Clinical impact of the dose and blood concentration of lacosamide in Japanese pediatric patients with epilepsy: A cohort study.

PURPOSE: The relationship between treatment efficacy/tolerability and the dose/blood concentration of lacosamide (LCM) was investigated in a clinical cohort of Japanese pediatric patients with epilepsy. METHODS: This retrospective analysis reviewed the medical records of patients treated with LCM for >6 months at the Department of Pediatrics, Hiroshima University Hospital, from September 2017 to January 2021. The collected data included age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events leading to LCM discontinuation, dose at any evaluation point, serum concentration, and concomitant antiepileptic drugs (AEDs). RESULTS: The study included 51 patients (31 male patients) between the ages of 2 and 19 years. All patients were Japanese. Epilepsy was classified as focal in 44 patients, generalized in six patients, and combined generalized and focal in one patient. The 50% responder rate for LCM treatment was 56.9%. Seven patients experienced complete seizure control (absence of seizures for 6 months before the follow-up visit). A relationship between dose and blood concentration was identified. Although the blood LCM concentration was higher in the responders than in the nonresponders (7.86 vs. 6.16 µg/mL; p = 0.028), there was no significant difference in dose between the two groups. Lacosamide showed efficacy at a dose >5 mg/kg/day in more than half of the 50% responders. The treatment-emergent adverse events (TEAEs) included seizure aggravation in five patients, irritability in two patients, and somnolence and drug eruption in one patient each. In six patients with TEAEs, the TEAEs developed within 1 month after treatment initiation and led to LCM discontinuation. CONCLUSION: In Japanese pediatric patients with epilepsy, LCM treatment is effective, particularly at higher doses. The blood concentration may be related more to efficacy than to dose. Lacosamide is generally well-tolerated by pediatric patients, and should be used at the maximum tolerable dose (needed to be gradually increased) in patients with otherwise insufficient seizure control. As TEAEs leading to discontinue treatment likely occur in early phase, it is needed to monitor patients carefully if TEAEs would happen in that phase.

Fractionated Stereotactic Intensity-Modulated Radiotherapy for Large Brain Metastases: Comprehensive Analyses of Dose-Volume Predictors of Radiation-Induced Brain Necrosis.

BACKGROUND: The objective was to explore dosimetric predictors of brain necrosis (BN) in fractionated stereotactic radiotherapy (SRT). METHODS: After excluding collinearities carefully, multivariate logistic models were developed for comprehensive analyses of dosimetric predictors in patients who received first-line fractionated SRT for brain metastases (BMs). The normal brain volume receiving an xx Gy biological dose in 2 Gy fractions (VxxEQD2) was calculated from the retrieved dose-volume parameters. RESULTS: Thirty Gy/3 fractions (fr) SRT was delivered to 34 patients with 75 BMs (median target volume, 3.2 cc), 35 Gy/5 fr to 30 patients with 57 BMs (6.4 cc), 37.5 Gy/5 fr to 28 patients with 47 BMs (20.2 cc), and 40 Gy/10 fr to 20 patients with 37 BMs (24.3 cc), according to protocols, depending on the total target volume (p < 0.001). After excluding the three-fraction groups, the incidence of symptomatic BN was significantly higher in patients with a larger V50EQD2 (adjusted odds ratio: 1.07, p < 0.02), V55EQD2 (1.08, p < 0.01), or V60EQD2 (1.09, p < 0.01) in the remaining five- and ten-fraction groups. The incidence of BN was also significantly higher in cases with V55EQD2 > 30 cc or V60EQD2 > 20 cc (p < 0.05). These doses correspond to 28 or 30 Gy/5 fr and 37 or 40 Gy/10 fr, respectively. CONCLUSIONS: In five- or ten-fraction SRT, larger V55EQD2 or V60EQD2 are BN risk predictors. These biologically high doses may affect BN incidence. Thus, the planning target volume margin should be minimized as much as possible.

Evaluation of cerebrospinal fluid biomarkers in pediatric patients with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterised by muscle weakness and muscle atrophy and classified into five known subtypes based on clinical features. The recent development of novel drugs to treat SMA has been encouraging, and nusinersen is the first drug approved to treat SMA. OBJECTIVE: To explore cerebrospinal fluid (CSF) biomarkers of SMA and investigate their relationship with symptoms and the treatment response in pediatric patients. METHODS: We analyzed the CSF levels of chitotriosidase 1 (CHIT1) and inflammatory cytokines (tumor necrosis factor [TNF]-α and interferon [INF]-γ) using enzyme-linked immunosorbent assays in pediatric SMA patients treated at Hiroshima University Hospital over 2 years. RESULTS: This study analyzed pediatric SMA patients. While the CSF inflammatory cytokines (TNF-α and INF-γ) in these SMA children were unchanged, the CHIT1 levels decreased significantly from year 1 to 2 of treatment. We also found a trend toward an inverse correlation between the motor function score (HINE-2 scores) and CHIT1 level from year 1 to 2 of treatment. CONCLUSIONS: CHIT1 may be a CSF biomarker of the treatment response in pediatric SMA.

Effect of Lacosamide therapy on blood cells and IgA levels in children and adolescents with epilepsy in a clinical setting.

INTRODUCTION: Lacosamide (LCM) is a third-generation antiepileptic drug (AED) that affects sodium channel inactivation. AEDs can affect multiple organ systems and blood parameters. Carbamazepine (CBZ) reportedly affects blood sodium, lipid, and immunoglobulin levels and thyroid function. Despite multiple studies on the adverse effects of AEDs, few reports have discussed the impact of LCM on blood parameters. The purpose of this study was to clarify the effects of LCM on blood parameters. METHODS: We retrospectively examined the medical records of 15 children and adolescents in whom LCM was initiated between April 2017 and March 2021, 6 and 12 months after treatment initiation. Blood cell counts, biochemical and thyroid function, and immunoglobulin levels were investigated at baseline and 6 and 12 months after initiation of LCM. RESULTS: Neutrophil levels were significantly reduced 12 months after LCM initiation (p = 0.0046); however, the value was not abnormal. Immunoglobulin A was significantly elevated 6 and 12 months after LCM initiation (p = 0.0078 and 0.020, respectively). No significant difference was identified in the other parameters. Electrolyte and lipid levels and thyroid function remained unaffected, unlike with CBZ. CONCLUSIONS: LCM may affect the immune system, as well as hematological parameters. Further investigation with larger samples is required in the future to assess the clinical impact.

[Analysis of photonuclear activation effect of high-energy medical linear accelerators--measurement of spatial dose distribution and temporal decay curve, and assessment of personnel dosimetry].

The characteristics of activation after high-energy X-rays have been generated by medical linear accelerators were measured using an ionization chamber. Radiation doses increased with rising X-ray energy, based on 10 MV, 15 MV, and 18 MVX-ray measurements. When the total irradiation dose was changed, radiation dose increased with total irradiation dose. When the collimator opened, the radiation dose at a position 15 cm from the isocenter reached about the maximum, which was 2.2 times the dose at the isocenter. The radiation dose became about 0.3 times its level at a position 40 cm from the isocenter, in the outer irradiation field. The dose distribution in the treatment room became almost the same dose extending from the isocenter to 200 cm. Radiation dose decreased gradually while moving away from the target on the treatment beam axis. But it increased again as it approached the floor face. The occupational exposure dose, which was presumed from measurements of the radiation dose 50 cm from the isocenter, was about 0.9 mSv during a year, assuming 600 MU for 1 person, 8 people a day, and 245 days a year. Radiation dose changed with X-ray energy in the machine used, and it was a geometrical constituent in the treatment room. It is important to understand the characteristics of radiation generated by medical linear accelerators.

Relationship between radiation doses to heart substructures and radiation pneumonitis in patients with thymic epithelial tumors.

Radiation doses to the heart are potentially high in patients undergoing radiotherapy for thymoma or thymic carcinoma because of their origin site and propensity for pericardial invasion. We investigated potential relationships between radiation pneumonitis (RP) and the dosimetric parameters of lung and heart substructures in patients with thymic epithelial tumors. This retrospective study included 70 consecutive patients who received definitive or postoperative radiotherapy at a median dose of 58.3 Gy. Heart substructures were delineated according to a published atlas. The primary end point of ≥ grade 2 RP was observed in 13 patients (19%) despite a low lung dose; median lung V20 (i.e. percentage of the volume receiving at least 20 Gy) was only 16.6%. In a univariate analysis, four lung parameters, heart V35, three pulmonary artery (PA) parameters, two left ventricle parameters, and left atrium V35 were associated with the development of RP. In a multivariate analysis, only PA V35 remained significant (hazard ratio 1.04; 95% CI 1.01-1.07, p = 0.007). PA V35 of the RP versus non-RP groups were 84.2% versus 60.0% (p = 0.003). The moderate dose sparing of PA could be a candidate as a planning constraint for reducing the risk of RP in thoracic radiotherapy.

Geometric discrepancy of image-guided radiation therapy in patients with prostate cancer without implanted fiducial markers using a commercial pseudo-CT generation method.

MR-only simulations provide pseudo-CT images which are segmented into 5 kinds of tissues from DIXON-based images. However, it is difficult to register pseudo-CT images to cone-beam CT (CBCT) images collected for image-guided radiation therapy (IGRT), because of the lack of contrasts among tissues. We validated gaps of IGRT between pseudo-CT or planning CT and CBCT for patients without implanted markers. We also propose calcification-assisted registration for MR-only simulation. We conducted retrospective analyses to verify the registration accuracy in 15 patients who underwent volumetric modulated arc therapy (VMAT) for prostate cancer. They underwent planning CT and pseudo-CT. Pseudo-CT images after deformable image registration (DIR) to planning CT images were rendered automatic pelvic bone matching to CBCT images. Patient positions on the pseudo-CT images after DIR were shifted on the basis of tissues around the prostate. We compared registration gaps between the images of planning CT and pseudo-CT with DIR, assuming that the tissue-based matching between the planning CT and CBCT was the gold standard. To the pseudo-CT images with DIR, calcifications detected on planning CT were added. We validated IGRT accuracy for a calcification-assisted registration. The absolute registration errors of the pseudo-CT, in comparison with the planning CT, were 0.34 ± 0.50 (lateral), 1.3 ± 1.3 (longitudinal), and 1.1 ± 1.0 mm (vertical). The absolute registration errors of the pseudo-CT with calcification contouring, in comparison with the planning CT, were 0.41 ± 1.0 (lateral), 0.87 ± 0.92 (longitudinal), and 0.74 ± 0.64 mm (vertical). Reduced absolute registration errors were observed in the proposed approach in the longitudinal (P < 0.01) and vertical (P < 0.01) dimensions when using calcification-assisted registration. The tissue-based registration using the MR-only simulation was not sufficient for use in patients with prostate cancer without implanted markers. The calcification-assisted registration might help to improve IGRT accuracy using MRI alone.