Causal association of polyunsaturated fatty acids with biliary tract diseases: A Mendelian randomization study.

OBJECTIVES: The evidence connecting polyunsaturated fatty acids (PUFAs) to biliary problems is still highly contested and speculative despite the fact that biliary diseases are common and PUFAs have long been studied for their potential health benefits. This work used Mendelian randomization (MR) techniques in conjunction with genome-wide association study (GWAS) data to clarify the causal relationships between PUFAs and biliary tract diseases. METHODS: We compiled data on PUFAs, including Omega-3 fatty acids, Omega-6 fatty acids, and the ratio of Omega-6 to Omega-3 fatty acids (Omega-6:Omega-3), using GWAS. MR was used to examine biliary tract problems (cholecystitis, cholelithiasis, gallbladder cancer, primary biliary cholangitis, primary sclerosing cholangitis, and disorders of gallbladder, biliary tract and pancreas). Single nucleotide polymorphisms significantly associated with PUFAs were selected as instrumental variables to estimate causal effects on biliary tract diseases. The final results were analyzed using five MR analysis techniques. Inverse variance weighting (IVW) was used as the primary outcome. And IVW was utilized in conjunction with the other MR analysis techniques (MR-Egger, weighted median, simple mode, and weighted mode). Additionally, we evaluated heterogeneity and horizontal multiplicity using the MR-Egger intercept test and Cochrane's Q test, respectively. Finally, to increase the accuracy and precision of the study outcomes, we carried out a number of sensitivity analyses. RESULTS: We found that Omega-3 fatty acids reduced the risk of cholecystitis (OR: 0.851, P = 0.009), cholelithiasis (OR: 0.787, P = 8.76e-5), and disorders of gallbladder, biliary tract and pancreas (OR: 0.842, P = 1.828e-4) but increased the primary biliary cholangitis (OR: 2.220, P = 0.004). There was no significant association between Omega-3 fatty acids and risk of gallbladder cancer (OR: 3.127, P = 0.530) and primary sclerosing cholangitis (OR: 0.919, P = 0.294). Omega-6 fatty acids were associated with a reduced risk of cholecystitis (OR: 0.845, P = 0.040). However, they were not linked to an increased or decreased risk of cholelithiasis (OR: 0.878, P = 0.14), gallbladder cancer (OR: 4.670, P = 0.515), primary sclerosing cholangitis (OR: 0.993, P = 0.962), primary cholestatic biliary cholangitis (OR: 1.404, P = 0.509), or disorders of gallbladder, biliary tract and pancreas. Omega-6:Omega-3 fatty acids were linked to a greater risk of cholecystitis, cholelithiasis, and disorders of gallbladder, biliary tract and pancreas (OR:1.168, P = 0.009, OR:1.191, P = 1.60e-6, and OR:1.160, P = 4.11e-6, respectively). But (OR: 0.315, P = 0.010) was linked to a decreased risk of primary biliary cholangitis. Not linked to risk of primary sclerosing cholangitis (OR: 1.079, P = 0.078) or gallbladder cancer (OR: 0.046, P = 0.402). According to the MR-Egger intercept, our MR examination did not appear to be impacted by any pleiotropy (all P > 0.05). Additionally, sensitivity studies validated the accuracy of the calculated causation. CONCLUSION: Inconsistent causative relationships between PUFAs and biliary tract diseases were revealed in our investigation. However, Omega-3 fatty acids were found to causally lower the risk of cholecystitis, cholelithiasis, and disorders of gallbladder, biliary tract and pancreas. Omega-3 fatty acids increased the risk of primary biliary cholangitis in a causative way. Omega-3 fatty acids with the risk of gallbladder cancer and primary sclerosing cholangitis did not have any statistically significant relationships. Omega-6 fatty acids were not significantly causally connected with the risk of cholelithiasis, gallbladder cancer, primary sclerosing cholangitis, or disorders of gallbladder, biliary tract and pancreas. However, they did play a causative role in lowering the risk of cholecystitis. Omega-6:Omega-3 fatty acids decreased the risk of primary biliary cholangitis but increased the risk of cholecystitis, gallstone disease, and disorders of gallbladder, biliary tract and pancreas. They had no effect on the risk of gallbladder cancer or primary sclerosing cholangitis. Therefore, additional research should be done to examine the probable processes mediating the link between polyunsaturated fatty acids and the risk of biliary tract diseases.

Synergistic effects of photodynamic therapy and chemotherapy: Activating the intrinsic/extrinsic apoptotic pathway of anoikis for triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) is a highly invasive and metastatic subtype of breast cancer that often recurs after surgery. Herein, we developed a cyclodextrin-based tumor-targeted nano delivery system that incorporated the photosensitizer chlorin e6 (Ce6) and the chemotherapeutic agent lonidamine (LND) to form the R6RGD-CMßCD-se-se-Ce6/LND nanoparticles (RCC/LND NPS). This nanosystem could target cancer cells, avoid lysosomal degradation and further localize within the mitochondria. The RCC/LND NPS had pH and redox-responsive to control the release of Ce6 and LND. Consequently, the nanosystem had a synergistic effect by effectively alleviating hypoxia, enhancing the production of cytotoxic reactive oxygen species (ROS) and amplifying the efficacy of photodynamic therapy (PDT). Furthermore, the RCC/LND NPS + light weakened anoikis resistance, disrupted extracellular matrix (ECM), activated both the intrinsic apoptotic pathway (mitochondrial pathway) and extrinsic apoptotic pathway (receptor death pathway) of anoikis. In addition, the nanosystem showed significant anti-TNBC efficacy in vivo. These findings collectively demonstrated that RCC/LND NPS + light enhanced the anticancer effects, induced anoikis and inhibited tumor cell migration and invasion through a synergistic effect of chemotherapy and PDT. Overall, this study highlighted the promising potential of the RCC/LND NPS + light for the treatment of TNBC.

Application of Multifunctional Nanozymes in Tumor Therapy.

Tumors are one of the main diseases threatening human life and health. The emergence of nanotechnology in recent years has introduced a novel therapeutic avenue for addressing tumors. Through the amalgamation of nanotechnology's inherent attributes with those of natural enzymes, nanozymes have demonstrated the ability to initiate catalytic reactions, modulate the biological microenvironment, and facilitate the adoption of multifaceted therapeutic approaches, thereby exhibiting considerable promise in the realm of cancer treatment. In this Review, the application of nanozymes in chemodynamic therapy, radiotherapy, photodynamic therapy, photothermal therapy, and starvation therapy are summarized. Moreover, a detailed discussion regarding the mechanism of conferring physiotherapeutic functionality upon catalytic nanosystems is provided. It is posited that this innovative catalytic treatment holds significant potential to play a crucial role within the domain of nanomedicine.

Glutathione Programmed Mitochondria Targeted Delivery of Lonidamine for Effective Against Triple Negative Breast Cancer.

Introduction: Mitochondria are a significant target of lonidamine (LND). However, its limited solubility and inability to specifically target mitochondria, LND can lead to hepatic toxicity and has shown only modest anticancer activity. The objective of this study is to establish a glutathione programmed mitochondria targeted delivery of LND for the effective treatment of triple negative breast cancer (TNBC). Methods: In this study, LND was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) wrapped with mitochondria-targeting short-chain triphenylphosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and tumor-targeting long-chain 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-S-S-polyethylene glycol-R6RGD (DSPE-S-S-PEG2000-R6RGD, DSSR), which were designated as LND-PLGA/TPS/DSSR NPs. The release behavior was evaluated, and cellular uptake, in vitro and in vivo antitumor activity of nanoparticles were investigated. The mechanism, including apoptosis of tumor cells and mitochondrial damage and respiratory rate detection, was also further investigated. Results: LND-PLGA/TPS/DSSR NPs were successfully prepared, and characterization revealed that they are globular particles with smooth surfaces and an average diameter of about 250 nm. Long-chain DSSR in LND-PLGA/TPS/DSSR NPs prevented positively charged LND-PLGA/TPS NPs from being cleared by the reticuloendothelial system. Furthermore, LND release rate from NPs at pH 8.0 was significantly higher than that at pH 7.4 and 5.5, which demonstrated specific LND release in mitochondria and prevented LND leakage in cytoplasm and lysosome. NPs could locate in mitochondria, and the released LND triggered apoptosis of tumor cells by damaging mitochondria and releasing apoptosis-related proteins. In addition, in TNBC mice model, programmed mitochondria targeted NPs improved efficacy and reduced LND toxicity. Conclusion: LND-PLGA/TPS/DSSR NPs may be a useful system and provide an effective approach for the treatment of TNBC.

PZR promotes tumorigenicity of lung cancer cells by regulating cell migration and invasion via modulating oxidative stress and cell adhesion.

PZR is a transmembrane glycoprotein encoded by the MPZL1 gene. It serves as a specific binding protein and substrate of tyrosine phosphatase SHP-2 whose mutations cause developmental diseases and cancers. Bioinformatic analyses of cancer gene databases revealed that PZR is overexpressed in lung cancer and correlated with unfavorable prognosis. To investigate the role of PZR in lung cancer, we employed the CRISPR technique to knockout its expression and recombinant lentiviruses to overexpress it in lung adenocarcinoma SPC-A1 cells. While knockout of PZR reduced colony formation, migration, and invasion, overexpression of PZR had the opposite effects. Furthermore, when implanted in immunodeficient mice, PZR-knockout SPC-A1 cells showed suppressed tumor-forming ability. Finally, the underlying molecular mechanism for these functions of PZR is its positive role in activating tyrosine kinases FAK and c-Src and in maintaining the intracellular level of reactive oxygen species (ROS). In conclusion, our data indicated that PZR plays an important role in lung cancer development, and it may serve as a therapeutic target for anti-cancer development and as a biomarker for cancer prognosis.

Deep brain stimulation for patients with refractory epilepsy: nuclei selection and surgical outcome.

Objective: By studying the surgical outcome of deep brain stimulation (DBS) of different target nuclei for patients with refractory epilepsy, we aimed to explore a clinically feasible target nucleus selection strategy. Methods: We selected patients with refractory epilepsy who were not eligible for resective surgery. For each patient, we performed DBS on a thalamic nucleus [anterior nucleus of the thalamus (ANT), subthalamic nucleus (STN), centromedian nucleus (CMN), or pulvinar nucleus (PN)] selected based on the location of the patient's epileptogenic zone (EZ) and the possible epileptic network involved. We monitored the clinical outcomes for at least 12 months and analyzed the clinical characteristics and seizure frequency changes to assess the postoperative efficacy of DBS on the different target nuclei. Results: Out of the 65 included patients, 46 (70.8%) responded to DBS. Among the 65 patients, 45 underwent ANT-DBS, 29 (64.4%) responded to the treatment, and four (8.9%) of them reported being seizure-free for at least 1 year. Among the patients with temporal lobe epilepsy (TLE, n = 36) and extratemporal lobe epilepsy (ETLE, n = 9), 22 (61.1%) and 7 (77.8%) responded to the treatment, respectively. Among the 45 patients who underwent ANT-DBS, 28 (62%) had focal to bilateral tonic-clonic seizures (FBTCS). Of these 28 patients, 18 (64%) responded to the treatment. Out of the 65 included patients, 16 had EZ related to the sensorimotor cortex and underwent STN-DBS. Among them, 13 (81.3%) responded to the treatment, and two (12.5%) were seizure-free for at least 6 months. Three patients had Lennox-Gastaut syndrome (LGS)-like epilepsy and underwent CMN-DBS; all of them responded to the treatment (seizure frequency reductions: 51.6%, 79.6%, and 79.5%). Finally, one patient with bilateral occipital lobe epilepsy underwent PN-DBS, reducing the seizure frequency by 69.7%. Significance: ANT-DBS is effective for patients with TLE or ETLE. In addition, ANT-DBS is effective for patients with FBTCS. STN-DBS might be an optimal treatment for patients with motor seizures, especially when the EZ overlaps the sensorimotor cortex. CMN and PN may be considered modulating targets for patients with LGS-like epilepsy or occipital lobe epilepsy, respectively.

KPT-330 and Y219 exert a synergistic antitumor effect in triple-negative breast cancer through inhibiting NF-κB signaling.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype, which has poor prognosis due to the lack of effective targeted drugs. KPT-330, an inhibitor of the nuclear export protein CRM-1, has been widely used in clinical medicine. Y219, a novel proteasome inhibitor designed by our group, shows superior efficacy, reduced toxicity, and reduced off-target effects as compared to the proteasome inhibitor bortezomib. In this study, we investigated the synergistic effect of KPT-330 and Y219 against TNBC cells, as well as the underlying mechanisms. We report that combination treatment with KPT-330 and Y219 synergistically inhibited the viability of TNBC cells in vitro and in vivo. Further analysis revealed that the combined use of KPT-330 and Y219 induced G2-M phase arrest and apoptosis in TNBC cells, and attenuated nuclear factor kappa B (NF-κB) signaling by facilitating nuclear localization of IκB-α. Collectively, these results suggest that the combined use of KPT-330 and Y219 may be an effective therapeutic strategy for the treatment of TNBC.

Design and discovery of novel dipeptide boronic acid ester proteasome inhibitors, an oral slowly-released prodrug for the treatment of multiple myeloma.

Multiple myeloma (MM), the second most common hematological malignancy, is a disease characterized by a clonal expansion of malignant plasma cells that accumulate in the bone marrow. Ixazomib citrate was the first commercially available oral proteasome inhibitor for the treatment of MM. However, it immediately hydrolyzed into the active form on exposure to aqueous solution and so it was a pseudo prodrug. Herein, a series of dipeptide boronic acid esters as novel oral proteasome inhibitors were designed, synthesized and biologically investigated for the inhibition of the ß5 subunit of 20S proteasome. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of MM cell line RPMI-8226. The results showed that some compounds were active against RPMI-8226 with IC50 values of less than 10 nM. The solution stability showed that ixazomib citrate was completely hydrolyzed to its active form ixazomib within 2 min in the simulated gastric juice. However, among the screened compounds, prodrug 18u was stable enough in simulated gastric juice and simulated intestinal juice, and its hydrolysis rate was 59.7% and 3.6% after 2 h, respectively. In addition, 18u exhibited good microsome stabilities and pharmacokinetic properties and displayed strong antiproliferative activity against the RPMI-8226 cell line (5.6 nM). Furthermore, compound 18u exhibited strong in vivo anticancer efficacy in human MM (RPMI-8226) xenograft mouse model.

Co-delivery of immunochemotherapeutic by classified targeting based on chitosan and cyclodextrin derivatives.

Herein, a cyclodextrin derivative (R6RGD-CMßCD) with tumor target and a carboxymethyl chitosan derivative (M2pep-CMCS) with tumor-associated macrophages 2 (TAM2) target were successfully synthesized, respectively. DOX-loaded nanoparticles (R6RGD-CMßCD@DOX NPs, RCNPDOX) and R848-loaded nanoparticles (M2pep-CMCS@R848 NPs, MCNPR848) were prepared. Furthermore, the RCNPDOX and MCNPR848 exhibited good DOX and R848 absorption. Meanwhile, the synergetic cell toxicity of RCNPDOX and MCNPR848 was found. Additionally, RCNPDOX + MCNPR848 nanoparticles greatly promoted the expression levels of cleaved Caspase3, which indicated that the nanoparticles could induce cell apoptosis. At the same time, the immunohistochemical images exhibited that RCNPDOX + MCNPR848 group could effectively transform the phenotype of tumor-associated macrophages. Importantly, in vivo experiments revealed that RCNPDOX + MCNPR848 NPs exerted excellent anticancer effects in tumor-bearing mice. To summarize, RCNPDOX + MCNPR848 NPs are effective anticancer treatment combining chemotherapy and immunotherapy, M2pep-CMCS and R6RGD-CMßCD are good delivery materials.

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer.

Colorectal cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 µM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 µM). Furthermore, compound 10 exhibited strong in vivo anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma.

Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

Biomimetic multifunctional nanozymes enhanced radiosensitization for breast cancer via an X-ray triggered cascade reaction.

Radiotherapy has been widely applied for breast cancer treatment in the clinic, while improving the radiation sensitivity of tumors and protecting normal tissues from radiation damage has drawn considerable attention. In this study, we reported a biomimetic multifunctional nanozyme (BSA@CeO/Fe2+), which can be used as a radiosensitizer for breast cancer treatment. It was demonstrated that BSA@CeO/Fe2+ presented a pH dependent multiple enzyme like activity that enhances the hydroxyl radical level by cascade catalytic reactions in a tumor microenvironment to obtain a desirable tumor-suppression rate (83.07%). Moreover, BSA@CeO/Fe2+ was also proved to reduce reactive oxygen species levels in normal cells. Additionally, BSA@CeO/Fe2+ nanozymes showed no obvious toxicity by routine blood examination and blood biochemistry assays. Therefore, this work provided a promising strategy for nanocatalytic tumor therapy by rationally designing biomimetic nanozymes with multienzymatic activities for achieving high radiotherapy efficacy and excellent biosafety simultaneously.

Classifying early stages of cervical cancer with MRI-based radiomics.

This study aims to establish a MRI-based classifier to distinguish early stages of cervical cancer with improved diagnostic performance to assist clinical diagnosis and treatment. 57 patients with pathological diagnosis of cervical cancer from January 2018 to May 2019 were enrolled in this study. MRI examinations, including T1-weighted image(T1WI), T2-weighted image(T2W), diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE), were performed before surgery. MR images from patients of stage Ib or IIa cervical cancer with tumor segmented were used as input. Feature extraction process extracted first-order statistics and texture and applied filters. The dimensionality of the radiomic features was reduced using the least absolute shrinkage and selection operator (LASSO). Models were trained by three machine-learning (k-nearest neighbor (KNN), support vector machine (SVM), and logistic regression (LR)) and diagnostic performance in differentiating stage Ib and stage IIa cases was evaluated. A total of 27 features were extracted to establish models, including 2 features from T1WI, 5 features from T2WI, 5 features from DWI (b = 50), 4 features from DWI (b = 800), 5 features from DCE, and 6 features from ADC. For each machine learning (ML) classifier, six sequences of training set and testing set are modeled and analyzed. Among all the models, the training set and testing set of T2WI model built by SVM classifier were the best (Area under the curve (AUC) 0.915) / (AUC 0.907). Radiomic analysis of ML-based texture features and first-order statistics features can be used to stage the early cervical cancer pre-operatively.

Role of experimental periodontitis in inducing pulmonary inflammation in mice.

OBJECTIVE: The aim of the study was to explore the potential role of experimental periodontitis in pulmonary inflammation in mice. MATERIALS AND METHODS: Mice were divided into control, ligature-induced periodontitis (L) and ligature plus Porphyromonas gingivalis (P. gingivalis)-induced periodontitis (LPG) groups. Alveolar bone resorption, pulmonary function, lung tissue histology and cytokine expression were examined at 2, 4 and 8 weeks. Then cytokines and neutrophils in the peripheral blood and lung tissue were further assessed at 8 weeks to determine the role of cytokines induced by LPG periodontitis, and the effect of P. gingivalis was evaluated using P. gingivalis-IgG and P. gingivalis gingipain. RESULTS: Alveolar bone resorption was more severe in the L and LPG groups. However, pulmonary inflammation was observed only in the LPG group at 8 weeks when cytokines and neutrophils in the peripheral blood and lung tissue were the most significant elevation, along with higher levels of P. gingivalis-IgG and P. gingivalis gingipain. Cytokine levels were also increased in the gingival tissue, peripheral blood and lung tissue in the L group, accompanied by elevated peripheral blood neutrophils, but not as significantly as that in the LPG group. CONCLUSIONS: LPG periodontitis can trigger pulmonary inflammation over the long term, in which cytokines and P. gingivalis play an important role.

Focal white matter microstructural alteration after anthracycline-based systemic treatment in long-term breast cancer survivors: a structural magnetic resonance imaging study.

Understanding the neural correlates of cognitive problems in patients with breast cancer (BC) after systemic treatment have been a topic of increasing investigation. The heterogeneity of the systemic treatment regimens may undermine our ability to identify brain microstructural alterations resulting from any given regimen. We investigated the detrimental effects of the anthracycline-based systemic treatment (AST) regimen (epirubicin and cyclophosphamide + docetaxel + tamoxifen) on brain gray matter (GM) and white matter (WM) microstructural alteration in long-term BC survivors. We performed a battery of neuropsychological tests and structural magnetic resonance imaging (MRI) to 31 long-term BC survivors who had received the AST regimen (AST group) and 43 healthy controls (HC group). Voxel-based morphometry evaluated the whole-brain voxel-wise GM volume, while diffusion tensor imaging technique with tract-based spatial statistics analysis evaluated whole-brain WM microstructural alteration. Partial least squares regression (PLSR) was used to evaluate the relationship between cognitive impairment and brain microstructural alteration in BC survivors. Compared with the HC group, the AST group exhibited a significantly poorer performance in attention, as well as a marginal significantly poorer performance in verbal working memory and executive function. Significantly lower fractional anisotropy (FA), higher radial diffusivity (RD), and lower axial diffusivity (AD) in multiple brain WM regions were showed in AST group compared with the HC group. Overlap of lower FA and higher RD was found in the body of corpus callosum (CC) and bilateral superior corona radiata (SCR), whereas overlap of lower FA and AD was found in the body of CC and right SCR. The PLSR results showed that the WM regions with overlap of lower FA and AD were significantly associated with executive and verbal working memory decline. No significant difference was observed in the GM volume between groups. Our results suggest that microstructural abnormalities of certain vulnerable WM regions in the AST regimen-exposed brain may provide neuroimaging evidence for the identification of brain injury and cognitive impairment induced by specific chemotherapy regimens.

Multiple ictal onset patterns underlie seizure generation in seizure-free patients with temporal lobe epilepsy surgery: an SEEG study.

PURPOSE: Seizure originates from different pathological substrate; however, the same pathologies may have distinct mechanisms underlying seizure generation. We aimed to improve the understanding of such mechanisms in patients with temporal lobe epilepsy (TLE) by investigating the stereoelectroencephalography (SEEG) ictal onset patterns (IOPs). METHODS: We analyzed data from a cohort of 19 consecutive patients explored by SEEG and had 1-3-year seizure-freedom following temporal lobe resection. RESULTS: Six IOPs were identified. They were low voltage fast activity (LVFA) (36.5%), rhythmic spikes or spike-waves at low frequency and with high amplitude (34.1%), runs of spikes (10.6%), rhythmic sharp waves (8.2%), low frequency high amplitude repetitive spiking (LFRS) (7.1%), and delta activity (3.5%). All six patterns were found in patients with mesial temporal onset and only two patterns were found in patients with temporal neocortical onset. The most prevalent patterns for patients with mesial temporal onset were rhythmic spikes or spike-waves, followed by LVFA with a mean discharge rate 74 Hz. For patients with temporal neocortical onset, the most prevalent IOP pattern was LVFA with a mean discharge rate 35 Hz, followed by runs of spikes. Compared with Lateral TLE (LTLE), the duration between the onset of the IOPs to the onset of the symptom was longer for patients with MTLE (Mesial TLE) (MTLE:55.7 ± 50.6 s vs LTLE:19.5 ± 16.4 s). CONCLUSION: Multiple IOPs underlie seizure generation in patients with TLE. However, the mesial and lateral temporal lobes share distinct IOPs.

Direct Targeting of the Anterior Nucleus of the Thalamus via 3 T Quantitative Susceptibility Mapping.

Objective: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a potentially effective, minimally invasive, and reversible method for treating epilepsy. The goal of this study was to explore whether 3 T quantitative susceptibility mapping (QSM) could delineate the ANT from surrounding structures, which is important for the direct targeting of DBS surgery. Methods: We obtained 3 T QSM, T1-weighted (T1w), and T2-weighted (T2w) images from 11 patients with Parkinson's disease or dystonia who received subthalamic nucleus (STN) or globus pallidus interna (GPi) DBS surgery in our center. The ANT and its surrounding white matter structures on QSM were compared with available atlases. The contrast-to-noise ratios (CNRs) of ANT relative to the external medullary lamina (eml) were compared across the three imaging modalities. Additionally, the morphology and location of the ANT were depicted in the anterior commissure (AC)-posterior commissure (PC)-based system. Results: ANT can be clearly distinguished from the surrounding white matter laminas and appeared hyperintense on QSM. The CNRs of the ANT-eml on QSM, T1w, and T2w images were 10.20 ± 4.23, 1.71 ± 1.03, and 1.35 ± 0.70, respectively. One-way analysis of variance (ANOVA) indicated significant differences in CNRs among QSM, T1w, and T2w imaging modalities [F(2) = 85.28, p < 0.0001]. In addition, both the morphology and location of the ANT were highly variable between patients in the AC-PC-based system. Conclusion: The potential utility of QSM for the visualization of ANTs in clinical imaging is promising and may be suitable for targeting the ANT for DBS to treat epilepsy.

Localization of the Epileptogenic Zone by Multimodal Neuroimaging and High-Frequency Oscillation.

Accurate localization of the epileptogenic zone (EZ) is a key factor to obtain good surgical outcome for refractory epilepsy patients. However, no technique, so far, can precisely locate the EZ, and there are barely any reports on the combined application of multiple technologies to improve the localization accuracy of the EZ. In this study, we aimed to explore the use of a multimodal method combining PET-MRI, fluid and white matter suppression (FLAWS)-a novel MRI sequence, and high-frequency oscillation (HFO) automated analysis to delineate EZ. We retrospectively collected 15 patients with refractory epilepsy who underwent surgery and used the above three methods to detect abnormal brain areas of all patients. We compared the PET-MRI, FLAWS, and HFO results with traditional methods to evaluate their diagnostic value. The sensitivities, specificities of locating the EZ, and marking extent removed versus not removed [RatioChann(ev)] of each method were compared with surgical outcome. We also tested the possibility of using different combinations to locate the EZ. The marked areas in every patient established using each method were also compared to determine the correlations among the three methods. The results showed that PET-MRI, FLAWS, and HFOs can provide more information about potential epileptic areas than traditional methods. When detecting the EZs, the sensitivities of PET-MRI, FLAWS, and HFOs were 68.75, 53.85, and 87.50%, and the specificities were 80.00, 33.33, and 100.00%. The RatioChann(ev) of HFO-marked contacts was significantly higher in patients with good outcome than those with poor outcome (p< 0.05). When intracranial electrodes covered all the abnormal areas indicated by neuroimaging with the overlapping EZs being completely removed referred to HFO analysis, patients could reach seizure-free (p < 0.01). The periphery of the lesion marked by neuroimaging may be epileptic, but not every lesion contributes to seizures. Therefore, approaches in multimodality can detect EZ more accurately, and HFO analysis may help in defining real epileptic areas that may be missed in the neuroimaging results. The implantation of intracranial electrodes guided by non-invasive PET-MRI and FLAWS findings as well as HFO analysis would be an optimized multimodal approach for locating EZ.

Fluid and White Matter Suppression Imaging and Voxel-Based Morphometric Analysis in Conventional Magnetic Resonance Imaging-Negative Epilepsy.

Purpose: Delineation of subtle lesions in magnetic resonance imaging (MRI)-negative patients is of great importance in preoperative epilepsy evaluation. The aim of our study was to explore the diagnostic value of the novel fluid and white matter suppression (FLAWS) sequence in comparison with a voxel-based MRI postprocessing morphometric analysis program (MAP) in a consecutive cohort of non-lesional patients. Methods: Surgical candidates with a negative finding on an official neuroradiology report were enrolled. High-resolution FLAWS image and MAP maps generated based on high-resolution three-dimensional (3D) T1 image were visually inspected for each patient. The findings of FLAWS or MAP-positive (FLAWS/MAP+) regions were compared with the surgical resection cavity in correlation with surgical outcome and pathology. Results: Forty-five patients were enrolled; the pathological examination revealed focal cortical dysplasia (FCD) in 32 patients and other findings in 13 patients. The positive rate, sensitivity, and specificity were 48.9%, 0.43, and 0.87, respectively, for FLAWS and 64.4%, 0.57, and 0.8, respectively, for MAP. Concordance between surgical resection and FLAWS+ or MAP+ regions was significantly associated with a seizure-free outcome (FLAWS: p = 0.002; MAP: p = 0.0003). A positive finding in FLAWS and MAP together with abnormalities in the same gyrus (FLAWS-MAP gyral+) was detected in 31.1% of patients. FLAWS+ only and MAP+ only were found in 7 (15.5%) and 14 (31.1%) patients, respectively. Conclusions: FLAWS showed a promising value for identifying subtle epileptogenic lesions and can be used as a complement to current MAP in patients with MRI-negative epilepsy.

Altered ripple density inside seizure onset zone in patients with focal cortical dysplasia-associated epilepsy.

PURPOSE: To evaluate the clinical and stereoelectroencephalography (SEEG) features and postsurgical outcome in a uniform series of patients who underwent epilepsy surgery and had pathologically confirmation of focal cortical dysplasia (FCD). METHODS: We studied consecutive patients with drug-refractory epilepsy who underwent SEEG recording. The high-frequency oscillations (HFOs) features of SEEG, clinical characteristics, and surgical outcome were evaluated. RESULTS: Sixty patients (31 FCD type I, 13 II, and 16 III) were analyzed retrospectively. Patients with type II tended to have their seizures at an earlier age than those with I and III (p < .01). Six different ictal onset patterns (IOPs) were identified. In patients with temporal lobe epilepsy (TLE), the most common patterns were rhythmic spikes or spike waves and LFRS, and in patients with extratemporal epilepsy, the most common patterns were low-voltage fast activity (LVFA) and rhythmic spikes or spike waves. In addition, ripple density was found to increase significantly from the interictal to ictal onset sections and from the ictal onset to ictal evolution sections in patients with FCD I (p < .001). Regarding the distinct IOPs, ripple density continued to increase significantly between the interictal and ictal onset sections in LVFA, rhythmic spikes or spike waves, and burst of high-amplitude polyspikes (p < .05). Ripple density decreased between ictal onset and ictal evolution sections in patterns of LVFA and rhythmic spikes or spike waves (p < .05). The mean follow-up duration was 2.7 years (range 1-4.2), and 66.7% (n = 40) were class I. Patients with subtypes III and II had favorable surgical outcome than those with I. CONCLUSION: The clinical expression of seizure may depend on the pathological types with FCD II patients exhibiting their seizures at an earlier age. Distinct IOPs may demonstrate different ripple features and distinguishing the IOPs is very necessary to have an insight into the electrophysiological characteristics.