Pediatric epilepsy (PE) is a common neurological disease. However, many challenges regarding the clinical diagnosis and treatment of PE and drug-resistant epilepsy (DRE) remain unsettled. Our study ...aimed to identify potential miRNA biomarkers in children with epilepsy and drug-resistant epilepsy by scrutinizing differential miRNA expression profiles.
In this study, miRNA expression profiles in plasma extracellular vesicles (EV) of normal controls, children with drug-effective epilepsy (DEE), and children with DRE were obtained. In addition, differential analysis, transcription factor (TF) enrichment analysis, Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and target gene prediction were used to identify specifically expressed miRNAs and their potential mechanisms of action. Potential diagnostic markers for DRE were identified using machine learning algorithms, and their diagnostic efficiency was assessed by the receiver operating characteristic curve (ROC).
The hsa-miR-1307-3p, hsa-miR-196a-5p, hsa-miR-199a-3p, and hsa-miR-21-5p were identified as diagnostic markers for PE, with values of area under curve (AUC) 0.780, 0.840, 0.832, and 0.816, respectively. In addition, the logistic regression model incorporating these four miRNAs had an AUC value of 0.940, and its target gene enrichment analysis highlighted that these miRNAs were primarily enriched in the PI3K-Akt, MAPK signaling pathways, and cell cycle. Furthermore, hsa-miR-99a-5p, hsa-miR-532-5p, hsa-miR-181d-5p, and hsa-miR-181a-5p showed good performance in differentiating children with DRE from those with DEE, with AUC values of 0.737 (0.534-0.940), 0.737 (0.523-0.952), 0.788 (0.592-0.985), and 0.788 (0.603-0.974), respectively.
This study characterized the expression profile of miRNAs in plasma EVs of children with epilepsy and identified miRNAs that can be used for the diagnosis of DRE.
Stroke is a prominent contributor to global mortality and morbidity, thus necessitating the establishment of dependable diagnostic indicators. The objective of this study was to ascertain metabolites ...linked to sphingolipid metabolism and assess their viability as diagnostic markers for stroke.
Two cohorts, consisting of 56 S patients and 56 healthy volunteers, were incorporated into this investigation. Metabolite data was obtained through the utilization of Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC-MS/MS). The mass spectrometry data underwent targeted analysis and quantitative evaluation utilizing the multiple reaction monitoring mode of triple quadrupole mass spectrometry. Various data analysis techniques, including Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA), least absolute shrinkage and selection operator (LASSO) regression, Support Vector Machine (SVM), logistic regression, and Receiver Operating Characteristic (ROC) curves were employed.
A comprehensive analysis detected a total of 129 metabolites related to sphingolipid metabolism, encompassing ceramides, 1-phosphoceramides, phytoceramides, glycosphingolipids, sphingomyelins, and sphingomyelins. The implementation of OPLS-DA analysis revealed significant disparities between individuals with stroke and controls, as it successfully identified 31 metabolites that exhibited significant differential expression between the two groups. Furthermore, functional enrichment analysis indicated the participation of these metabolites in diverse biological processes. Six metabolic markers, namely CerP(d18:1/20:3), CerP(d18:1/18:1), CerP(d18:1/18:0), CerP(d18:1/16:0), SM(d18:1/26:1), and Cer(d18:0/20:0), were successfully validated as potential diagnostic markers for stroke. The utilization of ROC analysis further confirmed their diagnostic potential, while a logistic regression model incorporating these markers demonstrated robust efficacy in distinguishing stroke patients from healthy controls.
these identified metabolic markers exhibit clinical significance and hold promise as valuable tools for the diagnosis of stroke.
Drug-free biocompatible nanoparticles with photosensitizers as both diagnostic and therapy agents represent an emerging approach for imaging-guided photodynamic therapy (PDT). Here, a NSH-active ...boron-dipyrromethene (BODIPY) derivative with a bromine substituted (BODIPY-Br2, for simplicity, BDP-Br) photosensitizer was synthesized; it showed a high ability of generating reactive oxygen species (ROS) upon irradiation for PDT and near infrared fluorescence imaging ability. Then, a simple PEGylated BDP-Br (PEG-BDP) as a kind of macro photosensitizer was prepared which showed superior cellular uptake ability, high efficiency of imaging, and curing with PDT therapy in vitro and in vivo. After administration with a 4T1 orthotopic tumor model, the resultant PEG-BDP showed prolonged blood circulation and preferential tumor accumulation compared with free BDP-Br molecules. Once accumulated in tumor tissues, therapeutic effects of PEG-BDP could significantly suppress primary tumor growth and has no evident side effects at a weak irradiation energy as low as 35 mW cm−2 for 20 minutes. The designation of this simple structure macro photosensitizer agent provides new avenues for efficient imaging-guided cancer PDT.
Background
The therapeutic landscape of mantle cell lymphoma (MCL) has evolved significantly since the early 2000s. We previously reported that a shift in frontline immunochemotherapy choices from ...2002−2009 to 2010−2015 was associated with improved event-free survival and overall survival (OS) in both younger (age ≤65) and older (age >65) patients in a prospective Mayo Clinic/University of Iowa cohort (Castellino, Blood Advances, 2022). In addition, we recently reported that changes in treatment for relapsed/refractory (R/R) disease over the last two decades were associated with steady improvements in OS for R/R MCL (Tawfiq, ASH, 2022). In this study, we utilized data from the National Cancer Database (NCDB) to investigate the impact of therapy in the modern era on survival outcomes of patients with MCL in the US since 2004.
Methods
The NCDB is an outcomes database of more than 1,500 hospital-based cancer registries covering approximately 70% of newly diagnosed cancers in the US. The latest version of NCDB was used to identify patients with newly diagnosed MCL from 2004 to 2020. Three treatment eras were defined as Era 1 (2004−2009), Era 2 (2010−2014), and Era 3 (2015−2020), based on immunochemotherapy changes (from Era 1 to Era 2) and increased access to novel agents such as Bruton's tyrosine kinase (BTK) inhibitors (from Era 2 to Era 3). Overall survival between different eras was stratified and analyzed based on 3 age groups: <65, 65−79, and ≥80 years. Survival analysis was performed using the Kaplan-Meier method and all Cox proportional hazards models were adjusted for age and sex.
Results
A total of 32,746 patients with newly diagnosed MCL was identified, 12,847 (39.2%) patients were age <65, 14,297 (43.7%) age 65−79, and 5,602 (17.1%) age ≥80. For every age group, the distributions in sex, stage, Charlson-Deyo score, and treatment facility type (academic vs non-academic) were largely similar between eras. As expected, the median OS was significantly worse for patients age ≥80 years (19.8 months) compared to patients age 65-79 years (60.9 months) and patients age <65 years (143.9 months; p <0.001).
In patients age <65 years, OS in Era 2 was improved when compared to Era 1, with a 5-year OS rate of 72.1% vs 67.6% (logrank p<0.001) (Figure 1) and an age- and sex-adjusted hazard ratio (HR) of 0.83 (95% CI 0.78−0.89, p<0.001). OS in Era 3 was similar to that in Era 2, with a 5-year OS rate of 72.2% vs 72.1% (logrank p=0.61) and an age- and sex-adjusted HR of 0.97 (95% CI 0.89−1.06, p=0.51).
In patients age 65-79 years, similar trends in OS changes between eras were observed. The 5-year OS rate in Era 1, Era 2, and Era 3 was 43.3%, 52.8%, and 54.9%, respectively (p<0.001 comparing Era 2 vs Era 1, and p=0.05 comparing Era 3 vs Era 2). Age- and sex-adjusted HR was 0.83 (95% CI 0.78−0.87, p<0.001) comparing Era 2 vs Era 1 and 0.95 (95% CI 0.89−1.01, p=0.07) comparing Era 3 vs Era 2.
In patients age ≥80 years, the improvement in OS from Era 1 to Era 2 was less prominent than other age groups. The 5-year OS rate was 22.9% vs 19.5% (p=0.03), and age- and sex-adjusted HR was 0.88 (95% CI 0.81−0.94, p<0.001). OS in Era 3 vs Era 2 was similar, with a 5-year OS rate of 23.1% vs 22.9% (logrank p=0.79) and an age- and sex-adjusted HR of 0.98 (95% CI 0.91−1.06, p=0.67).
Conclusions
This large NCDB study demonstrated that survival of patients with newly diagnosed MCL has improved over the last two decades. The results are consistent with our Mayo Clinic/University of Iowa prospective cohort study and confirm an improved OS after 2010, which was most likely driven by both frontline immunochemotherapy changes and better access to novel agents for R/R disease. The 5-year OS in patients diagnosed in 2015−2020 did not appear to be superior to those in 2010−2014, despite presumably having better access to novel agents such as BTK inhibitors in the R/R setting. This lack of a difference in OS may be partially due to short follow-up, but may also suggest that further improvement in frontline therapies by incorporating novel agents may be required to improve OS. The OS of patients age ≥80 years is limited and has only minimally improved after 2010, highlighting a significant unmet need for therapies with improved tolerability and efficacy in this age group.
pH-Sensitive doxorubicin conjugated polymeric micelles entrapped with near infrared (NIR) photosensitizer BODIPY (which works as an imaging agent at the same time) were designed and synthesized by ...ring opening polymerization of N-carboxyanhydride with mPEG-NH
as the initiator, following reaction with doxorubicin to form the hydrazone-bond linker for pH responsiveness. Then the NIR dye (BODIPY) was loaded in the micelles for both bioimaging and photodynamic therapy (PDT). A significant cytotoxicity of NIR imaging-guided combined PDT and chemotherapy could be found by MTT assays, which was also confirmed with a fluorescence microscope, indicating a new kind of polymeric nanoparticle for potential theranostic treatment of cancers. In addition, the energy density of the laser for the PDT is extremely low.
Variability in activity of CYP2C9, which is involved in the metabolism of approximately 15% of current therapeutic drugs, is an important contributor to interindividual differences in drug response. ...To evaluate the functional alternations of CYP2C9(*)2, CYP2C9(*)3, CYP2C9(*)8, CYP2C9(*)11 and CYP2C9(*)31, identified in our previous study in Chinese Han population, allelic variants as well as the wild-type CYP2C9 were transiently expressed in COS-7 cells. Kinetic parameters (Km, Vmax, and Clint) for S-warfarin 7-hydroxylation by these recombinant CYP2C9s were determined. Relative to CYP2C9.1, recombinant CYP2C9.3 and CYP2C9.11 exhibited significantly higher Km values, and all allelic variants showed significantly decreased Vmax and Clint values. Among all allelic variants, catalytic activity of CYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8% of Clint ratio, respectively; P < 0.001). These findings should be useful for predicting the phenotype profiles of CYP2C9 in Chinese Han population, comparing the functional results of these alleles accurately, and finally optimizing pharmacotherapy of drug treatment.
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Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or ...progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. Table: see text
Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab ...maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era.
Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up.
Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients.
The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response CR and 13% partial response PR). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1).
Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1).
A subset analysis of patients aged ≥65 years (n=471; 198 42% received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months.
Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.
To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study ...(NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.
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