The additive effect of intravitreal dexamethasone combined with bevacizumab in refractory diabetic macular edema.

PURPOSE: To evaluate the short-term structural and visual outcomes and side effects associated with intravitreal dexamethasone (IVD) combined with bevacizumab (IVB) in treating patients with diabetic macular edema (DME) and an inadequate response to anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: In this prospective interventional case series, a total of 81 eyes of 81 patients with type 2 diabetes mellitus (T2DM) and refractory DME were included and assigned to one of two groups: I) those receiving three monthly intravitreal injections of combined bevacizumab and dexamethasone (IVB+IVD) and II) those receiving three monthly intravitreal injections of bevacizumab alone (IVB). The primary outcome was the inter-group difference in central macular thickness (CMT); secondary outcomes included best-corrected visual acuity (BCVA), baseline optical coherence tomography (OCT) biomarkers, and intraocular pressure (IOP) one month after the last injection. RESULTS: Reduction in CMT and improvement in BCVA were significantly greater in the IVB+IVD group than the IVB group (109.88±156.25 vs. 43±113.67, respectively, P=0.03; and -0.13±0.23 vs. -0.01±0.17, respectively, P=0.008). Presence of neurosensory retinal detachment (NSD) (P<0.001) and complete inner segment/outer segment junction (IS-OS) disruption (P=0.049) on baseline OCT scans were associated with further CMT reductions in response to IVD. Conversely, identifiable epiretinal membrane (ERM) (P=0.002) and multiple hyperreflective foci (>20) (P=0.049) were associated with smaller reductions in CMT. Vitreomacular traction correlated with worse visual outcomes in the IVB+IVD group (P=0.003). The intergroup IOP difference was not clinically significant. CONCLUSION: In patients with refractory DME, addition of IVD to the standard IVB regimen can improve visual and structural outcomes without increasing the risk of endophthalmitis, IOP rise, or intraocular inflammation. Patients with NSD are more likely to respond well to IVD. The presence of ERM may predict poor treatment response.

Features of Visually AcceSAble Rembrandt Images: Interrater Reliability in Pediatric Brain Tumors.

BACKGROUND AND PURPOSE: At present, no evidence-based lexicon exists for pediatric intracranial tumors. The Visually AcceSAble Rembrandt Images terminology describes reproducible MR imaging features of adult gliomas for prediction of tumor grade, molecular markers, and survival. Our aim was to assess the interrater reliability of the pre-resection features of Visually AcceSAble Rembrandt Images in pediatric brain tumors. MATERIALS AND METHODS: Fifty consecutive pre-resection brain MR imaging examinations of pediatric intracranial neoplasms were independently reviewed by 3 neuroradiologists. The intraclass correlation coefficient for continuous variables and the Krippendorf alpha were used to evaluate the interrater agreement. Subgroup analysis was performed for 30 gliomas. RESULTS: Parameters with almost perfect agreement (α > .8) included tumor location (F1) and proportion of enhancing tumor (F5). Parameters with substantial agreement (α = .61-.80) were side of tumor epicenter (F2), involvement of eloquent brain (F3), enhancement quality (F4), proportion of non-contrast-enhancing tumor (F6), and deep white matter invasion (F21). The other parameters showed either moderate (α = .41-.60; n = 11), fair (α = .21-.40; n = 5), or slight agreement (α = 0-.20; n = 1). Subgroup analysis of 30 gliomas showed almost perfect agreement for tumor location (F1), involvement of eloquent brain (F3), and proportion of enhancing tumor (F5); and substantial agreement for side of tumor epicenter (F2), enhancement quality (F4), proportion of noncontrast enhancing tumor (F6), cysts (F8), thickness of enhancing margin (F11), and deep white matter invasion (F21). The intraclass correlation coefficient for measurements in the axial plane was excellent in both the main group (0.984 [F29] and 0.982 [F30]) and the glioma subgroup (0.973 [F29] and 0.973 [F30]). CONCLUSIONS: Nine features of Visually AcceSAble Rembrandt Images have an acceptable interrater agreement in pediatric brain tumors. For the subgroup of pediatric gliomas, 11 features of Visually AcceSAble Rembrandt Images have an acceptable interrater agreement. The low degree of reproducibility of the remainder of the features necessitates the use of features tailored to the pediatric age group and is likely related to the more heterogeneous imaging morphology of pediatric brain tumors.

Expanding the Neuroimaging Phenotype of Neuronal Ceroid Lipofuscinoses.

BACKGROUND AND PURPOSE: Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigments in neuronal cells. As a result of storage material in the brain and retina, clinical manifestations include speech delay, cognitive dysfunction, motor regression, epilepsy, vision loss, and early death. At present, 14 different ceroid lipofuscinosis (CLN) genes are known. Recently, the FDA approved the use of recombinant human proenzyme of tripeptidyl-peptidase 1 for CLN2 disease, while phase I/IIa clinical trials for gene therapy in CLN3 and CLN6 are ongoing. Early diagnosis is, therefore, key to initiating treatment and arresting disease progression. Neuroimaging features of CLN1, CLN2, CLN3, and CLN5 diseases are well-described, with sparse literature on other subtypes. We aimed to investigate and expand the MR imaging features of genetically proved neuronal ceroid lipofuscinoses subtypes at our institution and also to report the time interval between the age of disease onset and the diagnosis of neuronal ceroid lipofuscinoses. MATERIALS AND METHODS: We investigated and analyzed the age of disease onset and neuroimaging findings (signal intensity in periventricular, deep, and subcortical white matter, thalami, basal ganglia, posterior limb of the internal capsule, insular/subinsular regions, and ventral pons; and the presence or absence of supratentorial and/or infratentorial atrophy) of patients with genetically proved neuronal ceroid lipofuscinoses at our institution. This group consisted of 24 patients who underwent 40 brain MR imaging investigations between 1993 and 2019, with a male preponderance (male/female ratio = 15:9). RESULTS: The mean ages of disease onset, first brain MR imaging, and diagnosis of neuronal ceroid lipofuscinoses were 4.70 ± 3.48 years, 6.76 ± 4.49 years, and 7.27 ± 4.78 years, respectively. Findings on initial brain MR imaging included T2/FLAIR hypointensity in the thalami (n = 22); T2/FLAIR hyperintensity in the periventricular and deep white matter (n = 22), posterior limb of the internal capsule (n = 22), ventral pons (n = 19), and insular/subinsular region (n = 18); supratentorial (n = 21) and infratentorial atrophy (n = 20). Eight of 9 patients who had follow-up neuroimaging showed progressive changes. CONCLUSIONS: We identified reported classic neuroimaging features in all except 1 patient with neuronal ceroid lipofuscinoses in our study. CLN2, CLN5, and CLN7 diseases showed predominant cerebellar-over-cerebral atrophy. We demonstrate that abnormal signal intensity in the deep white matter, posterior limb of the internal capsule, and ventral pons is more common than previously reported in the literature. We report abnormal signal intensity in the insular/subinsular region for the first time. The difference in the median time from disease onset and diagnosis was 1.5 years.

Fractional Flow on TOF-MRA as a Measure of Stroke Risk in Children with Intracranial Arterial Stenosis.

BACKGROUND AND PURPOSE: Conventional angiography is the criterion standard for measuring intracranial arterial stenosis. We evaluated signal intensity ratios from TOF-MRA as a measure of intracranial stenosis and infarct risk in pediatric stroke. MATERIALS AND METHODS: A retrospective study was undertaken in children with intracranial arterial stenosis, who had TOF-MRA and conventional angiography performed within 6 months. Arterial diameters were measured for percentage stenosis. ROI analysis on TOF-MRA measured signal intensity in pre- and poststenotic segments, with post-/pre-signal intensity ratios calculated. The Pearson correlation was used to compare percentage stenosis on MRA with conventional angiography and signal intensity ratios with percentage stenosis; the point-biserial correlation was used for infarcts compared with percentage stenosis and signal intensity ratios. Sensitivity, specificity, and positive and negative predictive values were calculated for determining severe (≥70%) stenosis from MRA and signal intensity ratios against the criterion standard conventional angiography. P < .05 was considered statistically significant. RESULTS: Seventy stenotic segments were found in 48 studies in 41 children (median age, 11.0 years; range, 5 months to 17.0 years; male/female ratio, 22:19): 20/41 (48.8%) bilateral, 11/41 (26.8%) right, and 10/41 (24.4%) left, with the most common site being the proximal middle cerebral artery (22/70, 31%). Moyamoya disease accounted for 27/41 (65.9%). Signal intensity ratios and conventional angiography stenosis showed a moderate negative correlation (R = -0.54, P < .001). Receiver operating characteristic statistics showed an area under the curve of 0.86 for using post-/pre-signal intensity ratios to determine severe (≥70%) carotid stenosis, yielding a threshold of 1.00. Sensitivity, specificity, and positive and negative predictive values for severe stenosis were the following-MRA: 42.8%, 58.8%, 30.0%, and 71.4%; signal intensity ratio >1.00: 97.1%, 77.8%, 71.7%, and 97.4%; combination: 75.5%, 100%, 100%, and 76.8%, respectively. Signal intensity ratios decreased with increasing grade of stenosis (none/mild-moderate/severe/complete, P < .001) and were less when associated with infarcts (0.81 ± 0.52 for arteries associated with downstream infarcts versus 1.31 ± 0.55 for arteries without associated infarcts, P < .001). CONCLUSIONS: Signal intensity ratios from TOF-MRA can serve as a noninvasive measure of intracranial arterial stenosis and allow identification of high-risk lesions in pediatric stroke.

Predictive Value of MRI in Diagnosing Brain AVM Recurrence after Angiographically Documented Exclusion in Children.

BACKGROUND AND PURPOSE: MRI is routinely performed following brain AVM after treatment in children. Our aim was to determine the predictive values of contrast-enhanced MR imaging and TOF-MRA for brain AVM recurrence in children, compared with conventional angiography and the role of 3D rotational angiography-MR imaging fusion in these cases. MATERIALS AND METHODS: We included all pediatric patients with brain AVMs during an 18-year period with angiographically documented obliteration after treatment. Patients underwent 3T MR imaging, including contrast-enhanced MR imaging, TOF-MRA, and conventional angiography, with a subset undergoing 3D rotational angiography. The predictive values of contrast-enhanced MR imaging and TOF-MRA for brain AVM recurrence were determined. CTA sections reconstructed from 3D rotational angiography were coregistered with and fused to 3D-T1WI for analysis. RESULTS: Thirty-nine children (10.8 ± 3.9 years of age; range, 2-17 years; male/female ratio, 19:20; mean Spetzler-Martin grade, 1.9 ± 0.6) met the inclusion criteria. Of these, 13 had angiographically confirmed brain AVM recurrence, 8 following surgery and 5 following embolization. Sensitivity, specificity, and positive and negative predictive values for recurrence were the following: contrast-enhanced MR imaging: 84.6%, 38.5%, 40.7%, 81.8%; TOF-MRA: 50.0%, 96.1%, 85.7%, 79.3%; both: 75.0%, 90.9%, 85.7%, 83.3%. 3D rotational angiography-MR imaging fused images confirmed or excluded recurrence in all available cases (13/13). Embolization-only treatment was a significant predictor of recurrence (OR = 32.4, P = .006). MR imaging features predictive of recurrence included a tuft of vessels on TOF-MRA and nodular juxtamural/linear enhancement with a draining vein on contrast-enhanced MR imaging. CONCLUSIONS: MR imaging is useful for surveillance after brain AVM treatment in children, but conventional angiography is required for definitive diagnosis of recurrence. TOF-MRA and contrast-enhanced MR imaging provide complementary information for determining brain AVM recurrence and should be interpreted in conjunction. 3D rotational angiography-MR imaging fusion increases the diagnostic confidence regarding brain AVM recurrence and is therefore suited for intraoperative neuronavigation.

Hepatic steatosis is highly prevalent across the paediatric age spectrum, including in pre-school age children.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is 8% in the general population, and 34% in the context of obesity. There is a paucity of data on the prevalence of hepatic steatosis in healthy children in Ontario. AIMS: To determine the prevalence of hepatic steatosis using abdominal computed tomography (CT) scans in a cohort of previously healthy children across the paediatric age spectrum in Ontario, Canada, and to determine any association between measures of abdominal adiposity and hepatic steatosis. METHODS: Retrospective review of the SickKids Trauma Database from 2004-2015. Previously healthy children ages 1-17 years having undergone an abdominal CT scan as a part of routine trauma assessment were included, and those with an intra-abdominal injury excluded. Steatosis was defined as a difference between liver and spleen attenuation ≤-25HU. The percentage of the total area occupied by abdominal subcutaneous adipose and visceral adipose tissue was measured. Anthropometrics and baseline demographics were collected. RESULTS: A total of 503 (51% male) children with mean (±SD) age 9.5 ± 4.5 years and weight z-score of 0.37 ± 1.05 were studied. Seventy-seven (15%, 95% CI [12%-18%]) had hepatic steatosis; no differences found between sexes or across age quartiles. The abdominal subcutaneous adipose tissue area was greater in those with hepatic steatosis compared to those without (32% [22-42] vs 24% [17-36], P = 0.003). The visceral adipose tissue area was significantly greater in older children ≥9.8 years with hepatic steatosis (7.7% [5.1-10] vs 6.6% (4.9-8.5), P = 0.04). CONCLUSION: Hepatic steatosis was highly prevalent in previously healthy children in Ontario, including children of pre-school age. We found an association between hepatic steatosis and abdominal subcutaneous adipose tissue, and in older children with visceral adipose tissue.

Pilot study on 18 F-FDG PET/CT for detection of inflammatory changes in blood-induced knee arthropathy in a rabbit model.

RATIONALE: 18 F-FDG-PET/CT has a potential role in the early detection of haemophilic arthritis, at a time when treatment may still avoid further joint degeneration. The purposes of this pilot study were to determine the ability of 18 F-FDG-PET/CT to detect inflammatory changes associated with blood-induced arthropathy in knees of a rabbit model. METHODS: Ten juvenile rabbits were imaged at baseline and weeks 5 and 17 post intraarticular autologous blood injections (ABI). Five rabbits in group 1 (G1) had ABI into the same knee joint every 2 weeks (total, eight injections). Five rabbits in group 2 (G2) had only two injections into the same knee, at weeks 5 and 17. Images were assessed visually and semi-quantitatively by measuring maximal standardized uptake values (SUVmax) and standardized uptake ratio (SUR = SUVmax in affected knee/SUVmax in non-affected knee). RESULTS: More rabbits in G1 than G2 presented with positive chronic inflammatory synovial scores at week 17. Mean iron staining scores in injected knees were greater for G1 than for G2 (P = 0.049). No increased uptake was identified in the injected knees in any of the rabbits at baseline or at week 5. At week 17, all G1 rabbits demonstrated increased uptake in their affected knees with higher mean SUVmax (1.5) than normal knees (1.0) (P < 0.02). None of the G2 rabbits showed asymmetric increased uptake. The SUR of G1 was higher at week 17 compared to baseline (P < 0.01) and week 5 (P < 0.01). The SUR at week 17 was higher for G1 than for G2 (1.13) rabbits (P < 0.01). CONCLUSION: 18 F-FDG-PET is able to detect the inflammatory changes associated with haemophilic arthropathy in this experimental model.

Longitudinal assessment of bone loss using quantitative ultrasound in a blood-induced arthritis rabbit model.

INTRODUCTION: Osteoporosis is common in haemophilic arthropathy. Quantitative ultrasound (QUS) can be a suitable alternative for dual-energy x-ray absorptiometry for diagnosing osteoporosis in haemophiliacs due to its lack of ionizing radiation, and ease to use. AIM: We investigated the intra- and inter-operator reliability of QUS, its responsiveness to bone growth, its ability to differentiate bone adjacent to blood-injected vs. control joints, and the effect of soft tissues on the speed of sound (SOS) QUS values in a juvenile white New Zealand rabbit model of blood-induced arthritis. METHODS: Eight of 16 rabbits were injected with autologous blood (0.1 mL kg(-1) ) 8 times over a 17-week period, the remaining eight rabbits served as controls. SOS was measured at baseline, weeks 8 and 17 in vivo and after the bones were excised on week 17. RESULTS: Intra- and inter-operator coefficients of variation for QUS data were <5% and intraclass correlation coefficients were >60% for 22/27 (81.5%) of bones assessed. The level of interval increase in SOS values from baseline to week 17 was significantly different in tibiae of injected, contralateral to injected and non-injected knee groups by anova (P = 0.01). In vivo (mean ± SD, 4147.17 ± 96.27 m s(-1) ) and postmortem (4457.85 ± 104.00 m s(-1) ) measurements on week 17 differed (P < 0.01) indicating an effect of soft tissues on SOS. CONCLUSION: In conclusion, QUS' acceptable reliability, its responsiveness to growth-related changes and its ability to discriminate injected and non-injected joints make this technique a plausible candidate as a diagnostic tool for osteoporosis in the paediatric haemophilic population if these results are confirmed upon animal-human translation.

USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood-induced arthritis: a pilot study.

Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 µmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post-USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation.

Prevalence of transient hyperglycemia and diabetes mellitus in pediatric patients with acute leukemia.

BACKGROUND: The most common malignancy of children is Leukemia, accounting approximately one third of cancer diagnosis. Available data demonstrate improvement in survival of pediatric leukemia, so evaluation of side effects of treatment is very important. This study investigates hyperglycemia and diabetes mellitus prevalence in pediatric patients with acute leukemia. MATERIALS AND METHODS: This study was performed in children with acute leukemia. At the first admission, demographic data was collected and blood glucose and HbA1c levels were obtained. These tests examined at least two times during six months of follow up. Growth parameters and blood samples were obtained too. RESULT: Twenty nine patients were examined; three of them (10.3%) had diabetes mellitus and 5patients (17.2%) had transient hyperglycemia.Mean age of the patients was 6.26 years and nineteen Children (63%) were in preschool age. In preschool age children, incidence of hyperglycemia was meaningfully higher than school age children (p= 0.02). 24 of 29 patients (82.7%) were known case of acute lymphoblastic leukemia (ALL) and 5 patients (17.3%) were known case of acute myeloblastic leukemia (AML). No significant difference was found between sex groups. Also underweight was significant risk factor for hyperglycemia. CONCLUSION: The prevalence of hyperglycemia was in the range of other similar studies in different parts of the world. Underweight and preschool ages were significant predictors of hyperglycemia.

Non surgical treatment of sacral osteosarcoma.

Osteosarcoma may rarely originate from the axial bones such as pelvis or vertebrae. In some pelvic and most vertebral primary tumors, resection often is not possible completely. In general, these tumors cannot be resected with negative margins so they need additional radiotherapy and chemotherapy, but results are unfavourable because of poor local control and high incidence of distant metastases. This is a case report of sacral osteosarcoma which was treated successfully with chemotherapy and radiation therapy. The patient is a 14-year-old boy with a large osteosarcoma tumor in the first sacral vertebral body, with extra skeletal extension. The patient took radiotherapy (6000 centigray) plus chemotherapy regimen consisting of doxorubicin and cisplatin. In the last follow up 48 months later, the patient was completely asymptomatic with normal performance and there was not any evidence of local progression or distant metastasis.

Evaluation of anti-inflammatory and analgesic activity of a novel rigid 3, 4-dihydroxy chalcone in mice.

There have been many reports indicating the analgesic and anti-inflammatory effects of 3,4-dihydroxychalcones. We have designed and synthesized a rigid 3,4-dihydroxychalcone (RDHC) as a possible drug effecting inflammation and nociception. The analgesic and anti-inflammatory effects were evaluated by formalin and hot-plate tests, respectively. The results showed that RDHC induced significant antinociceptive and anti-inflammatory effects (P < 0.01). Maximum analgesia (63.7%) was observed at 37.5 mg/kg in the first phase of the formalin test. The effect of RDHC was higher in the chronic phase (inflammation phase) of the formalin test (86.4%, P < 0.01). In addition, a significant analgesia (maximum possible effect; MPE = 30.1%) was observed in the hot plate test 45 min after injection of 37.5 mg/kg RDHC (P < 0.01). As a result of our findings, this new RDHC could be suggested for further pharmacological studies.

Resorption kinetics of osseous substitute: natural coral and synthetic hydroxyapatite.

Coral and hydroxyapatite may be used as substitution biomaterials for bone grafts. In this work, we extracted the implants from the femora to study the kinetics of elementary mineral transformation of the osseous substitutes. The use of physical analysis methods such as PIXE (particle-induced X-ray emission) shows that coral and hydroxyapatite, after their implantation in vivo, reach a mineral composition comparable with that of bone. For the first time we have measured the concentration of mineral elements, at different time intervals after implantation, along a cross-section. The distribution according to mineral elements (Ca, P, Sr, Zn, Fe) in the implant, in the receiver site and also at the interface, showed that the kinetics of coral resorption was faster than that of hydroxyapatite; in the same way, the osseous attack was not global but, rather, centripetal.