Elexacaftor/tezacaftor/ivacaftor improves chronic rhinosinusitis detected by magnetic resonance imaging in children with cystic fibrosis on long-term therapy with lumacaftor/ivacaftor.

INTRODUCTION: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied. METHODS: 30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6-16y). MRI were evaluated using the CRS-MRI score. RESULTS: After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275-0.999). CONCLUSIONS: ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.

Magnetic Resonance Imaging of Pulmonary and Paranasal Sinus Abnormalities in Children with Primary Ciliary Dyskinesia Compared to Children with Cystic Fibrosis.

Rationale: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are characterized by inherited impaired mucociliary clearance leading to chronic progressive lung disease as well as chronic rhinosinusitis (CRS). The diseases share morphological and functional commonalities on magnetic resonance imaging (MRI) of the lungs and paranasal sinuses, but comparative MRI studies are lacking. Objectives: To determine whether PCD shows different associations of pulmonary and paranasal sinus abnormalities on MRI and lung function test results in children (infants to adolescents) compared with children with CF. Methods: Eighteen children with PCD (median age, 9.5 [IQR, 3.4-12.7] yr; range, 0-18 yr) and 36 age-matched CF transmembrane conductance regulator modulator-naive children with CF (median age, 9.4 [3.4-13.2] yr; range, 0-18 yr) underwent same-session chest and paranasal sinus MRI as well as spirometry (to determine forced expiratory volume in 1 s percent predicted) and multiple-breath washout (to determine lung clearance index z-score). Pulmonary and paranasal sinus abnormalities were assessed using previously validated chest MRI and CRS-MRI scoring systems. Results: Mean chest MRI global score was similar in children with PCD and CF (15.0 [13.5-20.8] vs. 15.0 [9.0-15.0]; P = 0.601). Consolidations were more prevalent and severe in children with PCD (56% vs. 25% and 1.0 [0.0-2.8] vs. 0.0 [0.0-0.3], respectively; P < 0.05). The chest MRI global score correlated moderately with forced expiratory volume in 1 second percent predicted in children with PCD and children with CF (r = -0.523 and -0.687; P < 0.01) and with lung clearance index in children with CF (r = 0.650; P < 0.001) but not in PCD (r = 0.353; P = 0.196). CRS-MRI sum score and mucopyocele subscore were lower in children with PCD than in children with CF (27.5 [26.3-32.0] vs. 37.0 [37.8-40.0] and 2.0 [0.0-2.0] vs. 7.5 [4.8-9.0], respectively; P < 0.01). CRS-MRI sum score did not correlate with chest MRI score in PCD (r = 0.075-0.157; P = 0.557-0.788) but correlated moderately with MRI morphology score in CF (r = 0.437; P < 0.01). Conclusions: MRI detects differences in lung and paranasal sinus abnormalities between children with PCD and those with CF. Lung disease does not correlate with CRS in PCD but correlates in CF.

Heidelberg ETV score to assess success of ETV in patients with occlusive hydrocephalus: a retrospective single-center study.

In aqueduct stenosis, pressure difference below and above level of obstruction leads to bulging of third ventricular floor (TVF) and lamina terminalis (LT). Endoscopic third ventriculocisternostomy (ETV) is the standard treatment in these patients. We tried to assess success of ETV depending on those two radiological changes in aqueduct stenosis. We implemented "Heidelberg ETV score" retrospectively to assess the state of TVF as well as LT in same manner in midsagittal MR image. Every patient had a preoperative, direct, 3-months and one-year postoperative score from -2 to + 2. We correlated the scores to clinical course to decide whether the score is reliable in defining success of ETV. Between 2017-2021, 67 (mean age 25.6 ± 23.9y) patients treated with ETV were included. Success rate of primary and Re-ETVs was 91% over 46.8 ± 19.0 months. A marked shift of score to the left after surgery in success group was noticed through the distribution of score immediate postoperative, 3-months later; 70.2% showed (+ 2) before surgery, 38.9% scored (0) after surgery and 50.9% showed further score drop to (-1) 3 months later, p < 0.001. In cases of failure, there was initial decrease after surgery followed by increase with ETV-failure (mean time to failure: 7.2 ± 5.7 months) in 100%. Significant difference was noticed in Heidelberg score at postoperative 1-year- and failure-MRI follow-up between two groups, p < 0.001. Heidelberg score describes anatomical changes in third ventricle after ETV and can serve in assessment of MR images to define success of the procedure in patients with aqueduct stenosis.

Intracranial arachnoid cysts: What is the appropriate surgical technique? A retrospective comparative study with 61 pediatric patients.

Objective: Symptomatic intracranial arachnoid cysts (ACs) should be treated either through microsurgical (MS) or endoscopic surgical (ES) fenestration. Implantation of cysto-peritoneal shunt (CPS) system is another treatment option with decreasing indication. In our study, we compared the complication and revision rates between the three operative techniques in pediatric patients. Methods: We included patients below 18 years with symptomatic intracranial ACs operated between 2004 and 2021. Initial symptoms, location, complication rate, clinical and radiological improvement, postoperative events and revision rate were compared retrospectively. Results: Sixty-one patients; 33 (54.1%) MS operated (mean age 7.6 years), 18 (29.5%) ES operated (mean age 6.2 years) and 10 (16.4%) with CPS (mean age 3.0 years) were collected. The most common initial symptom was headache in 45.9%. 20 (32.8%) postoperative events were documented. The highest revision rate (60%) was seen in the CPS group compared to 33.3% in MS group and 16.7% in ES group. 31 patients harbored perisylvian ACs, 89% remained event-free after ES, 71% after MS and 20% after CPS. Clinical improvement immediately after surgery was observed in 58 patients (96.9% in MS, 88.9% in ES and 100% in CPS). A radiological volume reduction could be proven postoperative in 51 patients (78.8% MS, 88.9% ES and 90% CPS). Conclusion: Endoscopic fenestration of AC is a safe and efficient technique which is being widely used nowadays with the highest event free survival compared to microsurgical fenestration especially in perisylvian arachnoid cysts. CPS shows on long terms the highest revision rate but carries the least surgical risks.

Long-term effects of lumacaftor/ivacaftor on paranasal sinus abnormalities in children with cystic fibrosis detected with magnetic resonance imaging.

Introduction: Chronic rhinosinusitis (CRS) usually presents with nasal congestion, rhinorrhea and anosmia impacts quality of life in cystic fibrosis (CF). Especially mucopyoceles pathognomonic for CRS in CF may cause complications such as spread of infection. Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of CRS from infancy to school age in patients with CF, and mid-term improvements of CRS in preschool and school-age children with CF treated with lumacaftor/ivacaftor for at least 2 months. However, long-term data on treatment effects on paranasal sinus abnomalities in preschool and school-age children with CF are lacking. Methods: 39 children with CF homozygous for F508del (mean age at baseline MRI 5.9 ± 3.0 years, range 1-12 years) underwent MRI before (MRI1) and about 7 months after starting lumacaftor/ivacaftor and then annually (median 3 follow-up MRI, range 1-4) (MRI2-4). MRI were evaluated using the previously evaluated CRS-MRI score with excellent inter-reader agreement. For intraindividual analysis ANOVA mixed-effects analysis including Geisser-Greenhouse correction and Fisher's exact test, and for interindividual group analysis Mann-Whitney test were used. Results: The CRS-MRI sum score at baseline was similar in children starting lumacaftor/ivacaftor in school age and children starting therapy at preschool age (34.6 ± 5.2 vs.32.9 ± 7.8, p = 0.847). Mucopyoceles were the dominant abnormality in both, especially in maxillary sinus (65% and 55%, respectively). In children starting therapy in school age the CRS-MRI sum score decreased longitudinally from MRI1 to MRI2 (-2.1 ± 3.5, p < 0.05), MRI3 (-3.0 ± 3.7, p < 0.01) and MRI4 (-3.6 ± 4.7, p < 0.01), mainly due to a decrease in the mucopyoceles subscore (-1.0 ± 1.5, p = 0.059; -1.2 ± 2.0, p < 0.05; -1.6 ± 1.8, p < 0.01; and -2.6 ± 2.8, p = 0.417, respectively). In children starting lumacaftor/ivacaftor in preschool age, the CRS-MRI sum score remained stable under therapy over all three follow-up MRI (0.6 ± 3.3, p = 0.520; 2.4 ± 7.6, p = 0.994; 2.1 ± 10.5, p > 0.999 and -0.5 ± 0.5, p = 0.740; respectively). Conclusion: Longitudinal paranasal sinus MRI shows improvements in paranasal sinus abnormalities in children with CF starting lumacaftor/ivacaftor therapy at school age. Further, MRI detects a prevention of an increase in paranasal sinus abnormalities in children with CF starting lumacaftor/ivacaftor therapy at preschool age. Our data support the role of MRI for comprehensive non-invasive therapy and disease monitoring of paranasal sinus abnormalities in children with CF.

Longitudinal Magnetic Resonance Imaging Detects Onset and Progression of Chronic Rhinosinusitis from Infancy to School Age in Cystic Fibrosis.

Rationale: Chronic rhinosinusitis (CRS) contributes to morbidity in patients with cystic fibrosis (CF). However, longitudinal data on CRS onset and progression is lacking. Objectives: To longitudinally evaluate CRS in CF from infancy to school age with paranasal sinus magnetic resonance imaging (MRI). Methods: A total of 64 children with CF (mean age at baseline, 1.1 ± 1.6 yr; range, 0-5 yr) underwent a mean of 5.8 ± 2.2 (range, 3-11 yr) subsequent annual MRI examinations. Additional 24 children (9.2 ± 4.4 yr; range, 3-17 yr) homozygous for the F508del mutation underwent MRI before and at least 2 months after starting lumacaftor/ivacaftor. MRI was assessed using the previously evaluated CRS-MRI score. Results: In infancy, 65-87% of paranasal sinuses were opacified, and mucosal swelling was the dominant abnormality (58-97%). At preschool age (1-5 yr), 79-94% of sinuses were opacified (P < 0.05 vs. infancy), and mucosal swelling was the most dominant abnormality (79-94%; P < 0.05). At school age (at least 6 yr), almost all sinuses were opacified (71-99%; P < 0.001-0.357 vs. preschool age), and mucopyoceles were the dominant abnormality in maxillary and frontal sinuses (53-56%; P < 0.05-0.808). The CRS-MRI sum score increased from 22.4 ± 9.6 in infancy to 34.2 ± 9.6 in preschool age (P < 0.001) and was 34.0 ± 5.7 in school age (P = 0.052). In children under lumacaftor/ivacaftor therapy, the CRS-MRI sum score (-0.5 ± 3.3; P < 0.05) and maxillary sinus subscore (-0.5 ± 1.5; P < 0.05) improved. Conclusions: Longitudinal paranasal sinus MRI detects an early onset and progression of the severity of CRS from infancy to school age, and response to lumacaftor/ivacaftor therapy in children with CF. Our data support its role in the comprehensive noninvasive monitoring of CRS in children with CF. Clinical trial registered with www.clinicaltrials.gov (NCT02270476).

ShuntScope-Guided Versus Free-Hand Technique for Ventricular Catheter Placement: A Retrospective Comparative Study of Intraventricular Catheter Tip Position and Complication Rate.

BACKGROUND: The position of the ventricular catheter (VC) is essential for a proper function of cerebrospinal fluid diversion system. A ShuntScope-guided (SG) method might be helpful in reducing complications. The purpose of this study is to compare the accuracy of catheter placement and the complication and revision rates between SG and free-hand (FH) techniques. METHODS: This is a retrospective study based on a prospectively acquired database of patients who underwent VC placement between September 2018 and July 2021. Accuracy of catheter placement was graded on postoperative imaging using the 3-point Hayhurst grading system. Complication and revision rates were documented and compared between both groups with an average follow-up period of 20.84 months. RESULTS: Fifty-seven patients were included. The SG technique was used in 29 patients (mean age was 6.3 years, 1.4-27.7 years, 48.1% females), and the FH technique was used in 28 patients (mean age was 26.7 years, 0.83-79.5 years, 67.9% female). The success rate for the optimal placement of the VC with grade I on the Hayhurst scale was significantly higher in the SG group (93.1%) than in the FH group (60.7%), p = 0.012. The revision rate was higher in the FH group with 35.7% versus 20.7% in the SG group, p = 0.211. CONCLUSION: VC placement using the SG technique is a safe and effective procedure, which enabled a significantly higher success rate and lower revision and complication rate. Accordingly, we recommend using the SG technique especially in patients with difficult anatomy.

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia.

BACKGROUND: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. RESULTS: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. CONCLUSION: An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01422499. Registered 24 August 2011.

Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma.

Nonresectable ependymomas are associated with poor prognosis despite intensive radiochemotherapy and radiation. The molecular pathogenesis of ependymoma initiation and progression is largely unknown. We here present a case of therapy-refractory, progressive ependymoma with cerebrospinal as well as extraneural metastases, which allowed us for the first time to follow the stepwise accumulation of chromosome aberrations during disease progression. Genome-wide DNA copy-number analysis showed sequential deletions on chromosomes 1, 9, and 14 as well as a homozygous deletion of the CDKN2A locus, underscoring its role in tumor progression. Gradual loss at 1p36 was associated with loss of protein expression of the putative tumor suppressor gene AJAP1/SHREW1. In summary, this is the first report on acquired genomic aberrations in ependymoma over time pointing to novel candidate tumor suppressor genes. This analysis provides molecular insights into the chronology of genetic events in this case from initial localized tumor to widespread metastasized disease.

EEG and MEG source analysis of single and averaged interictal spikes reveals intrinsic epileptogenicity in focal cortical dysplasia.

PURPOSE: Simultaneous interictal EEG and magnetoencephalography (MEG) recordings were used for noninvasive analysis of epileptogenicity in focal cortical dysplasia (FCD). The results of two different approach methods (multiple source analysis of averaged spikes and single dipole peak localization of single spikes) were compared with pre- and postoperative anatomic magnetic resonance imaging (MRI). PATIENTS: We studied nine children and adolescents (age, 3.5-15.9 years) with localization-related epilepsy and FCD diagnosis based on MRI. Five patients underwent epilepsy surgery, two of them after long-term recording with subdural grid electrodes, and one after intraoperative electrocorticography. METHODS: The 122-channel whole-head MEGs and 33-channel EEGs were recorded simultaneously for 25 to 40 min. Interictal spikes were identified visually and used as templates to search for similar spatiotemporal spike patterns throughout the recording. With the BESA program, similar spikes (r > 0.85) were detected, averaged, high-pass filtered (5 Hz) to enhance spike onset, and subjected to multiple spatiotemporal source analysis with a multishell spherical head model. Peak activity from single spikes was modeled by single dipoles for the same subset of spikes. Source localization was visualized by superposition on T1-weighted MRI and compared with the lesion identified in T1- and T2-weighted MRI. In the five cases undergoing epilepsy surgery, the results were correlated with invasive recordings, postoperative MRI, and outcome. RESULTS: In all cases, the analysis of averaged spikes showed a localization of onset- and peak-related sources within the visible lesion for both EEG and MEG. Of the single spikes, 128 (45%; total 284) were localizable at the peak in MEG, and 170 (60%) in EEG. Of these, 91% localized within the lesion with MEG, and 93.5% with EEG. In three of five patients operated on, the resected area included the onset zones of averaged EEG and MEG spike activity. These patients had excellent postoperative outcome, whereas the others did not become seizure free. CONCLUSIONS: Consistent MEG and EEG spike localization in the lesional zone confirmed the hypothesis of intrinsic epileptogenicity in FCD.