An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection.

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.

Clinical Research into Central Nervous System Inflammatory Demyelinating Diseases Related to COVID-19 Vaccines.

Various vaccines have been developed in response to the SARS-CoV-2 pandemic, and the safety of vaccines has become an important issue. COVID-19 vaccine-related central nervous system inflammatory demyelinating diseases (CNS IDDs) have been reported recently. We present one case of AstraZeneca vaccine-related myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease and a literature review of another 78 patients published from January 2020 to October 2022. Patients were divided into three vaccine types (viral vector, mRNA, and inactivated vaccines) for further analyses. Among 79 patients with COVID-19 vaccine-related CNS IDDs, 49 (62%) cases received viral vector vaccines, 20 (25.3%) received mRNA vaccines, and 10 (12.7%) received inactivated vaccines. Twenty-seven cases (34.2%) were confirmed with autoantibodies, including fifteen patients (19%) with anti-MOG, eleven (13.9%) with anti-aquaporin 4 (AQP4), and one (1.3%) with both antibodies. Significantly, more males developed CNS IDDs post viral vector vaccines compared to mRNA and inactivated vaccines. Patients receiving mRNA vaccines were older than those receiving other types. Furthermore, mRNA and inactivated vaccines correlated more with anti-AQP4 antibodies, while viral vector vaccines showed higher MOG positivity. This research suggests potential associations between COVID-19 vaccine-related CNS IDDs and gender, age, and autoantibodies, contingent on vaccine types. Protein sequence analysis implies similarities between the S protein and AQP4/MOG. Further studies may elucidate the mechanisms of CNS IDDs, aiding vaccine selection for specific types.

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Optimizing treatment persistence in epilepsy: a comparative analysis of combined antiseizure medications with different mechanisms of action.

Background: Combination therapy with antiseizure medications (ASMs) is a rational strategy if monotherapy cannot effectively control seizures, thereby aiming to improve tolerance and treatment persistence. Objectives: To compare the efficacy of different ASM combinations among patients. Design: Patients with epilepsy on monotherapy who had a second ASM added as concomitant two-drug therapy from January 2009 to May 2019 in the Chang Gung Research Database, Taiwan, were included in the analysis. Methods: ASM combinations were compared based on their primary mechanism of action (MoA) which are as follows: gamma-aminobutyric acid receptor (G), sodium channel blocker (SC), synaptic vesicle protein 2A (SV2), calcium channel blocker (C), and multiple mechanisms (M). Treatment persistence was compared, and the predictors of persistence were analyzed. Results: In total, 3033 patients were enrolled in this study. Combined ASMs with different MoAs had significantly longer treatment persistence than ASMs with similar MoAs, specifically SC and M combinations. Patients receiving combined ASMs with different MoAs were less likely to discontinue treatment [adjusted hazards ratio: 0.83 (95% CI: 0.75-0.93), p < 0.001]. Among all combinations, the SC + SV2 combination had the longest treatment persistence (mean ± SD: 912.7 ± 841.6 days). Meanwhile, patients receiving the G combination had a higher risk of treatment discontinuation than those receiving the SC + SV2 combination. Underlying malignancies were associated with an increased risk of treatment discontinuation across all MoA categories. Male patients receiving the SC, SV2, and M combinations were more likely to discontinue treatment than female patients. Moreover, patients with renal disease were more likely to discontinue treatment with the SV2 combinations. Conclusion: ASM combinations with different MoAs had superior efficacy and tolerability to ASM combinations with similar MoAs, particularly SC and M combinations. In our cohort, factors associated with treatment discontinuation included underlying malignancy, male sex, and renal disease. These findings may provide valuable insights into the use of ASM combinations if monotherapy cannot adequately control seizures.

Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study.

BACKGROUND: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. METHODS: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM request, test results, interpretation, and impact on patient management. RESULTS: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visit showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). CONCLUSIONS: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Aldolase B-driven lactagenesis and CEACAM6 activation promote cell renewal and chemoresistance in colorectal cancer through the Warburg effect.

Colorectal cancer (CRC) is a prevalent malignancy worldwide and is associated with a high mortality rate. Changes in bioenergy metabolism, such as the Warburg effect, are often observed in CRC. Aldolase B (ALDOB) has been identified as a potential regulator of these changes, but its exact role in CRC cell behavior and bioenergetic homeostasis is not fully understood. To investigate this, two cohorts of CRC patients were analyzed independently. The results showed that higher ALDOB expression was linked to unfavorable prognosis, increased circulating carcinoembryonic antigen (CEA) levels, and altered bioenergetics in CRC. Further analysis using cell-based assays demonstrated that ALDOB promoted cell proliferation, chemoresistance, and increased expression of CEA in CRC cells. The activation of pyruvate dehydrogenase kinase-1 (PDK1) by ALDOB-induced lactagenesis and secretion, which in turn mediated the effects on CEA expression. Secreted lactate was found to enhance lactate dehydrogenase B (LDHB) expression in adjacent cells and to be a crucial modulator of ALDOB-mediated phenotypes. Additionally, the effect of ALDOB on CEA expression was downstream of the bioenergetic changes mediated by secreted lactate. The study also identified CEA cell adhesion molecule-6 (CEACAM6) as a downstream effector of ALDOB that controlled CRC cell proliferation and chemoresistance. Notably, CEACAM6 activation was shown to enhance protein stability through lysine lactylation, downstream of ALDOB-mediated lactagenesis. The ALDOB/PDK1/lactate/CEACAM6 axis plays an essential role in CRC cell behavior and bioenergetic homeostasis, providing new insights into the involvement of CEACAM6 in CRC and the Warburg effect. These findings may lead to the development of new treatment strategies for CRC patients.

Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly.

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Juvenile Myoclonic Epilepsy: Seizure and Social Outcomes in Taiwan.

Patients with juvenile myoclonic epilepsy (JME) may not achieve seizure freedom despite optimal treatment with antiseizure medications (ASMs). The aim of this study was to investigate the clinical and social features of patients with JME, and to determine the factors associated with outcomes. We retrospectively identified 49 patients with JME (25 females, mean age 27.6 ± 8.9 years) who were assessed at the Epilepsy Centre of Linkou Chang Gung Memorial Hospital in Taiwan. The patients were divided into two groups, those who were seizure-free and those with ongoing seizures according to their seizure outcome at the last follow-up for one year. Clinical features and social status were compared between these two groups. Twenty-four (49%) of the JME patients were seizure-free for at least one year, while 51% continued to experience seizures despite being treated with multiple ASMs. The presence of epileptiform discharges in the last electroencephalogram and seizures during sleep were significantly associated with worse seizure outcomes (p < 0.05). The patients who were seizure-free had a higher employment rate compared to those who continued to experience seizures (75% vs. 32%, p = 0.004). Despite receiving ASM treatment, a considerable proportion of the patients with JME continued to have seizures. Moreover, poor seizure control was associated with a lower employment rate, which may lead to negative socioeconomic consequences related to JME.

Association of Long-term Antiseizure Medication Use and Incident Type 2 Diabetes Mellitus.

BACKGROUND AND OBJECTIVES: Diabetes mellitus (DM) contributes significantly to metabolic syndrome and cardiovascular events, and it may be a comorbidity of epilepsy. The objective of this study was to investigate whether long-term antiseizure medication (ASM) use is associated with the risk of developing type 2 diabetes. METHODS: We analyzed data from the Chang Gung Research Database. Patients aged ≥45 years who received ASM treatment from January 2001 to May 2019 were identified. Patients with DM-associated diseases and short-term ASM use were excluded. The patients were classified into nonenzyme interaction, enzyme-inducing, enzyme-inhibiting, and mixed ASM groups. The rate of incident diabetes associated with individual ASM was further analyzed. Propensity score weighting was performed to balance between-group differences. Analyses were conducted with Cox proportional regression models and stabilized inverse probability of treatment weighting (IPTW). Hazard ratios (HRs) were calculated at 3, 4, 6, and 9 years after the index date and the end of follow-up. RESULTS: A total of 5,103 patients were analyzed, of whom 474 took nonenzyme interaction ASMs, 1,156 took enzyme-inducing ASMs, 336 took enzyme-inhibiting ASMs, and 3,137 took mixed ASMs. During follow-up (39,248 person-years), 663 patients developed new-onset DM, and the prevalence was 13.0%. The incidence of DM plateaued at 6-9 years after ASM initiation. Enzyme-inhibiting ASMs were significantly associated with a higher HR starting at the third year and then throughout the study period. The HRs were 1.93 (95% CI 1.33-2.80), 1.85 (95% CI 1.24-2.75), and 2.08 (95% CI 1.43-3.03) in unadjusted, adjusted, and stabilized IPTW models, respectively, at the end of follow-up. The dosing of ASM did not increase the risk of DM, and none of the individual ASM analyses reached statistical significance. DISCUSSION: The long-term use of enzyme-inhibiting ASMs was associated with an increased risk of incident DM, and the risk increased with the duration of treatment. These findings may guide the choice of drugs in those requiring long-term ASM therapy, particularly in high-risk individuals. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that enzyme-inhibiting ASMs were associated with an increased risk of developing DM compared with nonenzyme interaction ASMs.

Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma.

The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence.

Long-term Outcome of Seizure Control and Neurologic Performance After Limited Hippocampal Radiofrequency Thermocoagulation for Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Limited hippocampal radiofrequency thermocoagulation (RFTC) for patients with mesial temporal lobe epilepsy was associated with good short-term seizure control and few complications. We aimed to demonstrate the neuropsychologic outcomes and assess the prognostic factors of long-term seizure control in these patients. METHODS: We included all patients with mesial temporal lobe epilepsy who underwent limited hippocampal RFTC from January 2016 to December 2020. Clinical data of age, sex, seizure control before and after operation were all corrected. Pre- and postoperative neuropsychologic function including full-scale intelligence quotient (FSIQ), memory quotient, and the Mini-Mental State Examination was used. RESULTS: Thirty-one patients (17 female and 14 male) with a mean epilepsy duration of 22.3 years and seizure frequency of 5.7 times per month were included. The intraoperative seizure rate was 19.3%, and a higher preoperative seizure frequency (P = 0.001) and longer duration of epilepsy (P = 0.042) were associated with the occurrence of intraoperative seizures. The postoperative FSIQ scores were significantly better than preoperative scores (mean 92.1 vs. 89.7, P = 0.014). Nine patients (29%) who underwent limited hippocampal RFTC were seizure-free at 1 year of follow-up. Responders represented 58% (n = 18) of patients at 1 year. The mean follow-up period was 34.7 ± 13.3 months. Five patients remained seizure free and 13 patients are still responders at the last follow-up visits. Long-term seizure frequency was 2.32 ± 2.86 times per month. CONCLUSIONS: Limited hippocampal RFTC is a safe stereotactic minimal invasive procedure with good neuropsychologic outcome and acceptable efficacy of seizure reduction in appropriately selected patients.

Albumin-Bilirubin Grade as a Novel Predictor of the Development and Short-Term Survival of Post-Banding Ulcer Bleeding Following Endoscopic Variceal Ligation in Cirrhotic Patients.

Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94−7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34−5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06−4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18−19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75−158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.

Evaluating the Different Stages of Parkinson's Disease Using Electroencephalography With Holo-Hilbert Spectral Analysis.

Electroencephalography (EEG) can reveal the abnormalities of dopaminergic subcortico-cortical circuits in patients with Parkinson's disease (PD). However, conventional time-frequency analysis of EEG signals cannot fully reveal the non-linear processes of neural activities and interactions. A novel Holo-Hilbert Spectral Analysis (HHSA) was applied to reveal non-linear features of resting state EEG in 99 PD patients and 59 healthy controls (HCs). PD patients demonstrated a reduction of ß bands in frontal and central regions, and reduction of γ bands in central, parietal, and temporal regions. Compared with early-stage PD patients, late-stage PD patients demonstrated reduction of ß bands in the posterior central region, and increased θ and δ2 bands in the left parietal region. θ and ß bands in all brain regions were positively correlated with Hamilton depression rating scale scores. Machine learning algorithms using three prioritized HHSA features demonstrated "Bag" with the best accuracy of 0.90, followed by "LogitBoost" with an accuracy of 0.89. Our findings strengthen the application of HHSA to reveal high-dimensional frequency features in EEG signals of PD patients. The EEG characteristics extracted by HHSA are important markers for the identification of depression severity and diagnosis of PD.

Anticoagulant drugs with or without proton pump inhibitor and colorectal cancer risk: a population-based, case-control study.

BACKGROUND: Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. METHODS: A retrospective case-control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. RESULTS: Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60-0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28-1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49-10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32-0.73). PPI plus clopidogrel showed no significant effect on the CRC. CONCLUSION: This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.

Reduced Sleep Quality Is Related to Poor Quality of Life in Patients with Juvenile Myoclonic Epilepsy, a Case-Control Study.

Juvenile myoclonic epilepsy (JME) is a primary generalized epilepsy which is closely related to the sleep-wake cycle. This study aimed to investigate whether sleep disturbance is more common among patients with JME and the impact this may have on their quality of life (QOL). Thirty-four patients with JME and age- and gender-matched controls were recruited into this case control study, and assessed using validated sleep questionnaires including the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Stanford Sleepiness Scale (SSS). QOL was assessed using the Quality of Life in Epilepsy Inventory (QOLIE-31). The patients had a significantly higher PSQI score and higher proportion of abnormal PSQI scores than the controls. They also had higher ESS and SSS scores, but without statistical significance. The patients with poor sleep quality had significantly lower overall QOL, emotional well-being, and energy/fatigue subscale scores. The use of a higher number of antiseizure medications, dosage of levetiracetam, and usage of antiseizure medication polytherapy were associated with sleep disorders. Our results showed that sleep disturbance is common in patients with JME, and also that it has an impact on their QOL.

Functional Role of Mitochondrial DNA in Cancer Progression.

Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

White matter structural connectivity as a biomarker for detecting juvenile myoclonic epilepsy by transferred deep convolutional neural networks with varying transfer rates.

Objective. By detecting abnormal white matter changes, diffusion magnetic resonance imaging (MRI) contributes to the detection of juvenile myoclonic epilepsy (JME). In addition, deep learning has greatly improved the detection performance of various brain disorders. However, there is almost no previous study effectively detecting JME by a deep learning approach with diffusion MRI.Approach. In this study, the white matter structural connectivity was generated by tracking the white matter fibers in detail based on Q-ball imaging and neurite orientation dispersion and density imaging. Four advanced deep convolutional neural networks (CNNs) were deployed by using the transfer learning approach, in which the transfer rate searching strategy was proposed to achieve the best detection performance.Main results. Our results showed: (a) Compared to normal control, the white matter' neurite density of JME was significantly decreased. The most significantly abnormal fiber tracts between the two groups were found to be cortico-cortical connection tracts. (b) The proposed transfer rate searching approach contributed to find each CNN's best performance, in which the best JME detection accuracy of 92.2% was achieved by using the Inception_resnet_v2 network with a 16% transfer rate.Significance. The results revealed: (a) Through detection of the abnormal white matter changes, the white matter structural connectivity can be used as a useful biomarker for detecting JME, which helps to characterize the pathophysiology of epilepsy. (b) The proposed transfer rate, as a new hyperparameter, promotes the CNNs transfer learning performance in detecting JME.

Aggressive cytoreduction and multiple subpial cortical transections may obtain good surgical outcomes in refractory epilepsy with multiple epileptic foci.

BACKGROUNDS: Epilepsy surgery is the most efficacious therapeutic modality for patients with medical refractory epilepsy, especially resective surgery. However, the variable etiologies and multiple epileptic foci are usually associated with the outcomes. The aim of this study was to demonstrate that combination of different intervention procedures might be an alternative option for patients of refractory epilepsy. METHODS: We retrospectively analyzed pre-operative and post-surgical outcomes in 30 patients who received epilepsy surgery between January 1, 2010 and December 31, 2014 at Chang Gung Memorial Hospital (CGMH), Linkou, according to Engel's classification. RESULTS: Twenty-six of the 30 patients (86.7%) had good outcomes, sum of class I and class II after epilepsy surgery. The good outcome rate of our complicated group was 80.0% (12/15), compared to 93.3% (14/15) in the simple group, but no significant differences between the two groups (p = 0.569). Four patients whose epileptic foci involved eloquent area and received multiple subpial cortical transection, and good outcome rate was 75% (3/4). At last, six patients had previously failed epilepsy surgery and received a reoperation, with a good outcome rate of 83.3% (5/6). CONCLUSION: After complete pre-surgical evaluation and combined interventional procedures, the patients with refractory epilepsy had satisfactory outcomes and few neurological complications. Moreover, re-operation can improve the outcome in some patients who previously failed epilepsy surgery.

Treatment of pharmacoresistant sleep-related hypermotor epilepsy (SHE) with the selective AMPA receptor antagonist perampanel.

This study aimed to evaluate the efficacy and tolerability of perampanel (PER) as adjunctive therapy in patients with pharmacoresistant sleep-related hypermotor epilepsy (SHE). Patients diagnosed with SHE who received PER treatment between 2016 and 2019 were included, and their data were reviewed retrospectively. Diagnosis was based on reports of patients or family members witnessing the events and clinical characteristics of seizures captured by video or during video-electroencephalography monitoring. Among 36 SHE patients, 20 with pharmacoresistant SHE (six female; mean age: 34.1 ± 9.0 years) who received PER as adjunctive therapy were included in this study. Fourteen out of the 20 patients received PER with mean length of PER exposure of 24.6 ± 15.7 months: 10 of them were responders and four non-responders. The remaining six patients discontinued PER for adverse events (n = 5) and patient choice (n = 1). Among the 10 responders, six (60%) reported seizure-free periods lasting ≥6 months. The most common PER-associated adverse event was dizziness (25%) followed by malaise (10%). Clinical experience with these patients demonstrated that PER might be considered as an add-on anti-seizure medication for patients with highly pharmacoresistant SHE.

Efficacy and safety of perampanel in refractory and super-refractory status epilepticus: cohort study of 81 patients and literature review.

BACKGROUND: The effective dose of perampanel in status epilepticus (SE), refractory SE (RSE), and super-refractory SE (SRSE) in humans is unknown, and the potential of perampanel in treating SE has not been evaluated in a large cohort. METHODS: Data of intensive care patients with RSE and SRSE treated with perampanel were retrospectively reviewed and analyzed. RESULTS: Eighty-one patients received perampanel, including 39 females with median age 64 [17-91] years, perampanel responders (n = 27), and non-responders (n = 54). The initial perampanel dose was positively associated with treatment response in patients with RSE or SRSE (OR = 1.27, 95% CI 1.03-1.57, p = 0.025), while the maximum dose was negatively associated with treatment response (OR = 0.74, 95% CI 0.58-0.96, p = 0.022). Hypoxia caused seizures in six patients; five died in hospital and one had severe disability. A statistically non-significant tendency toward better response was found in patients with unique SE type and cause, particularly in nonconvulsive status epilepticus (NCSE) without coma (NCSE without coma vs. generalized tonic-clonic seizure: OR = 4.14, 95% CI 0.98-17.47, p = 0.053). In the high-dose (≥ 16 mg/day) groups, although distributions of modified Rankin Scale (mRS) scores were similar between perampanel responders and non-responders at discharge, a greater proportion of perampanel responders had less change in mRS scores from baseline than did perampanel non-responders (median mRS: 0 vs 4, p = 0.064). No cardiorespiratory adverse events or laboratory abnormalities were noted with perampanel treatment. CONCLUSIONS: Perampanel is effective and has a satisfactory safety profile in the emergency treatment of established RSE and SRSE.