Cathepsin B-Activated PET Tracer for In Vivo Tumor Imaging.

Cathepsin B, a lysosomal protease, is considered as a crucial biomarker for tumor diagnosis and treatment as it is overexpressed in numerous cancers. A stimulus-responsive SF scaffold has been reported to detect the activity of a variety of tumor-associated enzymes. In this work, a small-molecule PET tracer ([68Ga]NOTA-SF-CV) was developed by combining an SF scaffold with a cathepsin B-specific recognition substrate Cit-Val. Upon activation by cathepsin B, [68Ga]NOTA-SF-CV could form the cyclization product in a reduction environment, resulting in reduced hydrophilicity. This unique property could effectively prevent exocytosis of the tracer in cathepsin B-overexpressing tumor cells, leading to prolonged retention and amplified PET imaging signal. Moreover, [68Ga]NOTA-SF-CV had great targeting specificity to cathepsin B. In vivo microPET imaging results showed that [68Ga]NOTA-SF-CV was able to effectively visualize the expression level of cathepsin B in various tumors. Hence, [68Ga]NOTA-SF-CV may be served as a potential tracer for diagnosing cathepsin B-related diseases.

Preclinical evaluation of 68 Ga-labeled peptide CK2 for PET imaging of NRP-1 expression in vivo.

PURPOSE: Neuropilin-1 (NRP-1) is a multifunctional protein involved in a variety of biological processes such as angiogenesis, tumorigenesis and immunomodulation. It was usually overexpressed in many cancer cell lines and correlated with poor prognosis of breast cancer. Positron emission tomography (PET) is an advanced imaging technique for detecting the function and metabolism of tumor-associated molecules in real time, dynamically, quantitatively and noninvasively. To improve the level of early diagnosis and evaluate the prognosis of breast cancer, an NRP-1 targeting peptide-based tracer [68 Ga]Ga-NOTA-PEG4-CK2 was designed to sensitively and specifically detect the NRP-1 expression in vivo via PET imaging. METHODS: In silico modeling and microscale thermophoresis (MST) assay were carried out to design the NRP-1 targeting peptide NOTA-PEG4-CK2, and it was further radiolabeled with 68 Ga to prepare the tracer [68 Ga]Ga-NOTA-PEG4-CK2. The radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), lipid-water partition coefficient (Log P) and stability of [68 Ga]Ga-NOTA-PEG4-CK2 were assessed. The targeting specificity of the tracer for NRP-1 was investigated by in vitro cellular uptake assay and in vivo PET imaging as well as blocking studies. The sensitivity of the tracer in monitoring the dynamic changes of NRP-1 expression induced by chemical drug was also investigated in vitro and in vivo. Ex vivo biodistribution, autoradiography, western blot, and immunofluorescence staining were also performed to study the specificity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1. RESULTS: [68 Ga]Ga-NOTA-PEG4-CK2 was designed and synthesized with high RCY (> 98%), high stability (RCP > 95%) and high affinity to NRP-1 (KD = 25.39 ± 1.65 nM). In vitro cellular uptake assay showed that the tracer [68 Ga]Ga-NOTA-PEG4-CK2 can specifically bind to NRP-1 positive cancer cells MDA-MB-231 (1.04 ± 0.04% at 2 h) rather than NRP-1 negative cancer cells NCI-H1299 (0.43 ± 0.05%). In vivo PET imaging showed the maximum tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 in MDA-MB-231 xenografts (4.16 ± 0.67%ID/mL) was significantly higher than that in NCI-H1299 xenografts (1.03 ± 0.19%ID/mL) at 10 min post injection, and the former exhibited higher tumor-to-muscle uptake ratio (5.22 ± 0.18) than the latter (1.07 ± 0.27) at 60 min post injection. MDA-MB-231 xenografts pretreated with nonradioactive precursor NOTA-PEG4-CK2 showed little tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 (1.67 ± 0.38%ID/mL at 10 min post injection). Both cellular uptake assay and PET imaging revealed that NRP-1 expression in breast cancer MDA-MB-231 could be effectively suppressed by SB-203580 treatment and can be sensitively detected by [68 Ga]Ga-NOTA-PEG4-CK2. Ex vivo analysis also proved the high specificity and sensitivity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1 expression in MDA-MB-231 xenografts. CONCLUSION: A promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was successfully prepared. It showed remarkable specificity and sensitivity in monitoring the dynamic changes of NRP-1 expression. Hence, it could provide valuable information for early diagnosis of NRP-1 relevant cancers and evaluating the prognosis of cancer patients.

ß-Galactosidase-Activated and Red Light-Induced RNA Modification Strategy for Prolonged NIR Fluorescence/PET Bimodality Imaging.

Improving the retention of small-molecule-based therapeutic agents in tumors is crucial to achieve precise diagnosis and effective therapy of cancer. Herein, we propose a ß-galactosidase (ß-Gal)-activated and red light-induced RNA modification (GALIRM) strategy for prolonged tumor imaging. A ß-Gal-activatable near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe 68Ga-NOTA-FCG consists of a triaaza triacetic acid chelator NOTA for 68Ga-labeling, a ß-Gal-activated photosensitizer CyGal, and a singlet oxygen (1O2)-susceptible furan group for RNA modification. Studies have demonstrated that the probe emits an activated NIR FL signal upon cleavage by endogenous ß-Gal overexpressed in the lysosomes, which is combined with the PET imaging signal of 68Ga allowing for highly sensitive imaging of ovarian cancer. Moreover, the capability of 68Ga-NOTA-FCG generating 1O2 under 690 nm illumination could be simultaneously unlocked, which can trigger the covalent cross-linking between furan and nucleotides of cytoplasmic RNAs. The formation of the probe-RNA conjugate can effectively prevent exocytosis and prolong retention of the probe in tumors. We thus believe that this GALIRM strategy may provide entirely new insights into long-term tumor imaging and efficient tumor treatment.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Long-term seizure and developmental outcomes of epilepsy surgery in children under 3 years old: A single-center study of 113 patients.

AIMS: To investigate the clinical characteristics, surgical strategy, developmental and seizure outcomes, and predictors of surgical outcome in children with drug-resistant epilepsy (DRE) under 3 years old. METHODS: One hundred thirteen consecutive children younger than 3 years of age with DRE underwent curative surgical treatment after multidisciplinary preoperative evaluation using the strategy developed in the pediatric epilepsy center of Peking University First Hospital (PKFHPEC) between 2014 and 2018. These patients were selected for retrospective study. The relevant clinical data were collected and analyzed. The surgical prognoses were classified using the Engel classification, and the developmental assessment results were collected. Statistical analysis of the clinical data was performed to analyze the predictors of seizure outcomes and their correlation with developmental outcomes. RESULTS: All the patients were followed up for more than 3 years, and 98 (86.7%) patients had no seizure recurrence. One year after surgery, the seizure-free rate was 86.7%, which was as high as that at the last follow-up. Cortical dysplasia was the most frequent etiology of DRE in this cohort, accounting for 77.0%. According to the Engel classification, acute postoperative seizure (APOS; p < 0.001) was a predictor of seizure recurrence. No deaths occurred. No unpredicted long-term severe complications occurred except for one ventricular peritoneal shunt. The patients' neurodevelopmental statuses were improved after successful surgery, while the scores of the pre- and postoperative developmental assessments were closely correlated. CONCLUSIONS: For children who are younger than 3 years old and have DRE and structural abnormalities, early curative treatment can lead to long-term good seizure outcomes and a low complication rate. The development of appropriate strategies for both presurgical evaluation and resection is crucial for the success of surgery.

Multifunctional Probe Based on "Chemical Antibody-Aptamer" for Noninvasive Detection of PD-L1 Expression in Cancer.

Immune checkpoint inhibitors (ICIs) therapy based on programmed cell death ligand 1 (PD-L1) has shown significant development in treating several carcinomas, but not all patients respond to this therapy due to the heterogeneity of PD-L1 expression. The sensitive and accurate quantitative analysis of in vivo PD-L1 expression is critical for treatment decisions and monitoring therapy. In the present study, an aptamer-based dual-modality positron emission tomography/near-infrared fluorescence (PET/NIRF) imaging probe was developed, and its specificity and sensitivity to PD-L1 were assessed in vitro and in vivo. The probe precursor NOTA-Cy5-R1 was prepared by using automated solid-phase oligonucleotide synthesis. PET/NIRF dual-modality probe [68Ga]Ga-NOTA-Cy5-R1 was successfully synthesized and radiolabeled. The binding specificity of [68Ga]Ga-NOTA-Cy5-R1 to PD-L1 was evaluated by flow cytometry, fluorescence imaging, and cellular uptake in A375-hPD-L1 and A375 cells, and it showed good fluorescence properties and stability in vitro. In vivo PET/NIRF imaging studies illustrated that [68Ga]Ga-NOTA-Cy5-R1 can sensitively and specifically bind to PD-L1 positive tumors. Meanwhile, the rapid clearance of probes from nontarget tissues achieved a high signal-to-noise ratio. In addition, changes of PD-L1 expression in NCI-H1299 xenografts treated with cisplatin (CDDP) were sensitivity monitored by [68Ga]Ga-NOTA-Cy5-R1 PET imaging, and ex vivo autoradiography and western blot analyses correlated well with the change of PD-L1 expression in vivo. Overall, [68Ga]Ga-NOTA-Cy5-R1 showed notable potency as a dual-modality PET/NIRF imaging probe for visualizing tumors and monitoring the dynamic changes of PD-L1 expression, which can help to direct and promote the clinical practice of ICIs therapy.

Surgical treatment for drug-resistant epilepsy due to early brain injury in children.

BACKGROUND: The study aimed to summarize the indications and clinical features of pediatric drug-resistant epilepsy associated with early brain injury, surgical outcomes, and prognostic factors. METHODS: We retrospectively analyzed children diagnosed with drug-resistant epilepsy due to early brain injury, who had undergone surgery at the Pediatric Epilepsy Center of Peking University First Hospital from May 2014 to May 2021. Clinical data of vasculogenic and non-vasculogenic injuries from early brain damage were compared and analyzed. The surgical outcomes were assessed using the Engel grading system. RESULTS: The median ages at acquiring injury, seizure onset, and surgery among 65 children were 19.0 (0-120) days, 8.6 (0-136.5) months, and 62.9 (13.5-234) months, respectively. Of the 14 children with non-vasculogenic injuries, 12 had posterior ulegyria. Unilateral or bilateral synchronous interictal epileptiform discharges were located mainly in the posterior quadrant in 10 children (71 %), and unilateral posterior quadrant or non-lateralized ictal region in eight children (57 %). The surgical approach was mainly temporo-parieto-occipital or parieto-occipital disconnection in nine children. Of 49 children with vasculogenic injuries, magnetic resonance imaging revealed hemispheric abnormalities in 38. Unilaterally hemispheric or bilateral interictal epileptiform discharges were observed in 36 children (73 %), whereas 42 (86 %) had unilateral hemispheric or non-lateralized ictal onset. The surgical procedure involved hemispherotomy in 38 children (78 %) and lobectomy or disconnection, multilobectomy or disconnection and hemispherotomy in 5, 20, and 40 children, respectively. Fifty-five patients (84.6 %) achieved remission from seizure during follow-up at 5.4 years. Age at surgery (odds ratio = 1.022, 95 % confidence interval = 1.003-1.042, P = 0.023) and etiology (odds ratio = 17.25, 95 % confidence interval = 2.778-107.108, P = 0.002) affected the seizure outcomes. CONCLUSION: Children with drug-resistant epilepsy due to early brain injury can successfully be treated with surgery after rigorous preoperative screening. Good surgical outcomes are associated with an early age at surgery and an etiology of vasculogenic injury.

Epilepsy Outcome and Pathology Analysis for Ganglioglioma: A Series of 51 Pediatric Patients.

BACKGROUND: The postoperative epilepsy outcome and clinicopathological features in children with ganglioglioma (GG) are not well understood. METHODS: Data from 51 consecutive pediatric patients diagnosed with GGs who underwent surgery were collected. The correlations between the expression of CD34 and BRAF V600E mutations and clinical features were analyzed. The related factors affecting the outcome of epilepsy were analyzed. RESULTS: The average follow-up was 44.2 months, and 48 patients were seizure-free. A high proportion of BRAF V600E mutation (78.8%) and CD34 expression (77.8%) was detected in GG. The onset age of epilepsy with the BRAF V600E mutation was earlier than that without. The expression of CD34 increased with the age of onset, the duration of epilepsy, and the age of operation. Focal cortical dysplasia (FCD) I was found in 62.7% of patients, and FCD II was found in 11.8% of patients approximately in the cortex surrounding GG. There was no significant correlation between the outcome of epilepsy and BRAF V600E mutation, CD34 expression, and combination with FCD. CONCLUSIONS: The overall outcome of GG and epilepsy in children is optimistic, and the outcome is not closely related to the presence of BRAF V600E mutation and CD34 (+). The FCD surrounding GG could be type I or type II. Incomplete resection of the surrounding FCD has the risk of unsatisfactory control of epilepsy. Children with the BRAF V600E mutation may be prone to early-onset epilepsy. The expression of CD34 is more likely to be detected in children with older age and a long duration of epilepsy.

M4IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit colon cancer cells.

Maintaining redox homeostasis is an essential feature of cancer cells, and disrupting this homeostasis to cause oxidative stress and induce cell death is an important strategy in cancer therapy. M4IDP, a zoledronic acid derivative, can cause the death of human colorectal cancer cells by increasing the level of intracellular reactive oxygen species (ROS). However, its potential molecular mechanism is unclear. Our in vitro studies showed that treatment with M4IDP promoted oxidative stress in HCT116 cells, as measured by the decreased ratios of GSH/GSSG and NADPH/NADP+ and increased level of MDA. M4IDP could cause the decrease of GSH content, the increase of GSSG content, the decrease of NADPH content and pentose phosphate pathway flux, the downregulation of G6PD expression, the upregulation of unprenylated Rap1A and total expression of RhoA and CDC42. The increase of ROS and cytotoxicity induced by M4IDP could be reversed by the supplementation of NADPH, the overexpression of G6PD and the supplementation of GGOH. In vivo studies showed that M4IDP inhibited tumor growth in the human colorectal cancer xenograft mouse model, which was accompanied with a decreased [18F]FDG uptake. Collectively, these results provide evidence that M4IDP can promote oxidation in colon cancer cells by inhibiting mevalonate pathway and pentose phosphate pathway and produce therapeutic effect. This study revealed for the first time a possible mechanism of bisphosphonate-induced increase of ROS in malignant tumor cells. This is helpful for the development of new molecular therapeutic targets and can provide new ideas for the combined therapy of bisphosphonates in tumors.

Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors.

Nowadays, one of the most effective methods of tumor immunotherapy is blocking programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) immune checkpoints. However, there is still a significant challenge in selecting patients to benefit from immune checkpoint therapies. Positron emission tomography (PET), a noninvasive molecular imaging technique, offers a new approach to accurately detect PD-L1 expression and allows for a better prediction of response to PD-1/PD-L1 target immunotherapy. Here, we designed and synthesized a novel group of aryl fluorosulfate-containing small-molecule compounds (LGSu-1, LGSu-2, LGSu-3, and LGSu-4) based on the phenoxymethyl-biphenyl scaffold. After screening by the time-resolved fluorescence resonance energy transfer (TR-FRET) assay, the most potent compound LGSu-1 (half maximal inhibitory concentration (IC50): 15.53 nM) and the low-affinity compound LGSu-2 (IC50: 189.70 nM) as a control were selected for 18F-radiolabeling by sulfur(VI) fluoride exchange chemistry (SuFEx) to use for PET imaging. [18F]LGSu-1 and [18F]LGSu-2 were prepared by a one-step radiofluorination reaction in over 85% radioconversion and nearly 30% radiochemical yield. In B16-F10 melanoma cell assays, [18F]LGSu-1 (5.00 ± 0.06%AD) showed higher cellular uptake than [18F]LGSu-2 (2.55 ± 0.04%AD), in which cell uptake could be significantly blocked by the nonradioactivity LGSu-1. In vivo experiments, micro-PET imaging of B16-F10 tumor-bearing mice and radiographic autoradiography of tumor sections showed that [18F]LGSu-1 was more effectively accumulated in the tumor due to the higher binding affinity with PD-L1. The above experimental results confirmed the potential of the small-molecule probe LGSu-1 as a targeting PD-L1 imaging tracer in tumor tissues.

Exolaccase Propels Humification to Decontaminate Bisphenol A and Create Humic-like Biostimulants.

Exolaccase-propelled humification (E-PH) helps eliminate phenolic pollutants and produce macromolecular precipitates. Herein, we investigated the influencing mechanism of 12 humic precursors (HPs) on exolaccase-enabled bisphenol A (BPA) decontamination and humification. Catechol, vanillic acid, caffeic acid, and gentian acid not only expedited BPA removal but also created large amounts of copolymeric precipitates. These precipitates had rich functional groups similar to natural humic substances, which presented great aromatic and acidic characteristics. The releasing amounts of BPA monomer from four precipitates were 0.08-12.87% at pH 2.0-11.0, suggesting that BPA-HP copolymers had pH stability. More excitingly, certain copolymeric precipitates could stimulate the growth and development of radish seedlings. The radish growth-promotion mechanisms of copolymers were involved in two aspects: (1) Copolymers interacted with root exudates to accelerate nutrient uptake; (2) Copolymers released auxins to provoke radish growth. These results may provide an innovative strategy for decontaminating phenolic pollutants and yielding humic-like biostimulants in E-PH.

Seizure features and outcomes in 50 children with GATOR1 variants: A retrospective study, more favorable for epilepsy surgery.

OBJECTIVES: To summarize the clinical features of epilepsy related to DEPDC5, NPRL2, and NPRL3 genes encoding the GATOR1 complex in children and to evaluate the factors affecting the prognosis of these epilepsies. METHODS: In this retrospective study, we reviewed the clinical and genetic characteristics of children with epilepsy related to GATOR1 variants who were admitted to the Peking University First Hospital between January 2016 and December 2021. Potential prognostic factors were assessed by comparing children with and without ongoing seizures. RESULTS: Fifty probands, including 31 boys and 19 girls were recruited. The median age at onset of epilepsy was 4 months, and 64% of patients had early-onset epilepsy (≤1 year). The most frequent epileptic seizure type was focal seizure (86%). Among the 50 patients, only six were with de novo variants. According to the novel classification framework for GATOR1 variants, 36 patients were with pathogenic variants and 14 with likely pathogenic variants. DEPDC5 variants were found in 37 patients, NPRL3 in 9, and NPRL2 in 4. The phenotype was similar among the probands, with variants in DEPDC5, NRPL2, or NPRL3. 76% (38/50) of epilepsy related to GATOR1 variants was neuroimaging positive, including brain MRI positive in 31 patients, and MRI combined F-18-fluorodeoxyglucose positron emission tomography positive in the other seven patients. Twenty-seven patients underwent epilepsy surgery. In total, after initial antiseizure medications alone, 92% (46/50) of patients were drug-resistant epilepsies, only 8% (4/50) of the probands became seizure-free but seizure-free (≥6 m) occurred in 92.6% (25/27) of patients with drug-resistant epilepsy after epilepsy surgery at the last follow-up. Patients undergoing epilepsy surgery had better epilepsy prognosis. SIGNIFICANCE: Epilepsy related to GATOR1 variants had high possibility to be drug-resistant epilepsy and to have positive neuroimaging finding. Epilepsy surgery is the only favorable factor for better seizure prognosis in this kind epilepsy.

Disconnection Surgery in Pediatric Epilepsy: A Single Center's Experience With 185 Cases.

BACKGROUND AND OBJECTIVES: Lobar and multilobar disconnections have gradually become common surgical methods in pediatric epilepsy surgery in recent years. However, the surgical procedures, postoperative epilepsy outcomes, and complications reported by each center are quite different. To review and analyze the clinical data from lobar disconnection in treating intractable pediatric epilepsy and study the characteristics, surgical outcomes, and safety of different disconnection surgeries. METHODS: This was a retrospective analysis of 185 children with intractable epilepsy who underwent various lobar disconnections at the Pediatric Epilepsy Center, Peking University First Hospital. Clinical information was grouped according to their characteristics. The differences in the abovementioned characteristics among the different lobar disconnections were summarized, and risk factors affecting the surgical outcome and postsurgical complications were explored. RESULTS: Among the 185 patients, 149 patients (80.5%) achieved seizure freedom with a follow-up of 2.1 years. There were 145 patients (78.4%) with malformations of cortical development (MCD). The seizure onset time (median 6 months, P = .001) and surgery time (median 34 months, P = .000) of the MCD group were smaller. Differences were found in etiology, resection of the insular lobe and epilepsy outcome among different disconnection approaches. Both parieto-occipital disconnection ( P = .038, odds ratio = 8.126) and MRI abnormalities larger than the disconnection extent ( P = .030, odds ratio = 2.670) affected the epilepsy outcome. Early postoperative complications were observed in 43 patients (23.3%), and long-term postoperative complications were observed in 5 patients (2.7%). CONCLUSION: The most common etiology of epilepsy in children undergoing lobar disconnection is MCD, whose onset and operative ages are the youngest. Disconnection surgery obtained good seizure outcomes in the treatment of pediatric epilepsy with a low incidence of long-term complications. With advances in presurgical evaluation, disconnection surgery will play a more important role in young children with intractable epilepsy.

Clinical characteristics and surgical outcomes in children with mild malformation of cortical development and oligodendroglial hyperplasia in epilepsy.

OBJECTIVE: Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new and rare histopathological entity of cortical developmental malformations. The clinical characteristics of MOGHE remain challenging. METHODS: Children with histologically confirmed MOGHE were retrospectively studied. The clinical findings, electroclinical and imaging features, and postoperative outcomes were analyzed, and previously published studies were reviewed up to June 2022. RESULTS: Thirty-seven children were included in our cohort. Clinical characteristics included early onset in infancy (94.6% before 3 years), multiple seizure types, and moderate or severe delay. Epileptic spasm is the most common seizure type and initial manifestation. The lesions were mainly multilobar (59.5% multiple lobes and 8.1% hemispheres), and predominance in the frontal lobe was observed. The interictal EEG pattern was circumscribed or widespread. The prominent MRI characteristics were cortical thickening, cortical/subcortical hyperintense T2/FLAIR signal, and blurring at the GM and WM transition. Among the 21 children followed up for more than 1 year after surgery, 76.2% were seizure-free. Preoperative interictal circumscribed discharges and larger resections were significantly associated with a good postoperative outcome. The clinical features of 113 patients in the reviewed studies were similar to those we reported, but the lesions were mainly unilobar (73.5%) and Engel I was achieved in only 54.2% after surgery. SIGNIFICANCE: Distinct clinical characteristics in MOGHE, especially age at onset, epileptic spasm, and age-related MRI characteristics, can help in early diagnosis. Preoperative interictal discharge and surgical strategy may be predictors of postoperative outcomes.

Pediatric epilepsy surgery in patients with Lennox-Gastaut syndrome after viral encephalitis.

Objective: To analyse the surgical outcomes of pediatric patients with Lennox-Gastaut syndrome (LGS) secondary to viral encephalitis. Methods: We retrospectively analyzed the data of four patients with LGS secondary to viral encephalitis who underwent surgery at the pediatric epilepsy center of Peking University First Hospital from January 2014 to December 2019. Preoperative evaluations included a detailed history, long-term video electroencephalography (VEEG), brain magnetic resonance imaging (MRI), positron emission tomography (PET) and a neuropsychological test. All patients were followed up at 1, 3, and 6 months and then yearly. The surgical outcome was evaluated according to the Engel classification. Results: Among the four children, the surgeries were right temporo-parieto-occipital disconnection (case 1), corpus callosotomy (case 2), left temporo-parieto-occipital disconnection (case 3), and left temporal lobectomy (case 4). The pathology was gliosis secondary to viral encephalitis. The median follow-up time was 4 years (3-5 years). At the last follow-up, one case had Engel I, two cases had Engel III, and one case had Engel IV. Conclusions: Preliminary observations shows that surgical treatment may be challenging for patients with LGS secondary to viral encephalitis. However, suitable surgical candidacy and approaches have a significant impact on the prognosis of the patients.

Efficacy of vagus nerve stimulation in 95 children of drug-resistant epilepsy with structural etiology.

Vagus nerve stimulation (VNS) is one of the treatment options for drug-resistant epilepsy (DRE). To analyze the efficacy of VNS in children of DRE with structural etiology, we conducted a cohort study including 95 patients of DRE with structural etiology who underwent VNS treatment. Patients were followed up every 3 months at the outpatient department or via a remote programming platform. The median follow-up period was 2.6 years (range 1.0-4.6 years). The respective responder rates at 6, 12, 18, and 24 months of follow-up were 40.0% (38/95), 52.6% (50/95), 56.0% (47/84), and 59.7% (37/62). The respective seizure-free rates at 12, 18, and 24 months of follow-up were 8.4% (8/95), 9.5% (8/84), and 9.7% (6/62). The patients were divided into four groups based on etiologies: malformations of cortical development (n = 26), post-encephalitic lesions (n = 36), perinatal brain injury lesions (n = 31), and hippocampal sclerosis (n = 2). The respective responder rates at 12 months of follow-up in these groups were 53.8% (14/26), 52.8% (19/36), 51.6% (16/31), and 50.0% (1/2). There were no significant differences in gender, age at onset, age at stimulator implantation, epilepsy duration prior to VNS implantation, number of anti-seizure medications ever tried before VNS treatment, pulse amplitude of VNS, specific structural etiologies, lobe distribution or hemispheric side of structural lesions between responders and non-responders. Of the 95 patients, 8 (8.4%) underwent lesion surgery or hemispherectomy before VNS implantation, and 6/8 (75%) of these patients had a >50% reduction in seizure frequency. One patient who had a corpus callosotomy before VNS implantation had no response to VNS treatment. In conclusion, VNS is an effective treatment in children of DRE with structural etiology. There was no significant difference in VNS efficacy in patients with different structural etiologies. Vagus nerve stimulation treatment may also control seizures well in some patients with poor outcomes after lesion resection or hemispherectomy before VNS implantation.

Neuropilin 1-targeted near-infrared fluorescence probes for tumor diagnosis.

Two neuropilin 1 (NRP1)-targeted near-infrared fluorescence probes for tumor imaging were synthesized via click reaction. These two probes achieve excellent solubility and less aggregation. Importantly, they were able to rapidly target NRP1-overexpressing tumors and had long retention within tumors. Additionally, QS-1 with appropriate hydrophilicity displays higher tumor to muscle (T/M) ratio. And QS-1 can be easily modified with other functional group, and serve as a platform for constructing dual-modal or dual-targeting probes.

Safety and efficacy of rapid withdrawal of antiseizure medications during long-term video-electroencephalogram monitoring in children with drug-resistant epilepsy: A retrospective study.

OBJECTIVE: Performing long-term video-electroencephalographic monitoring (LTVEM) to obtain the ictal electroencephalogram (EEG) is important for presurgical evaluation. This study aimed at investigating the safety and efficacy of our protocol developed at Peking University First Hospital (PUFH) for rapid withdrawal of antiseizure medications (ASMs) during LTVEM to induce seizures in children with drug-resistant epilepsy (DRE) exhibiting nondaily seizures. METHODS: Children with DRE who followed the PUFH protocol for rapid withdrawal of ASMs during LTVEM between 2018 and 2021 were enrolled. The occurrence of seizures, number of ASMs withdrawn, seizure onset time after ASM tapering initiation, changes in interictal epileptiform discharge (IED), and adverse events were evaluated during LTVEM. RESULTS: Among 80 children evaluated in this study, seizures were induced successfully in 72 (90%) children. Furthermore, no change in IED sites was observed in these 72 children following the initiation of ASM tapering while 2 children exhibited secondary bilateral tonic-clonic seizures. The median time from ASM tapering initiation to the onset of the first seizure was found to be 3 days (2-4), while the median number of ASMs withdrawn was 2 (1-2). Finally, 66 children (91.7%) had habitual seizures while 6 children had nonhabitual seizure semiology. SIGNIFICANCE: The PUFH protocol can be used for the rapid withdrawal of ASMs during LTVEM in children with DRE. Using this protocol, ictal EEG patterns can be obtained in a relatively short time for most patients with fewer adverse effects during LTVEM, which may provide meaningful electro-clinical information for presurgical evaluation.

Vagus nerve stimulation in children with drug-resistant epilepsy of monogenic etiology.

Vagus nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy (DRE). The present study evaluated the efficacy of VNS in pediatric patients with DRE of monogenic etiology. A total of 20 patients who received VNS treatment at our center were followed up every 3 months through outpatient visits or a remote programming platform. The median follow-up time was 1.4 years (range: 1.0-2.9). The rate of response to VNS at 12 months of follow-up was 55.0% (11/20) and the seizure-free rate was 10.0% (2/20). We found that 75.0% (3/4) of patients with an SCN1A variant had a >50% reduction in seizure frequency. Patients with pathogenic mutations in the SLC35A2, CIC, DNM1, MBD5, TUBGCP6, EEF1A2, and CHD2 genes or duplication of X q28 (MECP2 gene) had a >50% reduction in seizure frequency. Compared with the preoperative electroencephalography (EEG), at 6, 12, 18, and 24 months after stimulator implantation, the percentage of the patients whose background frequency increased >1.5 Hz was respectively, 15.0% (3/20), 50.0% (10/20), 58.3% (7/12) and 62.5% (5/8); the percentage of the patients whose interictal EEG showed a >50% decrease in spike number was respectively 10% (2/20), 40.0% (8/20), 41.6% (5/12) and 50.0% (4/8). In the 9 patients with no response to VNS treatment, there was no difference in terms of spike number and background frequency between preoperative and postoperative EEG. Five of the 20 children (25.0%) reached new developmental milestones or acquired new skills after VNS compared to the preoperative evaluation. The efficacy of VNS in pediatric patients with DRE of monogenic etiology is consistent with that in the overall population of pediatric DRE patients. Patients with Dravet syndrome (DS), tuberous sclerosis complex (TSC), or Rett syndrome/MECP2 duplication syndrome may have a satisfactory response to VNS, but it is unclear whether patients with rare variants of epilepsy-related genes can benefit from the treatment.

Lesional Intractable Epileptic Spasms in Children: Electroclinical Localization and Postoperative Outcomes.

To analyze the influence of seizure semiology, electroencephalography (EEG) features and magnetic resonance imaging (MRI) change on epileptogenic zone localization and surgical prognosis in children with epileptic spasm (ES) were assessed. Data from 127 patients with medically intractable epilepsy with ES who underwent surgical treatment were retrospectively analyzed. ES semiology was classified as non-lateralized, bilateral asymmetric, and focal. Interictal epileptiform discharges were divided into diffusive or multifocal, unilateral, and focal. MRI results showed visible local lesions for all patients, while the anatomo-electrical-clinical value of localization of the epileptogenic zone was dependent on the surgical outcome. During preoperative video EEG monitoring, among all 127 cases, 53 cases (41.7%) had ES only, 46 (36.2%) had ES and focal seizures, 17 (13.4%) had ES and generalized seizures, and 11 (8.7%) had ES with focal and generalized seizures. Notably, 35 (27.6%) and 92 cases (72.4%) showed simple and complex ES, respectively. Interictal EEG showed that 22 cases (17.3%) had bilateral multifocal discharges or hypsarrhythmia, 25 (19.7%) had unilateral dominant discharges, and 80 (63.0%) had definite focal or regional discharges. Ictal discharges were generalized/bilateral in 71 cases (55.9%) and definite/lateralized in 56 cases (44.1%). Surgically resected lesions were in the hemisphere (28.3%), frontal lobe (24.4%), temporal lobe (16.5%), temporo-parieto-occipital region (14.2%), and posterior cortex region (8.7%). Seizure-free rates at 1 and 4 years postoperatively were 81.8 and 72.7%, respectively. There was no significant difference between electroclinical characteristics of ES and seizure-free rate. Surgical treatment showed good outcomes in most patients in this cohort. Semiology and ictal EEG change of ES had no effect on localization, while focal or lateralized epileptiform discharges of interictal EEG may affect lateralization and localization. Complete resection of epileptogenic lesions identified via MRI was the only factor associated with a positive surgical outcome.