MEG3 in hematologic malignancies: from the role of disease biomarker to therapeutic target.

Maternally expressed gene 3 ( MEG3 ) is a noncoding RNA that is known as a tumor suppressor in solid cancers. Recently, a line of studies has emphasized its potential role in hematological malignancies in terms of tumorigenesis, metastasis, and drug resistance. Similar to solid cancers, MEG3 can regulate various cancer hallmarks via sponging miRNA, transcriptional, or posttranslational regulation mechanisms, but may regulate different key elements. In contrast with solid cancers, in some subtypes of leukemia, MEG3 has been found to be upregulated and oncogenic. In this review, we systematically describe the role and underlying mechanisms of MEG3 in multiple types of hematological malignancies. Particularly, we highlight the role of MEG3 in drug resistance and as a novel therapeutic target.

Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications.

ABSTRACT: Metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) is a well-established oncogenic long non-coding RNA, the higher expression of which is strongly correlated with cancer events such as tumorigenesis, progression, metastasis, drug resistance, and treatment outcome in solid cancers. Recently, a series of studies has highlighted its potential role in hematological malignancies in terms of these events. Similar to solid cancers, MALAT1 can regulate various target genes via sponging and epigenetic mechanisms, but the miRNAs sponged by MALAT1 differ from those identified in solid cancers. In this review, we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies, including regulation of cell proliferation, metastasis, stress response, and glycolysis. Clinically, MALAT1 expression is related to poor treatment outcome and drug resistance, therefore exhibiting potential prognostic value in multiple myeloma, lymphoma, and leukemia. Finally, we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

A new cytotoxic disaccharide glycoside from the tubers of Arisaema franchetianum.

A new disaccharide glycoside, franchoside A (1), and 17 known compounds were isolated from the tubers of Arisaema franchetianum Engler. The chemical structure of the previously undescribed compound 1 was elucidated on the basis of detailed spectroscopic analyses. Compounds 1, 2, 6, 10, 14 and 18 showed significant cytotoxic activities at varying IC50 values in the range of 4.0-10.6 µM against five cancer cell lines. Compounds 8, 10, 13 and 17 (10 µM) exhibited moderate anti-inflammatory activities by inhibiting the NF-κB signaling pathway and the release of NO from RAW264.7 macrophages induced by lipopolysaccharide (LPS), while compounds 1, 9, 14, 15 and 16 showed weak anti-inflammatory activities.

The lncRNA lnc-TSI antagonizes sorafenib resistance in hepatocellular carcinoma via downregulating miR-4726-5p expression and upregulating KCNMA1 expression.

Acquired drug resistance is a main reason for limiting the application of sorafenib in HCC treatment. This study aimed to explore the role and mechanisms of a novel long non-coding RNA (lncRNA), lnc-TSI, in sorafenib resistance of HCC. The interaction between lnc-TSI and miR-4726-5p, and miR-4726-5p and KCNMA1 were predicted using bioinformatic tools. Expression of the molecules in the lnc-TSI/miR-4726-5p/KCNMA1 axis in clinical samples and cell lines, as well as the sorafenib resistant HCC cell lines, was determined using qRT-PCR or western blotting. Expressions of lnc-TSI, miR-4726-5p, and KCNMA1 were manipulated in HepG2 and Huh7 cells through plasmid transfection or lentivirus infection. The CCK-8, flow cytometry, and Tunel assays were employed to determine the role of this axis on sorafenib resistance of HCC. A xenograft model was established using sorafenib-resistant HepG2 and Huh7 cells followed by in vivo sorafenib treatments to confirm the in vitro findings. Lnc-TSI and KCNMA1 expressions were significantly downregulated in HCC clinical samples and cell lines, especially in sorafenib resistance ones, while mi-4726-5p presented a reversed expression pattern. Lnc-TSI interacted with miR-4726-5p, and Lnc-TSI acts as a ceRNA via sponging miR-4726-5p in HCC cells. Overexpression of lnc-TSI and KCNMA1 promoted apoptosis and decreased cell viability of sorafenib-treated HCC cells, thus alleviated sorafenib resistance. miR-4726-5p mimic reversed the KCNMA1-mediated sorafenib sensitivity-promoting effect, while additional overexpression of lnc-TSI reversed the effect of miR-4726-5p. In vivo analysis also showed that overexpression of ln-TSI diminished sorafenib resistance in mice inoculated with sorafenib-resistant HCC cells via increasing KCNMA1 expression and decreasing miR-4726-5p expression. The lnc-TSI/miR-4726-5p/KCNMA1 axis plays a critical role in regulating the resistance of HCC to sorafenib, and might serve as a therapeutic target to manage sorafenib resistance of HCC in clinic.

Curative Effect of Bracketless and Invisible Orthodontic Treatment for Periodontitis and the Influence on Gingival Crevicular Fluid and Serum IL-6, MMP-8 and TNF-α Levels.

Objective: To observe the therapeutic effects of bracketless and invisible orthodontic treatment on periodontitis, as well as on gingival crevicular fluid and serum interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and tumors. The impact of necrosis factor-alpha (TNF-α) levels fills the current knowledge gap regarding the impact of different orthodontic treatment modalities on biomarker levels in periodontitis patients. Methods: 100 patients with malocclusion secondary to periodontitis were selected as subjects.They were divided into a control group (n=50) and a study group (n=50) according to the random number method. The control group was treated with a straight wire appliances, and the study group was given bracketless and invisible orthodontic treatment. Clinical effects, Periodontal indicators [plaque index (PLI), gingival crevicular bleeding index (SBI), gingival index (GI), periodontal pocket probe depth (PD), clinical attachment loss (CAL)], gingival crevicular fluid and serum IL-6, MMP-8 and TNF-α levels and the incidence of adverse reactions were compared between the two groups. The uniqueness of this method is that it compares the impact of traditional straight-wire orthodontic treatment and invisible orthodontic treatment without brackets on biomarker levels and clinical effects in patients with periodontitis. In order to understand the role of orthodontic treatment methods in Provides useful information for use in periodontitis treatment. Results: The main findings of this study highlight the significant impact of bracketless clear braces in improving periodontal indicators and cytokine levels. Patients treated with bracketless clear braces demonstrate better clinical outcomes in periodontitis treatment compared with traditional straight-wire orthodontic treatment. The response rate of the study group was higher than that of the control group (94.00% vs. 72.00%) (P < .05). After 2 years of treatment, PLT, SBI, GI, PD and CAL were decreased in both groups and the observation group was significantly lower than the control group (P < .05). After 6 months of treatment, the levels of IL-6, MMP-8 and TNF-α in gingival crevicular fluid and serum were decreased in both groups, and the observation group was significantly lower than the control group (P < .05). There was no significant difference in the incidence of adverse reactions between the two groups (P > .05). Conclusion: The treatment of periodontitis without brackets has a significant effect, which can improve the periodontal condition and reduce the levels of IL-6, MMP-8 and TNF-α in gingival crevicular fluid and serum. Bracketless invisible braces have shown potential clinical significance in improving periodontal indicators and cytokine levels in patients with periodontitis, providing support for providing more comfortable and effective orthodontic treatment options, which may help promote patients' Oral health. These findings suggest the positive role of bracketless invisible braces in comprehensive periodontal treatment, which is expected to influence the practice of orthodontics and periodontal treatment and improve patient treatment experience and effects.

Spatiotemporally sequential delivery of biomimetic liposomes potentiates glioma chemotherapy.

As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not only the limited permeability of the blood-brain barrier (BBB) but also the deficiency of targeting tumor lesions. Thus, spatiotemporally sequential delivery of therapeutics from BBB-crossing to glioma accumulation is considered a strategy to obtain better outcomes. Here, we developed a biomimetic chemotherapy nanodrug composed of the hybrid membrane envelope of U87 cell membranes and RAW264.7 cell membranes, and the core of paclitaxel (PTX)-loaded liposome (PTX@C-MMCL). In the research, PTX@C-MMCL showed superior ability to cross the BBB via RAW264.7 cell membranes and accurate targeting to the brain tumor lesions relying on the homotypic targeting capacity of U87 cell membranes. Furthermore, PTX@C-MMCL can maintain a prolonged circulation in vivo. Importantly, PTX@C-MMCL effectively inhibited the development of glioma. Conclusively, our biomimetic nanodrug holds great potential for brain tumor targeting therapy.

Prognostic MRI features to predict postresection survivals for very early to intermediate stage hepatocellular carcinoma.

OBJECTIVES: Contrast-enhanced MRI can provide individualized prognostic information for hepatocellular carcinoma (HCC). We aimed to investigate the value of MRI features to predict early (≤ 2 years)/late (> 2 years) recurrence-free survival (E-RFS and L-RFS, respectively) and overall survival (OS). MATERIALS AND METHODS: Consecutive adult patients at a tertiary academic center who received curative-intent liver resection for very early to intermediate stage HCC and underwent preoperative contrast-enhanced MRI were retrospectively enrolled from March 2011 to April 2021. Three masked radiologists independently assessed 54 MRI features. Uni- and multivariable Cox regression analyses were conducted to investigate the associations of imaging features with E-RFS, L-RFS, and OS. RESULTS: This study included 600 patients (median age, 53 years; 526 men). During a median follow-up of 55.3 months, 51% of patients experienced recurrence (early recurrence: 66%; late recurrence: 34%), and 17% died. Tumor size, multiple tumors, rim arterial phase hyperenhancement, iron sparing in solid mass, tumor growth pattern, and gastroesophageal varices were associated with E-RFS and OS (largest p = .02). Nonperipheral washout (p = .006), markedly low apparent diffusion coefficient value (p = .02), intratumoral arteries (p = .01), and width of the main portal vein (p = .03) were associated with E-RFS but not with L-RFS or OS, while the VICT2 trait was specifically associated with OS (p = .02). Multiple tumors (p = .048) and radiologically-evident cirrhosis (p < .001) were the only predictors for L-RFS. CONCLUSION: Twelve visually-assessed MRI features predicted postoperative E-RFS (≤ 2 years), L-RFS (> 2 years), and OS for very early to intermediate-stage HCCs. CLINICAL RELEVANCE STATEMENT: The prognostic MRI features may help inform personalized surgical planning, neoadjuvant/adjuvant therapies, and postoperative surveillance, thus may be included in future prognostic models. KEY POINTS: • Tumor size, multiple tumors, rim arterial phase hyperenhancement, iron sparing, tumor growth pattern, and gastroesophageal varices predicted both recurrence-free survival within 2 years and overall survival. • Nonperipheral washout, markedly low apparent diffusion coefficient value, intratumoral arteries, and width of the main portal vein specifically predicted recurrence-free survival within 2 years, while the VICT2 trait specifically predicted overall survival. • Multiple tumors and radiologically-evident cirrhosis were the only predictors for recurrence-free survival beyond 2 years.

Detection of Thyroid Nodule Prevalence and Associated Risk Factors in Southwest China: A Study of 45,023 Individuals Undergoing Physical Examinations.

Background: Thyroid nodules (TNs) are among the most common thyroid lesions, and rates of these nodules have risen over the past three decades. As the majority of TN patients remain asymptomatic when these nodules are in the early stages of development, malignant nodules may continue to develop into thyroid cancer when not detected. As such, early screening and diagnosis-based strategies represent the most promising means of preventing or treating TNs and associated cancers. The present study was thus developed to explore TN prevalence among individuals in Luzhou, China. Methods: Here, thyroid ultrasonography and metabolic-related indicators from 45,023 adults undergoing routine physical examinations in the Health Management Center of a large Grade A hospital in Luzhou over the last three years were retrospectively reviewed in an effort to identify factors associated with TN risk and the detection of these nodules through univariate and multivariate logistic regression analyses. Results: In total, 13,437 TNs were detected in these 45,023 healthy adults for an overall 29.8% detection rate. This TN detection rate rose with age, and multivariate logistic regression analyses revealed that independent risk factors associated with TNs included greater age (≥31 years old), female (OR = 2.283, 95% CI: 2.177-2.393), central obesity (OR = 1.115, 95% CI: 1.051-1.183), impaired fasting glucose (OR = 1.203, 95% CI: 1.063-1.360), overweight status (OR = 1.085, 95% CI: 1.026-1.147), and obesity (OR = 1.156, 95% CI: 1.054-1.268), while low BMI was a protective factor associated with lower rates of TN incidence (OR = 0.789, 95% CI: 0.706-0.882). When results were stratified by gender, impaired fasting glucose was not an independent predictor of TN risk among males, while high LDL levels were an independent predictor of TNs among females, and other risk factors were not significantly changed. Conclusion: TN detection rates were high among adults in Southwestern China. Female, elderly individuals, individuals exhibiting central obesity, and those with high levels of fasting plasma glucose are more likely to develop TN.

Development and validation of the OSASH score to predict overall survival of hepatocellular carcinoma after surgical resection: a dual-institutional study.

OBJECTIVE: To develop and validate a risk score based on preoperative clinical-radiological parameters for predicting overall survival (OS) in patients undergoing surgical resection for hepatocellular carcinoma (HCC). METHODS: From July 2010 to December 2021, consecutive patients with surgically-proven HCC who underwent preoperative contrast-enhanced MRI were retrospectively enrolled. A preoperative OS risk score was constructed in the training cohort using a Cox regression model and validated in a propensity score-matched internal validation cohort and an external validation cohort. RESULTS: A total of 520 patients were enrolled, among whom 210, 210, and 100 patients were from the training, internal validation, and external validation cohorts, respectively. Independent predictors for OS included incomplete tumor "capsule," mosaic architecture, tumor multiplicity, and serum alpha-fetoprotein, which were incorporated into the "OSASH score." The C-index the OSASH score was 0.85, 0.81, and 0.62 in the training, internal, and external validation cohorts, respectively. Using 32 as the cutoff point, the OSASH score stratified patients into prognostically distinct low- and high-risk groups among all study cohorts and six subgroups (all p < 0.05). Furthermore, patients with BCLC stage B-C HCC and OSASH-low risk achieved comparable OS to that of patients with BCLC stage 0-A HCC and OSASH-high risk in the internal validation cohort (5-year OS rates, 74.7 vs. 77.8%; p = 0.964). CONCLUSION: The OSASH score may help predict OS in HCC patients undergoing hepatectomy and identify potential surgical candidates among those with BCLC stage B-C HCC. CLINICAL RELEVANCE STATEMENT: By incorporating three preoperative MRI features and serum AFP, the OSASH score may help predict postsurgical overall survival in patients with hepatocellular carcinoma and identify potential surgical candidates among those with BCLC stage B and C HCC. KEY POINTS: • The OSASH score incorporating three MRI features and serum AFP can be used to predict OS in HCC patients who received curative-intent hepatectomy. • The score stratified patients into prognostically distinct low- and high-risk strata in all study cohorts and six subgroups. • Among patients with BCLC stage B and C HCC, the score identified a subgroup of low-risk patients who achieved favorable outcomes after surgery.

Effect of esketamine on postoperative depressive symptoms in patients undergoing thoracoscopic lung cancer surgery: A randomized controlled trial.

Background: Depressive symptoms are common among patients with lung cancer. We aimed to assess the effects of esketamine on postoperative depressive symptoms after thoracoscopic lung cancer surgery. Methods: In this randomized, double-blind, placebo-controlled trial, 156 patients undergoing thoracoscopic lung cancer surgery were randomly allocated in a 1:1 ratio to receive intravenous esketamine (intraoperatively and in patient-controlled analgesia until 48 h postoperatively) or normal saline placebo. The primary outcome was the proportion of patients with depressive symptoms at 1 month postoperatively, assessed using the Beck Depression Inventory-II (BDI-II). Secondary outcomes included depressive symptoms at 48 h postoperatively, hospital discharge and 3 months postoperatively, BDI-II scores, anxious symptoms, Beck Anxiety Inventory scores, Quality of Recovery-15 (QoR-15) scores, and 1- and 3-month mortality. Main results: A total of 151 patients (75 in the esketamine group and 76 in the normal saline group) completed the 1-month follow-up. The esketamine group had a significantly lower incidence of depressive symptoms at 1 month compared to the normal saline group (1.3% vs. 11.8%; risk difference = -10.5, 95%CI = -19.6% to -0.49%; p = 0.018). After excluding patients without lung cancer diagnosis, the incidence of depressive symptoms was also lower in the esketamine group (1.4% vs. 12.2%; risk difference = -10.8, 95%CI = -20.2% to -0.52%; p = 0.018). The secondary outcomes were similar between groups, except that the esketamine group had higher QoR-15 scores at 1 month postoperatively (median difference = 2; 95%CI = 0 to 5; p = 0.048). The independent risk factors for depressive symptoms were hypertension (odds ratio = 6.75, 95%CI = 1.13 to 40.31; p = 0.036) and preoperative anxious symptoms (odds ratio = 23.83, 95%CI = 3.41 to 166.33; p = 0.001). Conclusion: Perioperative administration of esketamine reduced the incidence of depressive symptoms at 1 month after thoracoscopic lung cancer surgery. History of hypertension and preoperative anxious symptoms were independent risk factors for depressive symptoms.Clinical trial registration: Chinese Clinical Trial Registry http://www.chictr.org.cn, Identifier (ChiCTR2100046194).

Long-term outcomes of relmacabtagene autoleucel in Chinese patients with relapsed/refractory large B-cell lymphoma: Updated results of the RELIANCE study.

BACKGROUND AIMS: The RELIANCE study has demonstrated the activity and safety of relmacabtagene autoleucel (relma-cel) (JW Therapeutics [Shanghai] Co, Ltd, Shanghai, China), a CD19-targeted chimeric antigen receptor T-cell product, in patients with heavily pre-treated relapsed/refractory large B-cell lymphoma (r/r LBCL). This study aimed to report the updated 2-year data of the RELIANCE study. METHODS: The RELIANCE study (NCT04089215) was an open-label, multi-center, randomized, phase 1/2 registrational clinical trial conducted at 10 clinical sites in China. Adult patients with heavily pre-treated r/r LBCL were enrolled and received lymphodepletion chemotherapy followed by infusion of 100 × 106 or 150 × 106 relma-cel. The primary endpoint was objective response rate (ORR) at 3 months, as assessed by investigators. Secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety profiles. RESULTS: From November 2017 to January 2022, a total of 68 patients were enrolled, and 59 patients received relma-cel infusion. As of March 29, 2022, a total of 59 patients had a median follow-up of 17.9 months (range, 0.3-25.6). ORR was 77.59% (95% confidence interval [CI], 64.73-87.49) and complete response rate was 53.45% (95% CI, 39.87-66.66). Median DoR was 20.3 months (95% CI, 4.86-not reached [NR]) and median PFS was 7.0 months (95% CI, 4.76-24.15). Median OS was NR and 1-year and 2-year OS rates were 75.0% and 69.3%, respectively. Three (5.1%) patients experienced grade ≥3 cytokine release syndrome and two (3.4%) patients had grade ≥3 neurotoxicity. CONCLUSIONS: The updated data of the RELIANCE study demonstrate durable response with and manageable safety profile of relma-cel in patients with heavily pre-treated r/r LBCL.

Signaling Network Response to α-Particle-Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors.

α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Methods: Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N (DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor-bearing nude mice. Results: TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to 225Ac-PP-F11N. As compared with the control and monotherapies, the combination of 225Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Conclusion: Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to 225Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.

A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer.

Background: Immune checkpoint blockade (ICB) therapy has brought remarkable clinical benefits to patients with advanced non-small cell lung carcinoma (NSCLC). However, the prognosis remains largely variable. Methods: The profiles of immune-related genes for patients with NSCLC were extracted from TCGA database, ImmPort dataset, and IMGT/GENE-DB database. Coexpression modules were constructed using WGCNA and 4 modules were identified. The hub genes of the module with the highest correlations with tumor samples were identified. Then integrative bioinformatics analyses were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of NSCLC. Cox regression and Lasso regression analyses were conducted to screen prognostic signature and to develop a risk model. Results: Functional analysis showed that immune-related hub genes were involved in the migration, activation, response, and cytokine-cytokine receptor interaction of immune cells. Most of the hub genes had a high frequency of gene amplifications. MASP1 and SEMA5A presented the highest mutation rate. The ratio of M2 macrophages and naïve B cells revealed a strong negative association while the ratio of CD8 T cells and activated CD4 memory T cells showed a strong positive association. Resting mast cells predicted superior overall survival. Interactions including protein-protein, lncRNA and transcription factor interactions were analyzed and 9 genes were selected by LASSO regression analysis to construct and verify a prognostic signature. Unsupervised hub genes clustering resulted in 2 distinct NSCLC subgroups. The TIDE score and the drug sensitivity of gemcitabine, cisplatin, docetaxel, erlotinib and paclitaxel were significantly different between the 2 immune-related hub gene subgroups. Conclusions: These findings suggested that our immune-related genes can provide clinical guidance for the diagnosis and prognosis of different immunophenotypes and facilitate the management of immunotherapy in NSCLC.

VICT2 Trait: Prognostic Alternative to Peritumoral Hepatobiliary Phase Hypointensity in HCC.

Background Peritumoral hepatobiliary phase (HBP) hypointensity is an established prognostic imaging feature in hepatocellular carcinoma (HCC), often associated with microvascular invasion (MVI). Similar prognostic features are needed for non-HBP MRI. Purpose To propose a non-hepatobiliary-specific MRI tool with similar prognostic value to peritumoral HBP hypointensity. Materials and Methods From December 2011 to November 2021, consecutive patients with HCC who underwent preoperative contrast-enhanced MRI were retrospectively enrolled and followed up until recurrence. All MRI scans were reviewed by two blinded radiologists with 7 and 10 years of experiences with liver MRI. A scoring system based on non-hepatobiliary-specific features that highly correlated with peritumoral HBP hypointensity was identified in a stratified sampling-derived training set of the gadoxetate disodium (EOB) group by means of multivariable logistic regression, and its values to predict MVI and recurrence-free survival (RFS) were assessed. Results There were 660 patients (551 men; median age, 53 years; IQR, 45-61 years) enrolled. Peritumoral portal venous phase hypoenhancement (odds ratio [OR] = 8.8), incomplete "capsule" (OR = 3.3), corona enhancement (OR, 2.6), and peritumoral mild-moderate T2 hyperintensity (OR, 2.2) (all P < .001) were associated with peritumoral HBP hypointensity and constituted the "VICT2 trait" (test set area under the receiver operating characteristic curve = 0.84; 95% CI: 0.78, 0.90). For the EOB group, both peritumoral HBP hypointensity (OR for MVI = 2.5, P = .02; hazard ratio for RFS = 2.5, P < .001) and the VICT2 trait (OR for MVI = 5.1, P < .001; hazard ratio for RFS = 2.3, P < .001) were associated with MVI and RFS, despite a higher specificity of the VICT2 trait for MVI (89% vs 80%, P = .01). These values of the VICT2 trait were confirmed in the extracellular contrast agent group (OR for MVI = 4.0; hazard ratio for RFS = 1.7; both P < .001). Conclusion Based on four non-hepatobiliary-specific MRI features, the VICT2 trait was comparable to peritumoral hepatobiliary phase hypointensity in predicting microvascular invasion and postoperative recurrence of hepatocellular carcinoma. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Predicting histologic differentiation of solitary hepatocellular carcinoma up to 5 cm on gadoxetate disodium-enhanced MRI.

BACKGROUND: To establish a preoperative score based on gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI) and clinical indicators for predicting histologic differentiation of solitary HCC up to 5 cm. METHODS: From July 2015 to January 2022, consecutive patients with surgically proven solitary HCC measuring ≤ 5 cm at preoperative EOB-MRI were retrospectively enrolled. All MR images were independently evaluated by two radiologists who were blinded to all clinical and pathologic information. Univariate and multivariate logistic regression analyses were performed to identify significant clinicoradiological features associated with poorly differentiated (PD) HCC, which were then incorporated into the predictive score. The predictive score was validated in an independent validation set by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. RESULTS: A total of 182 patients were included, 42 (23%) with PD HCC. According to the multivariate analysis, marked hepatobiliary phase hypointensity (odds ratio [OR], 9.98), LR-M category (OR, 5.60), and serum alpha-fetoprotein (AFP) level > 400 ng/mL (OR, 3.58) were incorporated into the predictive model; the predictive score achieved an AUC of 0.802 and 0.830 on the training and validation sets, respectively. The sensitivity, specificity, and accuracy of the predictive score were 66.7%, 85.7%, and 81.3%, respectively, on the training set and 66.7%, 81.0%, and 77.8%, respectively, on the validation set. CONCLUSION: The proposed score integrating two EOB-MRI features and AFP level can accurately predict PD HCC in the preoperative setting.

Extracellular Vesicles Expressing CD19 Antigen Improve Expansion and Efficacy of CD19-Targeted CAR-T Cells.

Background: CAR-T cell therapy is effective in the treatment of certain hematological malignancies, and the expansion and functional persistence of CAR-T cells in vivo are crucial to clinical efficacy. The aim of this study was to investigate the potential of extracellular vesicles (EVs) modified with the CAR antigen to promote the efficacy of CAR-T cells in vivo. Methods: We generated HEK293T-derived EVs to present the CD19 antigen as the CAR target. In vitro, EVs expressing CD19 antigen (CD19 EVs) were co-incubated with anti-CD19 CAR-T cells. Then, proliferation, cytokine secretion, CD107a expression, tumor killing, subsets, and immune checkpoint expression were measured to assess CAR-T cell function. After infusion of CD19 EVs pretreated CAR-T cells into a lymphoma xenograft mouse model, flow cytometry and digital PCR were used to measure the expansion of CAR-T cells, and tumor volumes were continuously monitored to assess the anti-tumor efficacy of CAR-T cells in vivo. Another mouse model was created to investigate the effect of in vivo injection of CD19 EVs on the functional persistence of CAR-T cells, and safety was determined by histopathology of the main organs. Results: CD19 EVs activated CAR-T cells in an antigen-specific and dose-dependent manner and promoted the selective expansion and cytokine secretion of co-cultured CAR-T cells. Specifically, CD19 EVs preferably increased the expansion of the CAR-T subpopulation with a high surface CD19-CAR density and consequently enhanced the anti-tumor activity of CAR-T cells. Futhermore, CD19-EVs-primed CAR-T cells achieved superior proliferation and anti-tumor effects in a mouse model with lymphoma xenograft. In vivo administration of CD19 EVs promoted the functional persistence of CAR-T cells in the xenograft mouse model. Conclusion: Our findings indicate that antigen-expressing EVs can be utilized as a boost to improve CAR-T cell efficacy in vitro and in vivo.

Prediction of outcomes by diffusion kurtosis imaging in patients with large (≥5 cm) hepatocellular carcinoma after liver resection: A retrospective study.

Purpose: To evaluate preoperative diffusion kurtosis imaging (DKI) in predicting the outcomes of large hepatocellular carcinoma (HCC) after liver resection (LR). Materials and methods: From January 2015 to December 2017, patients with a large (≥5cm) HCC who underwent preoperative DKI were retrospectively reviewed. The correlations of the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) with microvascular invasion (MVI) or histological grade were analyzed. Cox regression analyses were performed to identify the predictors of recurrence-free survival (RFS) and overall survival (OS). A nomogram to predict RFS was established. P<0.05 was considered as statistically significant. Results: A total of 97 patients (59 males and 38 females, 56.0 ± 10.9 years) were included in this study. The MK, MD, and ADC values were correlated with MVI or histological grade (P<0.01). With a median follow-up time of 41.2 months (range 12-69 months), 67 patients (69.1%) experienced recurrence and 41 patients (42.3%) were still alive. The median RFS and OS periods after LR were 29 and 45 months, respectively. The 1-, 3-, and 5-year RFS and OS rates were 88.7%, 41.2%, and 21.7% and 99.0%, 68.3%, and 25.6%, respectively. MK (P<0.001), PVT (P<0.001), and ADC (P=0.033) were identified as independent predictor factors for RFS. A nomogram including the MK value for RFS showed the best performance, and the C-index was 0.895. Conclusion: The MK value obtained from DKI is a potential predictive factor for recurrence and poor survival, which could provide valuable information for guiding the efficacy of LR in patients with large HCC.

Preoperative prediction of glypican-3 positive expression in solitary hepatocellular carcinoma on gadoxetate-disodium enhanced magnetic resonance imaging.

Purpose: As a coreceptor in Wnt and HGF signaling, glypican-3 (GPC-3) promotes the progression of tumor and is associated with a poor prognosis in hepatocellular carcinoma (HCC). GPC-3 has evolved as a target molecule in various immunotherapies, including chimeric antigen receptor T cell. However, its evaluation still relies on invasive histopathologic examination. Therefore, we aimed to develop an easy-to-use and noninvasive risk score integrating preoperative gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and clinical indicators to predict positive GPC-3 expression in HCC. Methods and materials: Consecutive patients with surgically-confirmed solitary HCC who underwent preoperative EOB-MRI between January 2016 and November 2021 were retrospectively included. EOB-MRI features were independently evaluated by two masked abdominal radiologists and the expression of GPC-3 was determined by two liver pathologists. On the training dataset, a predictive scoring system for GPC-3 was developed against pathology via logistical regression analysis. Model performances were characterized by computing areas under the receiver operating characteristic curve (AUCs). Results: A total of 278 patients (training set, n=156; internal validation set, n=39; external validation set, n=83) with solitary HCC (208 [75%] with positive GPC-3 expression) were included. Serum alpha-fetoprotein >10 ng/ml (AFP, odds ratio [OR]=2.3, four points) and five EOB-MR imaging features, including tumor size >3.0cm (OR=0.5, -3 points), nonperipheral "washout" (OR=3.0, five points), infiltrative appearance (OR=9.3, 10 points), marked diffusion restriction (OR=3.3, five points), and iron sparing in solid mass (OR=0.2, -7 points) were significantly associated with positive GPC-3 expression. The optimal threshold of scoring system for predicting GPC-3 positive expression was 5.5 points, with AUC 0.726 and 0.681 on the internal and external validation sets, respectively. Conclusion: Based on serum AFP and five EOB-MRI features, we developed an easy-to-use and noninvasive risk score which could accurately predict positive GPC-3 HCC, which may help identify potential responders for GPC-3-targeted immunotherapy.

Phenolic constituents with anti-inflammatory and cytotoxic activities from the rhizomes of Iris domestica.

Four undescribed flavonoid glucosides (iridins B-C, tectoridin A and ampelopsinin A); one undescribed phenolic glucoside (diplostephioside B); one undescribed phenolic compound (phenanthrenetriol A); and seventeen known compounds were isolated from the rhizomes of Iris domestica. The chemical structures of the undescribed compounds were established by spectroscopic/spectrometric data interpretation using HRESIMS, NMR, and ECD. Tectoridin A, nigricin A and naringenin exhibited anti-inflammatory activities with inhibition rates of 53.71%, 57.68% and 88.71%, respectively, against the NF-κB signaling pathway at a concentration of 10 µM. 4'-O-methylnyasol (10 µM) exhibited 84.91% antiproliferative activity against the K562 human leukemia cell line with an IC50 value of 4.20 µM.