Early Efficacy Research Articles

CTNI-43. MULTI-CENTER PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY (RT) IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES (BM) OR LEPTOMENINGEAL METASTASES (LM) HARBORING PI3K PATHWAY ALTERATIONS

Abstract INTRODUCTION Partial or whole brain RT is a standard treatment for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, may overcome radioresistance. METHODS This multi-center, phase I trial (NCT04192981) studied concurrent paxalisib with cranial RT (30Gy in 10 fractions) for PI3K pathway-altered BM/LM. Part A was a 3 + 3 dose escalation cohort of paxalisib at 45, 60 or 75mg to establish maximum tolerated dose (MTD). Part B was an expansion at MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS From 3/2020-2/2024, 21 patients (median age 58y, n=18 with BM, n=10 with breast cancer) were enrolled. PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg, and 2 DLTs at 60mg: grade 3 nausea and grade 4 neutropenic enterocolitis. Subsequently, 9 additional patients were enrolled during Part B at MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45mg/day paxalisib concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging. Of the remaining 12, there was robust response signal. At 1-month post-treatment, 6/12 (50%) had partial response (PR) and the remaining had stable disease (SD). To date, best CNS response is 67% PR (8/12) and 33% SD (4/12). CONCLUSIONS A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for PI3K pathway-altered BM/LM. Given significant unmet need, this novel therapeutic combination warrants further investigation given promising activity signal.

NIMG-29. EARLY REDUCTION IN MRI DIFFUSION APPARENT DIFFUSION COEFFICIENT (ADC) STRONGLY PREDICTS LONG TERM RESPONSE TO ONC201 THERAPY IN PATIENTS WITH H3K27M-DMG

Abstract ONC201 is the first monotherapy to improve outcomes in H3K27M- diffuse midline glioma (DMG) beyond radiation. Despite impressive early efficacy in H3K27M-DMG, individual response to ONC201 is variable and no radiographic biomarkers predict long term response. Previous studies demonstrated baseline MRI diffusion apparent diffusion coefficient (ADC) is lower in DMG with H3K27M compared to wildtype but change after radiation therapy was not correlated with improved OS or PFS. We hypothesize ADC will enable stratification of patients more likely to respond to ONC201. Imaging and clinical data were abstracted from chart review of patients treated with ONC201 at University of Michigan. Two neuroradiologists performed centralized review for RAPNO measurements and mean ADC was assessed using ROI measured in consistent anatomic locations, with areas of cystic degeneration or necrosis excluded. Sixty-one patients were identified for review. Preliminary analysis was performed on twenty-three patients, with upfront ONC201 therapy, median age 14.8 years old (5-25yo), primary site includes pontine (n=15), thalamic (n=7). Baseline characteristics of age, ADC and size at diagnosis or follow-up RAPNO scored size were not statistically significant. Patients with longer than median survival (334 days) demonstrated increased ADC (+58.25x10-6mm2/s) from baseline to cycle 2 whereas patients with shorter than median survival demonstrated decreased ADC (-174.8x10-6mm2/s) (p = 0.0076). Further, patients with decreased ADC demonstrated mean OS of 302.8 days and patients with increased ADC had mean OS of 588.0 (p = 0.0054). In H3K27M-DMG patients treated with ONC201, increased ADC after two cycles of ONC201 was strongly predictive of longer overall survival. Our recent work demonstrated that ONC201 disrupts metabolic and epigenetic pathways to restore pathognomonic H3K27me3 reduction, which may underline greater change in ADC. Ongoing work will validate these findings in an independent external cohort and integrate histogram analysis, parametric assessments, MRI perfusion and liquid biopsy biomarkers (cf-tDNA and metabolomics).

TMOD-02. PATIENT-DERIVED GLIOBLASTOMA ORGANOIDS AS REAL-TIME AVATARS FOR ASSESSING RESPONSES TO CLINICAL CAR-T CELL THERAPY

Abstract Patient-derived tumor organoids have been increasingly leveraged for disease modeling and preclinical studies, but rarely in real-time to aid with the interpretation of patient treatment responses in the clinical setting. Whether tumor organoids can be applied to mirror clinical activity in patients and even to predict responses for personalized medicine remains uncertain. We recently demonstrated promising early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma (clinical trial identifier: NCT05168423). Determination of meaningful clinical efficacy, in particular for CAR-T cell therapy, may take months to manifest. Given this challenge, real-time analysis of patient-derived glioblastoma organoids (GBOs) could help to provide early assessment of clinical efficacy and guide patient management. We analyzed six sets of GBOs generated on the same timeline as the production of patients’ CAR-T cell products. GBOs demonstrated the presence and retention of both targeted tumor-associated antigens EGFR and IL13Rα2 by immunohistochemistry. These GBOs were then treated with the same autologous CAR-T cell products received by patients in our phase 1 study in parallel with patient treatment. CAR-T cell treatment led to target antigen reduction assessed by immunohistochemistry and flow cytometry. Furthermore, we confirmed cytolysis of tumor cells in GBOs by cleaved caspase-3 immunostaining and by co-culture in the Axion Maestro Cellular Impedance platform. Importantly, the degree of cytolysis ex vivo significantly correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF) for all six patients. Furthermore, cytotoxic activity of CAR-T cells as measured by TNFα, IL-2, and IFNγ release kinetics in GBOs mirrored cytokine levels in patient CSF samples over time. Our findings highlight a unique trial design and suggest GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and for insights into immunotherapy efficacy.

AND-Gate Logic Förster Resonance Energy Transfer/Magnetic Resonance Tuning Nanoprobe for Programmable Antitumor Immunity Imaging.

Simultaneous detection of different biomarkers related to the spatiotemporally dynamic immune events is of particular importance for the accurate evaluation of antitumor immune effects. Here, we have developed an AND-gate logic dual resonance energy transfer nanoprobe (named DRET) for dynamic monitoring of programmed CD8+ T cell activation and tumor cell apoptosis. Immunotherapy-induced granzyme B secretion from CD8+ T cells and the subsequent caspase-3 release from apoptotic tumor cells individually activate one of the tiers of the "AND-gate" logic DRET. The resulting fluorescence recovery and magnetic resonance T1 enhancement can be used for precise immunomodulatory drug screening, early efficacy prediction, and immune stratification. Particularly, not only "Responders" can be distinguished from "Non-responders", but also "Acquired resistance" can be identified from "Maintain responders", providing a novel approach to put forward the accurate evaluation of antitumor immunity.

Advances in Graphene Field Effect Transistors (FETs) for Amine Neurotransmitter Sensing

Amine neurotransmitters (NTs) are crucial in the central nervous system, and dysregulation in their levels is implicated in a spectrum of neurological disorders. Thus, a precise and timely assessment of their concentrations is critical for early diagnosis and treatment efficacy monitoring. Graphene-based field effect transistors (GFETs) have become a ground-breaking instrument in the detection of these NTs because of their exceptional electrical characteristics and adaptability. This paper summarises the significant advancements in GFET biosensors in amine NT detection and highlights developments in the selectivity, sensitivity, and limit of detection (LOD) attained by selecting various graphene materials and functionalisation approaches.

Recent Approaches on Molecular Markers, Treatment and Novel Drug Delivery System Used for the Management of Colorectal Cancer: A Comprehensive Review.

Colorectal cancer affects 1 in 25 females and 1 in 24 males, making it the third most frequent cancer with over 6,08,030 deaths worldwide, despite advancements in detection and treatments, including surgery, chemotherapeutics, radiotherapy, and immune therapeutics. Novel potential agents have increased survival in acute and chronic disease conditions, with a higher risk of side effects and cost. However, metastatic disease has an insignificant long-term diagnosis, and significant challenges remain due to last-stage diagnosis and treatment failure. Early detection, survival, and treatment efficacy are all improved by biomarkers. The advancement of cancer biomarkers' molecular pathology and genomics during the last three decades has improved therapy. Clinically useful prognostic biomarkers assist clinical judgment, for example, by predicting the success of EGFR-inhibiting antibodies in the presence of KRAS gene mutations. Few biomarkers are currently used in clinical settings, so further research is still needed. Nanocarriers, with materials like Carbon nanotubes and gold nanoparticles, provide targeted CRC drug delivery and diagnostics. Light-responsive drugs with gold and silica nanoparticles effectively target and destroy CRC cells. We evaluate the potential use of the long non-coding RNA (non-coding RNA) oncogene plasmacytoma variant translocation 1 (PVT1) as a diagnostic, prognostic, and therapeutic biomarker, along with the latest nanotech breakthroughs in CRC diagnosis and treatment.

A cervical cancer control strategy for lower-resource settings: interventions to complement one-dose HPV vaccination

Abstract One-dose prophylactic HPV vaccination of pre-adolescents may reduce cervical cancer deaths dramatically in lower-resource settings, but the benefits of achieving immediate high coverage among pre-adolescents would not be realized for 20 to 40 years. Prophylactic vaccine efficacy is reduced after sexual debut, and current therapeutic intervention candidates designed to treat existing HPV infections or precancerous lesions have yielded insufficient evidence to warrant widespread use. However, we are developing a feasible, scalable, high-quality cervical screening approach that could prevent hundreds of thousands of deaths, while we work to achieve high coverage of one-dose vaccination for adolescent cohorts. A time-limited “one screen” campaign approach for lower-resource settings could complement parallel efforts to achieve high coverage with one-dose vaccination. This screen-triage-treat strategy would target the highest risk groups of screening age (ie, 25 to 49 years) for once-in-a-lifetime HPV testing of self-collected samples using a low-cost accurate HPV test; subsequent triage relying on extended genotyping and a validated deep-learning algorithm for automated visual evaluation (AVE) would stratify management based on risk to provide treatment for those most likely to develop cancer without overburdening health care systems. Early efficacy of this approach has been demonstrated in 9 countries within the HPV-AVE (PAVE) Study Consortium. We estimate that the cost per death averted of a screen-triage-treat campaign is of similar magnitude to prophylactic vaccination. We do not envision perpetual investment in ubiquitous brick-and-mortar screening programs if “one dose, one screen” is implemented with high coverage and targets the highest-risk populations. In collaboration with in-country stakeholders, efforts to ensure acceptability, risk communication, and cost-effectiveness are underway.

A Stacked Multimodality Model Based on Functional MRI Features and Deep Learning Radiomics for Predicting the Early Response to Radiotherapy in Nasopharyngeal Carcinoma

BackgroundThis study aimed to construct and assess a comprehensive model that integrates MRI-derived deep learning radiomics, functional imaging (fMRI), and clinical indicators to predict early efficacy of radiotherapy in nasopharyngeal carcinoma (NPC). MethodsThis retrospective study recruited NPC patients with radiotherapy from two Chinese hospitals between October 2018 and July 2022, divided into a training set (hospital I, 194 cases), an internal validation set (hospital I, 82 cases), and an external validation set (hospital II, 40 cases). We extracted 3404 radiomic features and 2048 deep learning characteristics from MRI modalities - T1WI, CE-T1WI, T2WI, and T2WI/FS. Additionally, both the ADC and its maximum (ADCmax) from DWI imaging, along with TBF and its maximum (TBFmax) from ASL imaging were derived. We used four classifiers (LR, XGBoost, SVM and KNN) and stacked algorithm as model construction methods. The receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) was used to assess models. ResultsThe manual radiomics model leveraging XGBoost and the deep learning model based on KNN (the AUCs in the training set: 0.909, 0.823, respectively) showed better predictive efficacy than other machine learning algorithms. The stacked model that integrated MRI-based deep learning radiomics, fMRI, and hematological indicators, has a large improvement of AUC in the training set [0.984 (95%CI: 0.972 - 0.996)], the internal validation set [0.936 (95%CI: 0.885 - 0.987)], and the external validation set [0.959 (95%CI: 0.901-1)]. ConclusionsOur research has developed a clinical-radiomics integrated model based on MRI which can predict early radiotherapy response in NPC and provide guidance for personalized treatment.

H558R: a common polymorphism may modify the efficacy and toxicity of flecainide in maintaining sinus rhythm; a cohort study

Abstract Background Certain mutations in the SCN5A gene alter the function of the type V voltage-gated cardiac sodium channel and the therapeutic effect of flecainide.(1) One such mutation, H558R, represents a polymorphism with a high prevalence associated with the development of atrial fibrillation (AF).(2–5) Purpose We aim to determine its relationship with the efficacy and adverse effects of flecainide, as well as describe for the first time its prevalence in a cohort of European patients with AF. Methods We conducted a cohort study collecting data through indirect methods, with the study being blinded to all parties involved except the statistician. Patients prescribed flecainide (dose of 100 mg/12 h) and followed up in our health area (n=450,000 people) between 2017 and 2021 were identified. A primary composite endpoint consisting of initial inefficacy and early toxicity and a secondary combined endpoint of toxicity or inefficacy during follow-up were predefined. Results Out of 104 patients who met the criteria and agreed to participate, 59 (56.4%) did not have the mutation (H558R-/-), 38 (36.5%) were heterozygous (H558R+/-), and 7 (6.7%) were homozygous (H558R+/+). This high prevalence in European patients with AF is significantly higher than that previously reported in healthy individuals (20.4% in Caucasians, 9.2% in Asians).(6) When compared with patients without the mutation, H558R+/- patients had a lower incidence of the primary endpoint (p=0.02, picture 1), with an absolute risk reduction (ARR) of -21.5% (95% confidence interval (CI): -38.4% to -4.6%) primarily due to a lower rate of initial inefficacy (ARR -18.35%, 95% CI: -1.37% to -35.3%), and a trend towards lower early toxicity (ARR -7.36; 95% CI: -19.9 to +5.2%). This difference remained in the multivariate analysis (p=0.03, table 1). Moreover, the H558R+/- genotype was associated with lower toxicity or inefficacy over an average follow-up of 492 days (p=0,04, picture 1), with a hazard ratio of 0.53 (95% CI: 0.27 to 0.999). Conclusions The H558R+/- mutation shows a marked prevalence in a selected sample of patients with AF. Its presence is clinically relevant both in terms of early efficacy or toxicity and during follow-up. If these results are confirmed, it may signify a step towards personalized treatment for patients with AF, not only from the standpoint of efficacy but also safety.Table 1.Picture 1.

Early clinical efficacy study on the efficacy of a three-stage conservative Chinese medicine external treatment for acute lateral ankle ligament injuries

To evaluate the clinical effect of a new three-phase Chinese medicine (CM) external treatment for acute lateral ankle ligament injuries. From July to December 2023, 64 patients with acute lateral ankle ligament injuries were randomly assigned to receive either the new three-phase CM external treatment combined with the POLICE(protect, optimal loading, ice, compression, elevation) treatment (observation group) or the POLICE treatment (control group), with 32 cases in each group. The observation group consisted of 17 males and 15 females, with an average age of(30.59±3.10) years old ranging from 25 to 36 years old, while the control group included 14 males and 18 females, with an average age of(30.03±3.19) years old ranging from 24 to 37 years old. Visual analogue scale (VAS) evaluation and Figure of 8 measurement were used to evaluate the degree of ankle joint pain and swelling of the subjects at the initial enrollment and after 1 week and sixth weeks of treatment. At the same time, the American Orthopaedic Foot and Ankle Society (AOFAS) and Karlsson Ankle Function Score System were used to evaluate the improvement of ankle joint function in patients at all stages. MRI imaging was employed to observe the degree of biological healing of the anterior talofibular ligament, with the signal to noise ratio(SNR) indicating the level of healing. A lower SNR suggests better ligament healing, as it represents lower water content in the ligament. All patients completed a 6-week follow-up. There was no significant difference in VAS, AOFAS score and Karlsson score between the two groups before treatment (P>0.05). After 1 week and 6 weeks of treatment, the VAS, AOFAS score and Karlsson score of the two groups were significantly improved (P<0.05). After 1 week of treatment, the VAS score of the observation group (3.21±0.87) was lower than that of the control group (4.21±1.50), and the difference was statistically significant (P<0.05). After 1 weeks of treatment, the AOFAS and Karlsson scores [(50.84±4.70) points, (49.97±4.00) points] of the observation group were higher than those [(46.91±5.56) points, (46.66±5.36) points]of the control group (P<0.05). MRI images showed that after 6 weeks of treatment, the SNR value of the observation group was significantly lower than that of the control group, and the difference was statistically significant(SNR of the observation group was 75.25±16.59, the contral gruop was 85.81±15.55), (P<0.05). Compared with the control group, the new three-phase CM external treatment is significantly effective in reducing pain and swelling, enhancing ligament repair quality, and promoting functional recovery of the ankle joint in patients with acute lateral malleolar ligament injuries.

Effect of groove splint fixation on early swelling and blood flow velocity of the injury limb in elderly patients with distal radius fractures

To observe the effects of groove splint fixation on early hand swelling, blood flow velocity, and clinical function in elderly patients with distal radius fractures. Between March 2021 and February 2022, 64 patients of unilateral closed distal radius fractures were treated with manual reduction and external fixation with splints. There were 10 males and 54 females, the age ranged from 60 to 78 years old, with an average age of (67.7±4.7) years old. According to the order of admission, the patients were divided into the groove splint group and the conventional splint group, with 32 cases in each group. In the groove splint group, there were 4 males and 28 females, with an average age of (68.6±4.8) years old. There were 13 patients with left-sided fractures, and 19 patients with right-sided fractures, with 22 cases classified as AO type A and 10 cases as AO type C. The mean time from injury to treatment was 3.0 (2.0, 4.0) h. In the conventional splint group, there were 6 males and 26 females, with an average age of (66.9 ± 4.4) years old. There were 17 patients with left-sided fractures and 15 patients with right-sided fractures, with 20 cases classified as AO type A and 12 cases as AO type C. The mean time from injury to treatment was 3.0 (2.0, 5.0) h. After manual reduction, patients were treated with groove splint or conventional splint. Swelling, assessed by the difference in limb circumference between the injured and healthy limbs, was measured at 1, 3, 7, and 14 days post-treatment. Blood flow velocities in the superficial palmar arch and dorsal metacarpal veins were measured at 1, 3, and 7 days post-treatment. Radiographic evaluations of radial styloid height, palmar tilt, and ulnar variance were performed preoperatively and 3 months post-treatment. Functional outcomes were assessed using the DASH (Disabilities of the Arm, Shoulder, and Hand) score 3 and 12 months post-treatment. Statistical analyses were conducted to compare the outcomes between the two groups. All 64 patients were followed up for the least 12 months. The swelling value of the palm in the groove splint group [(1.897±0.071) cm, (1.200±0.169) cm, (0.994±0.085) cm] was significantly improved compared to the conventional splint group[(2.283±0.268) cm, (1.893±0.269) cm, (1.183±0.126) cm] on days 3, 7, and 14 days posttreatment, with a statistically significant difference (P<0.001). On the first and third day after splint fixation, the difference in blood flow velocity of the superficial palmar arch in the groove splint group(0.017±0.009), (0.018±0.011) L·min-1 were lower than that in the conventional splint group(0.023±0.011), (0.025±0.013) L·min-1, with statistical significance (P<0.05). On the 3rd and 7th days, the difference was not statistically significant (P>0.05). Comparison of blood flow velocity differences between the dorsal metacarpal vein and the two groups showed no statistically significant difference on the first day after splint fixation (P>0.05). On the 3rd and 7th days, the blood flow velocity difference between the groove splint group[(0.037±0.019), (0.021±0.013) L·min-1] decreased compared to the conventional splint group[(0.062±0.033), (0.037±0.022) L·min-1], and the difference was statistically significant (P<0.05). There was no statistically significant difference in the palm angle, ulnar deviation angle, and radius height of the distal radius before and after reduction (P>0.05). The DASH score showed a statistically significant difference at follow-up 3-month[(6.1±2.8) scores vs (8.2±3.7) scores] , P<0.05, but no statistically significant difference at follow-up 12-month (P>0.05). Fixing distal radius fractures with groove splints in the early stage can reduce the impact on the blood flow velocity of the superficial palmar arch and dorsal palmar vein, reduce venous reflux obstruction and swelling of injury limb, alleviate wrist and finger joint stiffness, and improve early clinical efficacy of the affected limb. However, it has no significant impact on clinical function one year after injury.

Simultaneous bilateral and staged total knee arthroplasty combined with unicompartmental knee arthroplasty in the treatment of bilateral knee osteoarthritis: comparison of early clinical outcomes, complications, and prosthesis survival

ObjectiveKnee osteoarthritis (KOA) is usually bilateral. In many patients, the degree of bilateral knee degeneration varies, with one side involving multiple compartments and the other a single compartment degeneration. Therefore, the objective of this study was to compare the early clinical efficacy of simultaneous bilateral and staged total knee arthroplasty (TKA) combined with unicompartmental knee arthroplasty (UKA) in the treatment of bilateral KOA with different degrees.MethodsWe compared clinical data from 71 simultaneous bilateral TKA/UKA (SB-TKA/UKA) patients with 52 Staged TKA/UKA (Staged-TKA/UKA) patients. Staged-TKA/UKA is defined as TKA on one knee followed by UKA on the other knee. The comparison included Hospital for Special Surgery (HSS) score, range of motion(ROM), complication rate and prosthetic survival rate at the last follow-up between the two groups.ResultsThe follow-up time of SB-TKA/UKA group was (69.08 ± 14.35) months, and that of Staged-TKA/UKA group was (73.25 ± 18.39) months. Staged-KA/UKA group had a shorter hospital stays, less hospitalization costs and shorter operating time (p < 0.001 for hospital stay, p < 0.001 for hospitalization costs and p < 0.001 for operating time). There were no significant differences in HSS and ROM between the two groups at the last follow-up (p > 0.05). There was no significant difference in complication rate between the two groups (χ2 = 0.56, p = 0.454). For the TKA-side knee joint, there was no significant difference in the prosthetic survival rate (χ2 = 0.05, p = 0.824) and the prosthetic survival curve (χ2 = 0.052, p = 0.82) between the two groups. For UKA-side knee joint, there was no significant difference in prosthetic survival rate (χ2 = 0.08, p = 0.777) and prosthetic survival curve (χ2 = 0.074, p = 0.786) between the two groups.ConclusionsCompared to Staged-TKA/UKA, SB-TKA/UKA has the same early clinical efficacy, shorter operating time and hospital stays, less hospitalization costs, and no increased postoperative complications and prosthesis revision rates. Therefore, SB-TKA/UKA may be recommended for patients who can tolerate simultaneous bilateral surgery as assessed before surgery.

The value of predicting neoadjuvant chemotherapy early efficacy in nasopharyngeal carcinoma based on amide proton transfer imaging and diffusion weighted imaging.

Early detection of nasopharyngeal carcinoma (NPC) patients who are not sensitive to neoadjuvant chemotherapy (NAC) can guard against overtreatment. This study aimed to evaluate the effectiveness of amide proton transfer (APT) imaging and diffusion-weighted imaging (DWI) in predicting the early response to NAC in patients with NPC. This prospective study enrolled fifty patients with biopsy-confirmed NPC from September 2021 to May 2023. Magnetic resonance imaging (MRI) including APT and DWI, was performed before NAC. After NAC, patients were divided into complete response (CR), partial response (PR), and stable disease (SD) and progressive disease (PD) groups based on the Response Evaluation Criteria in Solid Tumours Version 1.1. The Kruskal-Wallis H test was used for statistical analysis. The differences in APT and apparent diffusion coefficient (ADC) values among the different efficacy groups were compared, the receiver operating characteristic (ROC) curve was drawn for statistically significant parameters, and the area under the curve (AUC) was calculated. Fifty patients (mean age: 47±14 years; 42 males and 8 females) were included in the final analysis (11 were in the CR group, 30 in the PR group, 9 in the SD group, and 0 in the PD group). The ADC values showed no significant differences among the different treatment response groups. The SD group showed significantly lower APTmax (P=0.025), APTskewness (P=0.025) and APT90% (P=0.001) values than the CR and PR groups. Setting APT90% =3.10% as the cut-off value, optimal diagnostic performance (AUC: 0.831; sensitivity: 0.778; specificity: 0.878) was obtained in predicting the SD group. APT imaging can predict the early tumour response to NAC in patients with NPC. APT imaging may be superior to DWI in predicting tumour response.

The effect of early childhood teacher efficacy and relationships with colleagues and directors on teachers’ leadership

The effect of early childhood teacher efficacy and relationships with colleagues and directors on teachers’ leadership

A novel carboxylesterase 2-targeted fluorescent probe with cholic acid as a recognition group for early diagnosis of drug- and environment-related liver diseases

Due to the detrimental effects of various harmful substances—such as carcinogens, drug toxicity, and environmental pollutants—on the liver, which can trigger or exacerbate conditions like hepatocellular carcinoma (HCC), drug-induced liver injury (DILI), and non-alcoholic fatty liver disease (NAFLD), accurate detection and monitoring of these diseases are crucial for effective treatment. Carboxylesterase 2 (CES2) is primarily found in the liver and, as a potential biomarker, its accurate detection can enhance the early diagnosis and treatment efficacy of liver diseases. Traditional fluorescence probes for CES2 detection suffer from non-specific recognition groups, leading to poor targeting specificity. To address this limitation, we propose a novel CES2-responsive fluorescent probe utilizing cholic acid (CA) as a recognition group. The probe, LAN-CA, was synthesized by esterifying CA with a near-infrared fluorophore, LAN-OH. This novel fluorescent probe leverages the unique affinity of CA for hepatocytes, ensuring that LAN-CA remains and accumulates specifically within the hepatoenteric circulation. In vitro experiments showed that the probe exhibits superior optical performance compared to traditional benzoate-based probe (LAN-PH), with a detection limit of 0.015 μg/mL. Examination of 56 common biological interferents demonstrated that using CA as a recognition group offers high selectivity. Cell experiments confirmed that LAN-CA is an effective tool for monitoring endogenous CES2 in live cells. Comprehensive evaluations of fluorescence imaging in various mouse models of liver diseases, such as HCC, DILI, and NAFLD, demonstrated that LAN-CA provides exceptional imaging accuracy and therapeutic monitoring capabilities. In conclusion, this probe not only can be a promising tool for accurate liver disease diagnosis, but also can provide valuable insights into treatment efficacy.

Identifying Proteomic Prognostic Markers for Alzheimer's Disease with Survival Machine Learning: the Framingham Heart Study.

Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations. Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9% women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in an independent group of 430 participants younger than 55 years (mean age 46, 56.7% women). Over a mean follow-up of 20 years, 132 (15.4%) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4+ status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4+ status across 15 to 25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in 339 participants (beta = -0.061, P = 0.046), 430 independent participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003). These findings highlight the utility of proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

Clinical characteristics of patients with early gastric prematurity cancer and analysis of complications by endoscopic resection.

Gastric cancer, a prevalent malignancy, poses a severe threat to the health of residents in China. Timely intervention in early stages can extend patients' survival. To analyze clinical characteristics of patients with early gastric cancer and efficacy and risk of complications associated with endoscopic resection. This study included 175 patients with early gastric cancer treated at our hospital, with no restrictions on sex or age. General data, pathological information, and endoscopic biopsy results were obtained. The clinical characteristics of early gastric cancer were analyzed, and endoscopic resection was performed. Postoperative efficacy and incidence of complications were monitored. Statistical analysis was performed using SPSS 26.0 and GraphPad Prism 8.0 software. A total of 175 patients with early gastric cancer were included, with 75.43% (n = 132) males and 24.57% (n = 43) females. 38.29% (n = 67) and 35.43% (n = 62) of patients had a history of smoking and alcohol consumption, respectively. Comorbidities included diabetes (8.57%, n = 15), coronary heart disease (10.29%, n = 18), and hypertension (43.43%, n = 76), which was highly prevalent. A history of abdominal surgery and family history of digestive system cancer accounted for 21.14% and 17.14%, respectively. The most common lesion location was the antral part of the stomach (52.00%, n = 91), followed by the gastric angle, body, and fundus. The pathological types were predominantly high-grade intraepithelial neoplasia (28.00%, n = 49) and well-differentiated adenocarcinoma (26.86%, n = 47), followed by moderately differentiated adenocarcinoma, high-moderately differentiated adenocarcinoma, and moderate-lowly differentiated adenocarcinoma. 89.14% of the patients had intestinal metaplasia and 85.14% had atrophy. After endoscopic resection, re-examination revealed that 13 patients had cancer cells at the tissue margin, with a positive margin rate of 7.43%. Postoperative complications included no cases of gastrointestinal obstruction, but incisional infection (2.86%, n = 5), gastric perforation (1.14%, n = 2), and gastric bleeding (4%, n = 7) were present, with an overall incidence of 8.00%. Analysis of the clinical characteristics indicated that early gastric cancer is more prevalent in males with a history of hypertension, with lesions most commonly occurring in the antral region of the stomach. The pathological types are often high-grade intraepithelial neoplasia and well-differentiated adenocarcinoma, with over 85% of patients having comorbid intestinal metaplasia and atrophy. Despite endoscopic resection, a positive margin rate persisted, indicating a probability of residual cancer at the margins. Postoperative complications, such as gastrointestinal obstruction, incisional infection, gastric perforation, and gastric bleeding can occur and require timely symptomatic treatment.

Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.

While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.

53803 Early and Sustained Efficacy of Fixed-Combination Halobetasol Propionate and Tazarotene Lotion in Participants with Moderate-to-Severe Scaling or Plaque Elevation

53803 Early and Sustained Efficacy of Fixed-Combination Halobetasol Propionate and Tazarotene Lotion in Participants with Moderate-to-Severe Scaling or Plaque Elevation

A Coronary-Friendly Device Mitigating Risk of Coronary Obstruction in Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR) induced coronary artery obstruction (CAO) is a rare but devastating complication. Current preventive strategies need additional procedures and may be associated with adverse events. This study aimed to evaluate the early safety and efficacy of stand-alone TAVR using the J-Valve (Jianshi JieCheng Medical Technology Co. Ltd, Shanghai, China) in patients at potential high risk for CAO. CAO was defined as coronary ostia obstruction requiring intervention. Patients at potential high risk for CAO were identified retrospectively from 673 consecutive patients who underwent TAVR from January 2015 to July 2021 at Zhongshan Hospital, Fudan University. Procedural results and early outcomes were evaluated according to Valve Academic Research Consortium-3 definitions. A total of 20 consecutive patients (age 72 ± 9 years; 85% female;) were included. The Society of Thoracic Surgeons-Predicted Risk of Mortality was 5% (interquartile range, 4 to 10%). All patients (100%) had at least 2 classical risk factors for CAO by pre-procedural computed tomography analysis, and 90% patients had native aortic valve diseases. TAVR was successful in 95% of cases, with only 1 patient requiring second device implantation. Early safety at 30 days was achieved in all cases without death. All patients were free from CAO, stroke or emergency reintervention. Post-procedural mean aortic valve gradient was 7 (interquartile range, 4, 12) mmHg, and none/trace or mild aortic regurgitation was present in all patients. Stand-alone TAVR using the J-Valve may mitigate the risk of TAVR-induced CAO.