Clinical, pathologic, and genomic characteristics of two pediatric glioneuronal tumors with a CLIP2::MET fusion.

Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.

Shunt timing in low-weight infants in the treatment of hydrocephalus.

OBJECTIVE: The optimal timing of ventricular shunt placement in low-weight and preterm infants remains an unresolved topic in modern pediatric neurosurgery. Shunt placement for hydrocephalus is performed over a wide range of infant weights, and the standard weight threshold for shunt placement can vary substantially across institutions. The aim of this study was to investigate shunt outcome in infants of low body weight. METHODS: An IRB-approved retrospective analysis of 76 infants (29 females, 47 males) who received primary shunt placement between 2003 and 2018 was performed. Uniform criteria were used over the entire dataset to determine the safety for ventriculoperitoneal (VP) shunt placement: 1) weight near or above 1500 g, 2) feeding tolerance, and 3) lack of necrotizing enterocolitis or active systemic infection. Infants were classified into a low-weight (LW) (< 2000 g) or standard weight (SW) (2000-3000 g) group based on their body weight at the time of initial shunt placement. Shunt survival was compared between the groups. The threshold weight separating the LW and SW groups and outcomes was additionally varied and systematically reanalyzed. RESULTS: Shunts were placed in 24 LW infants and 52 SW infants over the inclusion period. Etiologies for hydrocephalus were similar across groups: predominantly intraventricular hemorrhage (54%) (p = 0.13) and open neural tube defect (29%) (p = 0.61). Both LW and SW groups had 58% 1-year shunt survival rates. Overall, 46% of shunts failed in the LW group compared with 54% in the SW group over a median follow-up of 47 months (range 0-170 months). A log-rank test comparing shunt survival rates did not show significance (p = 0.43). Groups were repartitioned using a range of threshold weights (1600-2400 g) to divide LW from SW infants. The lack of association between VP shunt placement in LW infants and time frame of revision was consistently observed over the full range of varied threshold weights. CONCLUSIONS: There was no significant difference in overall time to shunt revision between infants weighing < 2000 g and infants weighing 2000-3000 g. No correlation between weight and shunt survival was detected. Combined with other clinical features pertinent to the management of hydrocephalus in the neonatal population, this investigation provides insight toward clinical decision-making regarding infants of low birth weight and suggests that further multi-institutional study on this topic is warranted.

Surgical management of pediatric spinal aneurysmal bone cysts: patient series.

BACKGROUND: Aneurysmal bone cysts (ABCs) are rare, highly vascular osteolytic bone lesions that predominantly affect pediatric populations. This report evaluates the clinicopathological data of pediatric patients with spinal ABCs. The medical records for all patients at Children's Hospital Los Angeles with biopsy-proven ABCs of the spine between 1998 and 2018 were evaluated. OBSERVATIONS: Seventeen patients, 6 males and 11 females, were identified. The mean age at surgery was 10.4 years (range, 3.5-20 years). The most common presenting complaint was pain at the lesion site 16/17 (94%), followed by lower-extremity weakness 8/17 (47%). Resection and intralesional curettage were performed in all patients. Three (18%) of 17 patients underwent selective arterial embolization prior to resection. Spinal stability was compromised in 15 of 17 patients (88%), requiring instrumented fusion. Five (29%) of the 17 patients received additional therapy including radiation, calcitonin-methylprednisolone, or phenol. Four (23.5%) of 17 patients experienced a recurrence, and the mean time to recurrence was 15 months. The postoperative follow-up ranged from 6 to 108 months (median, 28 months). Reoperation occurred after an average of 35 months. At the recent follow-up, patients were free of disease. LESSONS: Gross-total resection by intralesional curettage with case-dependent instrumented spinal fusion for instability remains an effective strategy for managing pediatric spinal ABCs. Long-term follow-up is necessary to detect tumor recurrence.

Low-pass whole-genome and targeted sequencing of cell-free DNA from cerebrospinal fluid in pediatric patients with central nervous system tumors.

Background: Central nervous system tumors are the most common pediatric solid tumors and the most frequent cause of cancer-related morbidity in childhood. Significant advances in understanding the molecular features of these tumors have facilitated the development of liquid biopsy assays that may aid in diagnosis and monitoring response to therapy. In this report, we describe our comprehensive liquid biopsy platform for detection of genome-wide copy number aberrations, sequence variants, and gene fusions using cerebrospinal fluid (CSF) from pediatric patients with brain, spinal cord, and peripheral nervous system tumors. Methods: Cell-free DNA was isolated from the CSF from 55 patients, including 47 patients with tumors and 8 controls. Results: Abnormalities in cell-free DNA were detected in 24 (51%) patients including 11 with copy number alterations, 9 with sequence variants, and 7 with KIAA1549::BRAF fusions. Positive findings were obtained in patients spanning histologic subtypes, tumor grades, and anatomic locations. Conclusions: This study demonstrates the feasibility of employing this platform in routine clinical care in upfront diagnostic and monitoring settings. Future studies are required to determine the utility of this approach for assessing response to therapy and long-term surveillance.

Use of tranexamic acid in trauma patients requiring massive transfusion protocol activation: a reassessment of prescribing behaviours in a major trauma centre in New Zealand.

AIM: To re-investigate prescribing behaviours for tranexamic acid (TXA) use in the early management of severe trauma, and to compare against the standards considered to be best practice and the same study conducted at this centre two years prior. METHODS: We undertook a retrospective analysis of trauma patients requiring massive transfusion protocol (MTP) activation across a 26-month period. Physical and electronic inpatient records and ambulance documentation were reviewed to determine dose and timing of TXA administration. RESULTS: During the period studied, 53 trauma patients requiring activation of the MTP were identified. Of those for whom TXA was indicated, 90.9% received at least an initial dose of TXA and 50.0% received both doses. In total, 16.7% of patients received a dose within one hour of injury, 73.8% between one and three hours and 9.52% outside three hours. CONCLUSIONS: Compared with the previous study, the utilisation of TXA is now more consistent with what is considered best practice. Delayed administration beyond the three-hour therapeutic window was less than the 26.3% figure previously reported, and comparable to that of major trauma centres internationally. Persistent issues include the under-utilisation of the second dose and the potential for much earlier use, as has been achieved at centres where pre-hospital administration is the norm.

The ability of a potassium oxalate gel strip to occlude human dentine tubules; a Novel in vitro: In situ Study.

OBJECTIVES: To determine if an oxalate strip reduced fluid flow in dentine samples and whether this reduction was maintained following a 14 day intra-oral period. METHODS: Dentine tubule fluid flow was measured by a modified Pashley cell in 40 acid-etched dentine discs 1 mm thick, diameter >10 mm, with an acquired pellicle, pre-equilibrated with Hartmann's solution and conditioned by toothbrushing, pre and post treatment (10 min) with an oxalate (3.14 %) gel strip or no treatment. One control and one test sample were exposed in-situ for 14 days to the oral environment in 20 healthy adult volunteers, and fluid flow re-measured. The appliance containing the two samples was removed for brushing with water after mealtimes when the participant brushed their teeth and for a 2 min daily soak in chlorhexidine. RESULTS: Fluid flow rate was reduced significantly immediately following treatment with the oxalate strip compared to baseline flow rate by 58 %. Following 14 days in-situ oral environment phase, a significant further reduction in fluid flow compared to baseline was identified in both control and oxalate strip treated samples, both (p < 0.0001), but the reduction was greater in the test samples, 94 % vs 87 %, p < 0.01. CONCLUSIONS: This novel investigation is the first to show fluid flow measurement using the Pashley model in dentine samples that have been housed in the mouth for 14 days. Treatment with an oxalate strip designed for dentine hypersensitivity alleviation reduced dentine fluid flow more than control providing evidence that the oxalate treatment withstood the oral environment over a prolonged time. CLINICAL SIGNIFICANCE: This study demonstrated the efficacy and durability of the oxalate precipitate over a 14 day period in achieving and maintaining dentine tubule occlusion when participants had no dietary restrictions. This demonstrates the suitability of the oxalate strip for the treatment of patients suffering from dentine hypersensitivity pain.

Three randomized studies of dentine hypersensitivity reduction after short-term SnF2 toothpaste use.

AIM: To evaluate effects of a 0.454% stannous fluoride test toothpaste on dentine hypersensitivity (DH) applied by fingertip, then 3 days' brushing, versus a sodium monofluorophosphate-based control. MATERIALS AND METHODS: In three randomized clinical studies, DH was assessed using evaporative (Schiff scale) and tactile (Yeaple probe) stimuli. Participants applied toothpaste to two sensitive teeth by fingertip (60 s each); DH was re-assessed, prior to brushing. Test treatment participants brushed their sensitive teeth, with all participants then brushing all teeth for ≥60 s, twice daily for 3 days. DH was re-assessed. Data were analysed by study and then pooled. RESULTS: In two studies, test treatment significantly reduced DH versus control treatment after fingertip application and 3 days' brushing (both measures). In one study, both treatments significantly reduced DH without between-treatment differences. Mean Schiff differences (95% confidence intervals) for fingertip/3d were as follows: Study 1: -0.09 (-0.280, 0.092)/ -0.18 (-0.442, 0.072); Study 2: -0.72 (-0.839, -0.610)/ -1.02 (-1.150, -0.882); and Study 3: -0.26 (-0.387, -0.123)/ -0.92 (-1.055, -0.793). Pooled analysis indicated test treatment significantly reduced DH versus control (both timepoints, both measures). Toothpastes were generally well-tolerated. CONCLUSION: Studies indicated that single, fingertip application of a SnF2 toothpaste reduced DH versus a control. DH relief increased over 3 days.

Introduction of an interproximal mineralisation model to measure remineralisation caused by novel formulations containing calcium silicate, sodium phosphate salts and fluoride.

OBJECTIVES: To introduce a new interproximal mineralisation model and to investigate the effectiveness of novel toothpaste and dual phase gel formulations to remineralise acid softened enamel in a simulated interproximal environment. METHODS: Specimens were positioned opposite each other with an approximately 100 µm space between enamel surfaces to simulate an interproximal environment. Target specimens were demineralised in 1% (w/v) citric acid, pH3.75. Specimens were daily immersed in artificial saliva (AS) for 1h, treated with formulations, re-immersed in AS for 6h, re-treated and re-immersed in AS for a further 1h. Study 1 evaluated prototype calcium silicate/phosphate fluoride toothpaste formulations. Study 2 evaluated novel calcium silicate/phosphate fluoride toothpaste and dual phase gel formulations. Both studies contained fluoridated and non-fluoridated controls. The surface microhardness of each target enamel block was measured following demineralisation and following days three, seven and fourteen for study one and after days one, three and seven for study two. RESULTS: This new mineralisation model was able to show increased remineralisation from calcium silicate/phosphate fluoride prototype formulations over fluoridated formulations alone, after three and seven days of treatment. Using this new model, the combined application of novel calcium silicate/phosphate fluoride toothpaste and novel calcium silicate/phosphate fluoride dual phase gel showed the greatest amount of remineralisation, which was significantly greater than sodium fluoride and non-fluoride controls. CONCLUSIONS: Employing a new interproximal mineralisation model successfully determined the remineralisation potential of novel calcium silicate/phosphate fluoride oral healthcare formulations. CLINICAL SIGNIFICANCE: Modifying a mineralisation model to include specimens positioned in an interproximal environment allows us to better understand the remineralisation potential of oral healthcare products. It is important to minimise mineral loss at interproximal sites as the enamel within these areas is thinner than the rest of the crown.

Comparison of gallbladder function obtained with regular CCK-8 and pharmacy-compounded CCK-8.

UNLABELLED: This study was undertaken to test whether the octapeptide of cholecystokinin (regular CCK-8) and pharmacy-compounded CCK-8 produce similar results with regard to gallbladder function. METHODS: Twenty patients with suspected gallbladder disease were enrolled into quantitative cholescintigraphy. Each patient was infused for 10 min with 3 ng/kg/min of regular CCK-8 and pharmacy-compounded CCK-8, sequentially, with a 30-min interval between the beginning of infusion. The gallbladder ejection fraction, latent period, ejection period, and ejection rate were measured with both agents. RESULTS: Both regular CCK-8 and pharmacy-compounded CCK-8 produce similar, but not identical, results with close correlation between them with reference to all of the measured functions of the gallbladder. There is neither potentiation nor inhibition of the first dose on the effects of the second dose of CCK-8. CONCLUSION: Pharmacy-compounded CCK-8 functions much similar to that of regular CCK-8 as long as an interval of at least 30 min is allowed between doses.