechanism is still unclear. Additionally, astrocytes have been identified as a potential target, given they play multiple roles in maintaining normal brain function. In this study, we explored the toxic mechanism of whole cigarette smoke condensates (WCSC) using murine astrocytes. Cell proliferation, the percentage of cells in the G2/M phase, and LDH concentrations in the cell supernatants were all reduced in WCSC-treated cells. In addition, oxidative stress was induced, together with shortening of processes, structural damage of organelles, disturbances in mitochondrial function, blockage of autophagic signals, accumulation of amyloid ß precursor protein, and loss of chemotactic functions. Based on these results, we hypothesize that dysfunction of astrocytes may contribute to the occurrence of cigarette-smoking-induced AD.

Repeated intratracheal instillation of zinc oxide nanoparticles induced pulmonary damage and a systemic inflammatory response in cynomolgus monkeys.

Recently, some researchers have demonstrated that inhaled zinc oxide nanoparticles (ZnONPs) induce an acute systemic inflammatory response in workers. Considering nonhuman primates are preferably considered an animal model for translational research due to their proven similarity with humans in terms of genetics and physiology, we intratracheally instilled ZnONPs to cynomolgus monkey for 14 days and identified the toxic mechanism and bioaccumulation. ZnONPs were rapidly ionized or aggregated in a simulated pulmonary fluid, and they attracted neutrophils to the lungs and increased the pulmonary level of inflammatory mediators. Additionally, thickened alveolar walls, fibrin clots, and hemorrhages were observed in the lungs of the monkeys instilled with the higher dose accompanied by cell debris in the alveolar ducts and alveoli. Dark-field microscopy images revealed translocation of ZnONPs into other tissues accompanied by an increase in the relative weight of livers to body weight. In addition, when instilled at the higher dose, the albumin/globulin ratio notably decreased compared to the control, whereas the C-reactive protein (CRP) level was significantly elevated. ZnONPs also clearly induced apoptotic cell death in a 24 h exposure to alveolar macrophages. Taken together, part of inhaled ZnONPs may be ionized in the lung, resulting in acute toxic effects, including cell death and tissue damage, and the rest may move to other tissues in the form of particles, causing a systemic inflammatory response. Based on the proven evidence among workers, we also suggest that the CRP level can be recommended as a biomarker for ZnONPs-induced adverse health effects.

Thermal and Spectroscopic Analyses of Human Adipose Tissue-Derived Extracellular Matrix.

In this study, nanofibrous extracellular matrix (ECM) was prepared from human adipose tissue, and the stepwise products were analyzed using differential thermal analysis (DTA)/thermogravimetric analysis (TGA) and Fourier-transform infrared (FTIR)/Raman spectroscopy. Human adipose tissue was liposuctioned (sample 1), centrifuged (sample 2), pulverized, centrifuged again (sample 3), and finally freeze-dried (sample 4). Each sample was subjected to DTA/TGA and FTIR/Raman analyses. In the DTA curve of sample 1, the major peak was observed at approximately 60 °C. However, relatively flat DTA curves were detected in samples 2 and 4. In the TGA results, sample 1 showed a more rapid weight loss pattern than the other samples. Samples 1, 2, and 3 showed similar FTIR spectra with a strong, broad absorption feature at ~3400 cm-1. Amide I, II, and III bands were clearly observed in the FTIR spectrum of sample 4. Samples 1 and 2 showed typical adipose tissue Raman spectra. However, in samples 3 and 4, the Raman signal was low. Scanning electron microscopic analysis of the freeze-dried ECM (sample 4) confimed its three-dimensional porous nanofibrous structure. These findings suggest that human adipose tissue, intermediate products, and human adipose tissue-derived ECM can be easily and effectively characterized with thermal and spectroscopic analyses. These efficient analyses can aid in the preparation of ECM and in clinical applications for regenerative medicine.

Detection of intracellular lamellar bodies as a screening marker for fibrotic lesions.

With the rapid increase in application of disinfectants worldwide as a method to block the spread of coronavirus, many new products are being introduced into the market without thorough verification of their impacts on human health and the environment. In the present study, we aimed to propose a screening marker for materials that can induce fibrotic lung disease using disinfectants, which had been demonstrated as causative materials of chronic inflammation and interstitial fibrosis. We first calculated the corresponding LC50 level based on results from cell viability test and exposed the LC50 level of disinfectants to human bronchial epithelial cells for 24 h. Formation of lamellar body-like structures, cleavage of the nuclear matrix, structural damage of mitochondria were found in the cytosol of the treated cells. We also dosed disinfectants by pharyngeal aspiration to mice to determine the LD0 level. The mice were sacrificed on Day 14 after a single dosing, and lamellar body-like structures were observed in the lung tissue of mice. Herein, we hypothesize that DNA damage and metabolic disturbance may play central roles in disinfectant-induced adverse health effects. Additionally, we propose that formation of lamellar bodies can be a screening marker for interstitial fibrosis.

Drug resistance-free cytotoxic nanodrugs in composites for cancer therapy.

Drug resistance is a major cause of treatment failure for small-molecule cancer chemotherapies, despite the advances in combination therapies, drug delivery systems, epigenetic drugs, and proteolysis-targeting chimeras. Herein, we report the use of a drug resistance-free cytotoxic nanodrug as an alternative to small-molecule drugs. The present nanodrugs comprise 2 nm core gold nanoparticles (AuNPs) covered completely with multivalent hydrocarbon chains to a final diameter of ∼10 nm as single drug molecules. This hydrophobic drug-platform was delivered in composite form (∼35 nm) with block-copolymer like other small-molecular drugs. Upon uptake by cells, the nanodrugs enhanced the intracellular levels of reactive oxygen species and induced apoptosis, presumably reflecting multivalent interactions between aliphatic chains and intracellular biomolecules. No resistance to our novel nanodrug was observed following multiple treatment passages and the potential for use in cancer therapy was verified in a breast cancer patient-derived xenograft mouse model. These findings provide insight into the use of nano-scaled compounds as agents that evade drug resistance to cancer therapy.

A Case Report of Cholangiocarcinoma Arising from a Biliary Adenofibroma: Radiologic Findings and Review of Literature.

Biliary adenofibromas are rare biliary epithelial tumors that are classified as benign. Nevertheless, some cases have been reported to show malignant transformations. The radiologic findings of biliary adenofibromas and their malignant transformation are not well-established because of their rarity. We present a case of a cholangiocarcinoma arising from a biliary adenofibroma assessed using ultrasonography, CT, and MRI. The differential diagnoses include other hepatic tumors.

Delayed treatment-free response after romiplostim discontinuation in pediatric chronic immune thrombocytopenia.

We report the case of a 16-month-old patient with chronic immune thrombocytopenia (ITP) patient who experienced delayed treatment-free response (TFR) after romiplostim treatment. He received intravenous immunoglobulin every month to maintain a platelet count above 20,000/µL for 2 years. Thereafter, he received rituximab and cyclosporine as second-line therapy, with no response, followed by romiplostim. After 4 weeks of treatment, the platelet count was maintained above 50,000/µL. Following 7 months of treatment, he discontinued romiplostim, and the platelet count decreased. His platelet counts remained above 50,000/µL, without any bleeding symptoms, 2 years after romiplostim discontinuation. This is the first report of TFR after romiplostim treatment in pediatric chronic ITP.

Toxicity of orally administered food-grade titanium dioxide nanoparticles.

This year, France banned the application of titanium dioxide nanoparticles as a food additive (hereafter, E171) based on the insufficient oral toxicity data. Here, we investigated the subchronic toxic responses of E171 (0, 10, 100, and 1,000 mg/kg) and tried to elucidate the possible toxic mechanism using AGS cells, a human stomach epithelial cell line. There were no dose-related changes in the Organisation for Economic Cooperation and Development test guideline-related endpoints. Meanwhile, E171 deeply penetrated cells lining the stomach tissues of rats, and the IgM and granulocyte-macrophage colony-stimulating factor levels were significantly lower in the blood from rats exposed to E171 compared with the control. The colonic antioxidant protein level decreased with increasing Ti accumulation. Additionally, after 24-h exposure, E171 located in the perinuclear region of AGS cells and affected expression of endoplasmic reticulum stress-related proteins. However, cell death was not observed up to the used maximum concentration. A gene profile analysis also showed that immune response-related microRNAs were most strongly affected by E171 exposure. Collectively, we concluded that the NOAEL of E171 for 90 days repeated oral administration is between 100 and 1,000 mg/kg for both male and female rats. Additionally, further study is needed to clarify the possible carcinogenesis following the chronic accumulation in the colon.