Citations

Abstract INTRODUCTION Glioblastoma (GBM) is a brain cancer known for its complex tumor microenvironment and ability to reprogram glucose metabolism and evade host immune responses. CAR-T cell therapy has attracted considerable attention due to its potential for high specificity and efficacy across various cancer types. However, its success in GBM has been limited due to the unique and hostile metabolic landscape of the tumor microenvironment. GBM tumor cells exhibit enhanced aerobic glycolysis, resulting in elevated glucose consumption. This restricts glucose availability for T cells, impairing activation and anti-tumor response. In our study, we enhanced the tumoricidal activity of CD70 CAR T-cells by overexpressing the glucose transporters GLUT1 and GLUT3, thereby improving their metabolic fitness and enabling them to overcome tumor-induced glucose deprivation. METHODS The CD70 CAR T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The efficacy and safety of metabolically modified CD70 CAR T-cells was investigated in in vitro and in vivo platforms. RESULTS GLUTs overexpression does not negatively affect T-cell differentiation and function but improves glucose consumption and intra-tumoral T-cell trafficking. We then used CD70 CAR-T platform and overexpress GLUT1 and GLUT3 to engineer T-cells. GLUT overexpression provided metabolic advantage to CD70CAR T-cells, which showed enhanced activation and cell avidity when co-cultured with GBM cells in both glucose enriched and restricted conditions. The metabolic modifications regulate CAR T-cell efficacy by enhancing intra-tumoral trafficking and persistence, followed by improved anti-tumor response and survival in mice. The lack of significant alterations in body weight and organ morphology in mice receiving GLUT-overexpressing CD70 CAR T-cells suggests that the adoptive transfer of these metabolically enhanced T cells does not elicit toxicity, thereby demonstrating a favorable safety profile during treatment. CONCLUSION Our study demonstrates development of immunotherapeutic strategies by incorporating core principles of tumor and immune cell metabolism, thus providing evidence that targeting immune-metabolic pathways is a potential approach to treat brain tumor.

ABSTRACT Background and objective Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for managing malignant biliary obstruction (MBO), but it is challenging in patients with surgically altered anatomy (SAA). EUS-guided hepaticogastrostomy (EUS-HGS) and enteroscopy-assisted ERCP are alternative techniques, but their comparative efficacy and safety in this population are not well-researched. Herein, we evaluated the outcomes of EUS-HGS versus single-balloon–assisted enteroscopy ERCP (SBE-ERCP) in MBO patients with SAA. Patients and methods This retrospective study included 70 patients with MBO who underwent EUS-HGS (n = 29) or SBE-ERCP (n = 41) at a single center between April 2015 and June 2024. Data on the patient characteristics, procedure details, time to recurrent biliary obstruction (TRBO), and adverse events (AEs) were analyzed. Results The EUS-HGS group showed a higher technical success rate (100% vs. 68%, P = 0.002), shorter procedure time (23 vs. 50 min, P < 0.001), and longer TRBO (251 vs. 103 d, P = 0.020) as compared with the SBE-ERCP group. Subgroup analysis revealed that pancreatobiliary cancer and SBE-ERCP were significantly associated with a shorter TRBO. When stratified by stent type, the median TRBO in the SBE-ERCP with PS group was 49 days, serving as the reference. In comparison, the median TRBO was 140 days in the SBE-ERCP with the self-expandable metallic stent group (hazard ratio [HR], 0.46; P = 0.181), 127 days in the EUS-HGS with PS group (HR, 0.38; P = 0.055), and 701 days in the EUS-HGS with the self-expandable metallic stent group (HR, 0.13; P = 0.014). The overall incidence of AEs was comparable between the 2 groups (20.6% vs. 17.1%), and there were no severe AEs. Regarding reintervention, there was no significant difference in technical success rate and procedure time between EUS-HGS and SBE-ERCP. Conclusion EUS-HGS was associated with a superior technical success rate, shorter procedure time, and longer stent patency, without an increased risk of AEs, as compared with SBE-ERCP. Thus, EUS-HGS should be appropriate for managing MBO patients with SAA.

100 Background: HER2 is overexpressed in various GI tumors. Tucatinib (TUC), which is approved in combination with trastuzumab (Tras) in the US for previously treated RAS WT HER2+ metastatic colorectal cancer (mCRC), is a tyrosine kinase inhibitor highly selective for HER2. Preliminary safety and antitumor activity results of TUC + trastuzumab + FOLFOX in patients (pts) with HER2+ GI cancers are presented. Methods: The phase 1b/2 SGNTUC-024 (NCT04430738) study evaluated TUC + Tras + FOLFOX in pts with HER2+ metastatic GI cancers in Cohorts 1A, 1B, 1D (pts in Japan), and 2B. For Cohorts 1A, 1B, and 1D (enrolled sequentially), eligible pts had unresectable or metastatic HER2+ GI malignancies, including mCRC. Cohort 2B is still enrolling, and pts with HER2+ mCRC are eligible. Pts received a combination of TUC 150 mg orally twice a day (PO BID; Cohort 1A) or TUC 300 mg PO BID (Cohorts 1B, 1D, and 2B) + Tras + FOLFOX. Pts in Cohort 2B were enrolled to further assess the study regimen. Antidiarrheal prophylaxis was required for Cohort 1D. Results: As of July 10, 2023, 25 pts were treated (5, 11, 7, and 2 in Cohorts 1A, 1B, 1D, and 2B, respectively). In Cohort 1A (TUC 150 mg PO BID), the most common TEAEs were diarrhea, fatigue, nausea, and proteinuria (each in 60.0% [3/5]). For pts receiving TUC 300 mg PO BID, the most common TEAEs were diarrhea (90.0% [18/20]) and fatigue (65.0% [13/20]). Table 1 presents the overall summary of adverse events. In Cohort 1A, Treatment-emergent adverse events (TEAEs) leading to any treatment discontinuation were reported in 40.0% (2/5) pts, with 20.0% (1/5) discontinuing tucatinib. For pts treated with TUC 300 mg, TEAEs leading to treatment discontinuation were reported in 35.0% (7/20), with 15.0% (3/20) discontinuing tucatinib. One TEAE leading to death (aspiration) in Cohort 1A was unrelated to study treatment. Grade ≥3 diarrhea was observed in 45.5% (5/11) pts in Cohort 1B; most were observed in elderly pts or pts with gastric, gastroesophageal, or esophageal cancer or pts who were generally noncompliant with antidiarrheal treatment. No grade ≥3 diarrhea was observed in Cohort 1D. Among pts receiving TUC 300 mg, confirmed objective response rate was 83.3% (5/6) for mCRC, 40.0% (4/10) for gastroesophageal cancers, and 0% (0/4) for biliary tract cancer. Conclusions: TUC + Tras + FOLFOX showed manageable safety in the enrolled pt population and preliminary antitumor activity in pts with HER2+ mCRC and gastroesophageal cancer. This regimen will be compared with the standard of care (FOLFOX with or without bevacizumab/cetuximab) in the ongoing randomized, phase 3 study (MOUNTAINEER-03; NCT05253651) for pts with HER2+ RAS WT mCRC. Clinical trial information: NCT04430738 . [Table: see text]

Abstract Monoclonal B-cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Improved prediction of progression would greatly benefit individuals with MBL. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. Here, we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs a cohort of 226 patients with CLL revealed ELCLV3-21 high-risk individuals with MBL had significantly shorter time to therapy (P = .003) and reduced overall survival (P = .03) compared with ELCLV3-21 low-risk individuals with CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

AbstractBackgroundThe damping ratio (DR) and the loss modulus (G″) obtained by 3D MR elastography complex modulus analysis has been reported recently to reflect early intrahepatic inflammation, and is expected to be a noninvasive biomarker of inflammation in nonalcoholic fatty liver disease (NAFLD). However, the role of the DR and the G″ in Japanese NAFLD patients remains unclear.MethodsWe enrolled 39 Japanese patients with NAFLD who underwent liver biopsy and 3D MR elastography within 1 month and analyzed the association between DR, G″, and histological activity.ResultsRegarding DR, no evident correlation was observed between the DR and histological activity (p = 0.14) when patients with all fibrosis stages were included. However, when patients were restricted up to stage F2 fibrosis, the association of the DR and inflammation became significant, the DR increasing with the degree of activity (p = 0.02). Among the constituents of fibrosis activity, ballooning correlated with the DR (p < 0.01) while lobular inflammation did not. Regarding G″, it was correlated with histological activity (p < 0.01), ballooning (p < 0.01), and lobular inflammation (p < 0.01) in patients with all fibrosis stages and in patients up to F2 fibrosis (p = 0.03 for activity and p = 0.04 for ballooning). The best cutoff value of DR for hepatitis activity in patients within the F2 stage was 0.094 (area under the receiver operating characteristic curve 0.775, 95% CI: 0.529–1.000) and G″ was 0.402 (area under the receiver operating characteristic curve 0.825, 95% CI: 0.628–1.000).ConclusionsThe DR and G″ reflected the histological activity in Japanese patients with NAFLD during the early stage, indicating these values for noninvasive diagnosis of inflammation in Japanese patients with NAFLD.

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams‐Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain‐of‐function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP‐10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain‐of‐function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895–901

Background: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. Methods: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. Results: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2–14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3–5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7–12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4–37.7; P , 0.026). Conclusions: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

AbstractBackgroundPathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs) and neurofibrillary tangles (NFTs), which are formed from highly phosphorylated tau. Lithium chloride (LiCl) has been shown to inhibit phosphorylated tau by inhibiting glycogen synthase kinase‐3β (GSK‐3β). In addition, autophagy lysosome system (Hamano et al., Eur J Neurosci 27; 1119, 2008) and proteasome (J Neurochem 2000) are known to play an important role as tau degradation pathways. We investigated the decrease of phosphorylated tau by LiCl by using cell culture model expressing wild‐type tau via TetOff induction system.MethodsTen to 50mM of LiCl treatment (24 hours) was performed to neuroblastoma cells (M1C) expressing wild‐type tau protein (4R0N) via TetOff induction. Total and phosphorylated tau (PHF‐1) levels and autophagy activation were examined by Western blot (WB) analysis.ResultsReduction of total tau (Tau5) and phosphorylated tau (PHF‐1, and CP13) with LiCl treatment was detected by WB analysis. C‐terminal truncated tau species detected by TauC3 was decreased by LiCl, too. In addition, increase of LC3Ⅱ/I, and decrease of P62 suggesting autophagy activation was observed. Major Tau kinase GSK3β was inactivated by LiCl.ConclusionsThese results imply that LiCl may decrease the phosphorylated tau through suppression of tau phosphokinase and activation of autophagy.