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Results of a multicenter retrospective cohort study evaluating the safety and efficacy of FTD/TPI plus ramucirumab in advanced gastric cancer (HGCSG2302).

351 Background: In advanced gastric cancer, trifluridine/tipiracil (FTD/TPI) is one of the standard treatments for later-line chemotherapy. Ramucirumab (RAM), an anti-VEGFR-2 monoclonal antibody, has shown promising efficacy in combination with FTD/TPI in phase II studies conducted in Japan, suggesting that this combination could improve treatment outcomes. However, there remains a paucity of real-world clinical data comparing the efficacy and safety of FTD/TPI monotherapy and FTD/TPI plus RAM combination therapy in general clinical practice. Methods: This retrospective analysis to evaluate safety and efficacy included patients with gastric cancer who were received FTD/TPI plus RAM combination therapy or FTD/TPI monotherapy between August 2019 and March 2023 at 21 institutions. Results: 164 patients were analyzed, 38 patients in the RAM combination group and 126 in the FTD/TPI monotherapy group. The distribution of treatment lines (third/fourth/fifth) was 10/13/15 in the RAM group and 26/54/46 in the monotherapy group, respectively. RAM had been previously administered to 34 patients (89.5%) in the RAM group. Objective response rate and disease control rate were 11.1% / 55.6% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the RAM group and 5.5% /38.5% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the monotherapy group, respectively. Median progression-free survival (PFS) was 3.5 months in the RAM group and 2.1 months in the monotherapy group (HR 0.69, 95% C.I. 0.49-1.02, p=0.06), respectively. Median overall survival (OS) was 8.4 months in the RAM group and 5.8 months in the monotherapy group (HR 0.82, 95% C.I. 0.54-1.25, p=0.350), respectively. Grade 3 neutropenia was reported in 48.6%/52.4% (p=0.707), and there were no significant differences in other adverse event profiles between the two groups. Additionally, in the RAM group, a comparison between patients receiving standard dosing (2 weeks on/2 weeks off; n=7) and those on biweekly dosing (1 week on/1 week off; n=24) showed no notable differences in efficacy or safety. Conclusions: FTD/TPI plus RAM combination therapy showed a trend toward prolonged PFS compared to FTD/TPI monotherapy, but no significant difference in OS.

Disease-free survival as a surrogate endpoint for overall survival in adults with early-stage pancreatic cancer: A trial-level surrogacy analysis.

708 Background: In early-stage cancer, overall survival (OS) is the gold-standard endpoint for assessing therapeutic efficacy. However, long follow-up periods make OS challenging and costly to measure in clinical trials. Disease-free survival (DFS), which captures the time to recurrence or death, has been proposed as a surrogate endpoint for OS in early-stage pancreatic cancer (PC). This surrogacy relationship could allow for a more rapid assessment of treatment benefits, but its validity requires robust analysis across clinical trials. Understanding the trial-level correlation between DFS and OS is crucial to optimizing trial design and grant accelerated drug approval. Methods: We conducted a systematic search of Embase, PubMed, and Cochrane databases through August 2024, identifying randomized controlled trials (RCTs) that evaluated adjuvant or neoadjuvant systemic therapies in adult patients with PC. Included studies reported both OS and DFS outcomes. Hazard ratios for DFS (HR_DFS) were analyzed as surrogate endpoints for OS (HR_OS). Statistical analyses utilized linear regression models, weighted by trial sample sizes, to determine the strength of the correlation. Surrogacy strength was categorized by the coefficient of determination (R²), with R² ≥ 0.7 indicating a strong correlation, 0.69–0.5 a moderate correlation, and values < 0.5 indicating weak correlation. Results: Out of 3,048 studies screened, 30 RCTs met the inclusion criteria, comprising 5,275 patients in adjuvant therapy trials and 557 patients in neoadjuvant therapy trials. The median follow-up duration ranged from 16 to 53.5 months, with 12 phase II trials included. Overall, DFS showed strong surrogacy for OS in adjuvant trials (R² = 0.70; 95% CI, 0.50–0.91). Subgroup analysis indicated strong correlation in phase III trials (R² = 0.71; 95% CI, 0.46–0.96) and moderate correlation in phase II trials (R² = 0.67; 95% CI, 0.21–1.00). The strongest surrogacy was observed in studies incorporating adjuvant radiation therapy (R² = 0.81; 95% CI, 0.52–1.00). In the analysis of neoadjuvant trials, HR-DFS also presented strong correlation with OS (R² = 0.90; 95% CI, 0.56–1.00). Conclusions: There is a strong trial-level correlation between DFS and OS in both adjuvant and neoadjuvant therapy trials for early-stage pancreatic cancer, particularly in phase III studies and trials incorporating adjuvant radiation therapy. However, the strength of this surrogacy varies depending on the treatment setting and trial design.

Rapid learning with phase-change memory-based in-memory computing through learning-to-learn

Abstract There is a growing demand for low-power, autonomously learning artificial intelligence (AI) systems that can be applied at the edge and rapidly adapt to the specific situation at deployment site. However, current AI models struggle in such scenarios, often requiring extensive fine-tuning, computational resources, and data. In contrast, humans can effortlessly adjust to new tasks by transferring knowledge from related ones. The concept of learning-to-learn (L2L) mimics this process and enables AI models to rapidly adapt with only little computational effort and data. In-memory computing neuromorphic hardware (NMHW) is inspired by the brain’s operating principles and mimics its physical co-location of memory and compute. In this work, we pair L2L with in-memory computing NMHW based on phase-change memory devices to build efficient AI models that can rapidly adapt to new tasks. We demonstrate the versatility of our approach in two scenarios: a convolutional neural network performing image classification and a biologically-inspired spiking neural network generating motor commands for a real robotic arm. Both models rapidly learn with few parameter updates. Deployed on the NMHW, they perform on-par with their software equivalents. Moreover, meta-training of these models can be performed in software with high-precision, alleviating the need for accurate hardware models.

Highly Efficient Monolithic Perovskite/TOPCon Silicon Tandem Solar Cells Enabled by “Halide Locking”

Abstract Perovskite/silicon tandem solar cells (TSCs) are promising candidates for commercialization due to their outstanding power conversion efficiencies (PCEs). However, controlling the crystallization process and alleviating the phases/composition inhomogeneity represent a considerable challenge for perovskite layers grown on rough silicon substrates, ultimately limiting the efficiency and stability of TSC. Here, this study reports a “halide locking” strategy that simultaneously modulates the nucleation and crystal growth process of wide bandgap perovskites by introducing a multifunctional ammonium salt, thioacetylacetamide hydrochloride (TAACl), to bind with all types of cations and anions in the mixed halide perovskite precursor. The approach not only enables excellent compositional uniformity in the wet‐film stage but also induces preferred orientation along the (001) plane following nucleation, leading to enhanced homogeneity of the perovskite film in both vertical and horizontal directions over long‐length scales. The resulting wide‐bandgap perovskite solar cells yield exceptional open‐circuit voltage‐fill factor products ( V OC × FF) of 1.074 and 1.040 in small‐ (0.0414 cm 2 ) and large‐area (1.0208 cm 2 ) devices, respectively. Corresponding large‐area tandem solar cells based on the Tunnel Oxide Passivated Contact (TOPCon) silicon subcells achieve a record PCE of 31.32% with a remarkable V OC of 1.931 V and FF of 81.54%.

Effect of baseline geriatric and quality of life assessments on treatment outcomes in ECOG-ACRIN EA2186 (GIANT): A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer.

676 Background: Data is lacking to guide the care of vulnerable older adults (OA) with newly diagnosed metastatic pancreatic adenocarcinoma (mPDAC). EA2186 trial demonstrated poor outcomes among vulnerable OA with mPDAC treated with dose-reduced chemotherapy. To understand the factors driving treatment outcomes in this patient population, we analyzed the correlation between baseline geriatric and quality of life (QOL) assessments and treatment outcomes. Methods: Vulnerable OA ≥70 yo with mPDAC, ECOG PS 0-2 were enrolled. Vulnerability was defined by screening geriatric assessment (GA) demonstrating mild abnormalities in function, comorbidities, cognition, or age≥80y. Pts were randomized to Arm A: Gemcitabine (1000mg/m2) + Nab-Paclitaxel (125mg/m2) q14 days or Arm B: 5-Fluorouracil (2400mg/m2 46hr) + Leucovorin (400mg/m2) + Liposomal Irinotecan (50mg/m2) q14 days. GA and QOL evaluations were completed at baseline and 3 time points. Secondary endpoints of the study included evaluating the correlation between baseline GA, QOL and treatment outcomes. Regression models were used to evaluate the associations between baseline GA and QOL factors, survival and grade 3 or higher toxicity, with 80% power to detect doubling in grade 3 toxicity for GA/QOL measures. Results: 176 pts (88 per arm) enrolled with median age 77 (range 70-90), 24% ECOG-0, 64% ECOG-1 and 12% ECOG-2. Pts were deemed vulnerable by cognition (46%), age (36%) or comorbidities (31.4%), with 35% meeting vulnerability criteria in ≥2 domains. No significant difference was seen in median OS (4.7 vs. 4.4 months; p=0.72) or ≥grade 3 toxicity rate (45.6% vs. 58.7%; p=0.10) between arms A and B, respectively. Strong correlation was found between OS and baseline instrumental activities of daily living score (HR 0.84; p=0.02), nutritional scores (HR 0.82; p<0.0001), depression scores (HR 1.07; p=0.02), and scores of all QOL measures (HR 0.98; p<0.0001). No correlation was found between OS and comorbidity, cognition, and Activities of Daily Living scores. After adjustment for age and PS, only baseline WBC level (OR=0.35; p=0.0054), and depression scores (OR=1.20 per score unit; p=0.021) and to a lesser extent FACT-G score (OR=0.98 per score unit; p=0.061) were found to correlate with rates of ≥grade 3 toxicity. Conclusions: Baseline GA and QOL factors among vulnerable older adults with mPDAC correlate strongly with survival and treatment tolerance. Supportive care to address these factors may favorably affect outcomes in this patient population. Clinical trial information: NCT04233866 .

HCC in the Rio Grande Valley: Outcomes in a predominant Latino community.

550 Background: Hepatocellular carcinoma (HCC) has slowly increased in the U.S. in recent years, with a higher incidence among racial and ethnic minorities, particularly Latinos. This retrospective study examines the different etiologies, presentation of diagnosis, management, and outcomes of patients presented in a multidisciplinary-liver tumor board in the Rio Grande Valley, home of 1.3 million Latinos. Methods: A retrospective chart review was conducted on patients with HCC diagnosis who were presented at the Liver Tumor Board of DHR Health Transplant Institute between 2017 and 2023. The data collected was extracted from the EHR, including medical history, laboratory results, and radiological studies required for staging, transplant eligibility assessments, clinical characteristics, and treatments. Results: A total of 250 cases were reviewed, and 70 patients with complete clinical data and a diagnosis of HCC were included in the study. Of those, 98.5% were identified as White/ Hispanic. The median age at diagnosis was 64.4 ± 9.2 years, with 72.9% male and 11.4% uninsured. The average BMI was 31.5 kg/m 2 , metabolic-associated liver disease (MALD) was present in 28.6% of patients, 25.7% were alcohol-related, and 38.6% presented multiple etiologies. A descriptive analysis of this population is found in the table. Ablative therapy was used in 68 (97.1%) of the patients. The number of patients sent for liver transplant evaluation was 31 (44%), and only 3 (4.2%) patients received a liver transplant. Barriers to transplant included lack of transportation, inadequate social support, underinsurance, and fear of the transplant itself. Conclusions: Our data by staging aligns with the national distribution of incidence cases from 2012-2022 per SEER program. The rate of transplantation at our institution is below the national average, highlighting the need to bridge this disparity and address race-specific barriers to transplant within the Latino community. Sociodemographic data. Parameter Stage IAN=15 (21.4%) Stage IBN=20 (28.6%) Stage IIN=10 (14.3%) Stage IIIAN=8 (11.4%) Stage IIIBN=9 (12.9%) Stage IVAN=5 (7.1%) Stage IVBN=3 (4.3%) All StagesN=70 (100%) Child Pugh A 7 (46.7%) 8 (40.0%) 5 (50.0%) 4 (50.0%) 2 (22.2%) 2 (40.0%) 1 (33.3%) 29 (41.4%) Child Pugh B 6 (40.0%) 6 (30.0%) 5 (50.0%) 2 (25.0%) 5 (55.6%) 2 (40.0%) 2 (66.7%) 28 (40.0%) Child Pugh C 2 (13.3%) 6 (30.0%) 0 (0.0%) 2 (25.0%) 2 (22.2%) 1 (20.0%) 0 (0.0%) 13 (18.6%) MELD-Na mean, (min-max) 12.8(7.0-21.0) 13.6(6.0-23.0) 12.8(6.0-20.0) 12.3(5.0-17.0) 13.6(8.0-26.0) 13.0(10.0-19.0) 11.3(7.0-14.0) 13.6(6.0-26.0) Therapy*:Ablative (TACE, Y90, Radiation, other) 15 21 10 6 8 6 2 Surgery (including transplant)** 1 1 2 2 2 0 0 Systemic 2 6 5 4 6 3 1 Overall Survival (months) 29.5 26.8 34.7 17.5 24.1 17.3 14.9 25.3 *Several patients received one or more types of therapy. **All transplant patients received ablation therapy.

Avutometinib plus cetuximab after chemotherapy in patients with <i>KRAS</i> -mutated metastatic colorectal cancer: Results of phase 1 dose escalation.

199 Background: Anti-EGFR antibodies like cetuximab are ineffective in KRAS mutated (mt) colorectal cancer (CRC) due to constitutive activation of downstream pathways. Avutometinib is a first in class, oral, novel, dual RAF/MEK inhibitor. In patient-derived xenograft models of KRAS mt CRC, the combination of an anti-EGFR antibody with avutometinib conferred stronger tumor growth inhibition than either agent alone. We present results from the dose escalation phase (1b) of an ongoing phase 1b/2 trial evaluating the combination avutometinib plus cetuximab in KRAS mt metastatic (m) CRC. Methods: This is a single-center, open-label, phase 1b/2 study evaluating the safety and combined tolerability of avutometinib and cetuximab. Patients received avutometinib 2.4mg (at DL0) or 3.2mg (at DL1) orally twice a week for 3 weeks out of a 4-week cycle + cetuximab 500mg/m 2 intravenously q2week. Patients with disease progression on, or intolerance to 5-FU, oxaliplatin, and irinotecan, and measurable disease per RECIST v1.1 were enrolled. The primary endpoint for phase 1b was to establish the maximum tolerated dose (MTD) and hence determine the recommended phase 2 dose (RP2D). Dose limiting toxicity (DLT) period was 28 days. A 3+3 dose escalation design was used with dose level (DLs) 0 (2.4mg avutometinib) as the starting level and one dose escalation to DL+1 (3.2mg avutometinib). Results: We report safety results of phase 1b. 10 patients, 7 at DL0 and 3 at DL+1, were enrolled. Median age was 52.5 yrs (range 41 – 75). Any grade (G) treatment related adverse events (TRAEs) were seen in all 10 patients. Most common TRAEs were acneiform rash (100%), chills (30%), diarrhea (30%), and fatigue (30%). G3 TRAEs at DL0 were seen in 4/7 (57.1%) patients and at DL+1 in 2/3 (66.7%) patients. No G4 TRAEs were seen. G3 TRAEs seen at DL0 are noted in the table. One patient from the initial three enrolled was not evaluable due to underdosing. Another patient was later found to not meet eligibility criteria, but they did clear the DLT period. Hence, 6/7 patients at DL0 were evaluated for AE assessment, of which 1 had a DLT. 3 additional patients were enrolled in DL+1. 2/3 patients in DL+1 had grade 3 toxicities (both DLTs) of rash. Hence DL0 was established as the MTD/RP2D. Conclusions: This is the first trial evaluating the combination avutometinib plus cetuximab in KRAS mt mCRC. RP2D for avutometinib was established at 2.4mg orally twice a week for 3 weeks out of a 4-week cycle when used in combination with q2week 500mg/m 2 cetuximab for KRAS mt mCRC. Enrollment continues currently for the dose expansion phase for efficacy assessment. Clinical trial information: NCT05200442 . G3 TRAEs at DL0 attributed to both drugs unless specified. G3 TRAE # of patients Acneiform rash 3/7 (42.9%) Hand-Foot syndrome 1/7 (14.3%) Extremity edema 1/7 (14.3%) Cellulitis 1/7 (14.3%) Sepsis 1/7 (14.3%) Anemia 1/7 (14.3%) Creatine phosphokinase elevation 1/7 (14.3% – avutometinib only)

Spatial integration of multi-omics single-cell data with SIMO

High‐Entropy Metal Interstitials Activate TiO₂ for Robust Catalytic Oxidation

AbstractSubstitution metal doping strategies are crucial for developing catalysts capable of activating O2, but the leaching of metal dopants has greatly hindered their potential for extensive oxidation reactions under mild conditions. Here, the study develops an entropy‐increase strategy to synthesize high‐entropy metal (Mg, Ca, Mn, Fe, and Co) interstitial functionalized anatase TiO2 (HE‐TiO2) nanosheets, demonstrating remarkable degradation efficiency across a wide pH range and exceptional stability in a flow‐by electro‐catalytic reactor. Relative to that of pristine TiO2, the intense lattice distortion on the (001) plane, an average lattice expansion of 2% on the (100) plane, and decrease of second shell peak of X‐ray absorption spectra serve as compelling evidence for the formation of metal interstitials in HE‐TiO2. Theoretical analysis and in situ synchrotron radiation Fourier transform infrared studies reveal that the electron of metal interstitials can populate the subgap states within the host TiO2, enabling a moderate adsorption band for robust and efficient O2 activation. This study introduces a universal strategy for synthesizing a novel class of high‐entropy materials with integrated metal interstitials in metal oxides, promising to enhance the stability and efficiency of O2 activation catalysts and broaden their potential applications.

Preclinical and phase 1/2 data of the CHK1 inhibitor BBI-355 in development for esophageal and gastric cancers (EGC) with <i>EGFR</i> or <i>FGFR2</i> amplifications.

TPS517 Background: High-copy number amplifications of oncogenes (e.g., EGFR , FGFR2 ) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. While targeted therapies have improved survival for patients with oncogene mutations, they have limited activity in oncogene amplified cancers. In Barrett’s esophagus-associated esophageal adenocarcinoma (EAC) ecDNA can be found early in the transition from high-grade dysplasia to EAC. In EAC and gastric cancer (EGC), ~7% and ~3% have EGFR and FGFR2 amplifications, respectively, with possibly &gt;50% occurring on ecDNA. Tumor cells with oncogene amplifications, particularly on ecDNA, have increased DNA replication stress and are sensitive to inactivation of checkpoint kinase 1 (CHK1). We developed BBI-355, an oral, potent, and selective small molecule inhibitor of CHK1, which is in Phase 1/2 clinical development. Methods: BBI-355-101 is a first-in-human Phase 1/2 study of BBI-355 alone or in combination with targeted therapies for advanced or metastatic solid tumors with oncogene amplification (NCT05827614). Part 1 is dose escalation of BBI-355 (PO Q2D). In Parts 2 and 3, patients with EGFR or FGFR 1-3 amplifications are treated with BBI-355 in combination with the EGFR inhibitor erlotinib (150 mg PO QD) or the FGFR inhibitor futibatinib (20 mg PO QD). While this study is enrolling all tumor types, EGC are some of the most likely to harbor ecDNA amplifications. Amplification-driven cancers rarely contain driver oncogene mutations or fusions, and so are excluded. Results: Preclinical: Tumors that harbor oncogene amplifications on ecDNA can evade targeted therapeutic pressure via ecDNA-based resistance mechanisms. BBI-355 in combination with agents targeting the amplified oncogenes ( FGFR2 or EGFR ) prevented resistance to targeted therapies in multiple ecDNA+ gastric cancer CDX and PDX models. Clinical: Safety and PK data of BBI-355 alone and in combination with erlotinib or futibatinib will be presented. The most common drug-related TEAEs, SAEs, and DLTs were hematologic (i.e., leukopenia, neutropenia, lymphopenia and thrombocytopenia) which are on target for CHK1 inhibition and generally well managed. Dose escalation is ongoing and the RP2D/MTD has not been determined. PK showed dose-dependent increase in exposure of BBI-355. Target engagement as determined by pCHK1 IHC as a PD biomarker was observed at all dose levels of BBI-355. Conclusions: The first ecDNA directed therapy, BBI-355, demonstrated significant synergistic anti-tumor activity in combination with targeted therapies in multiple ecDNA+ oncogene amplified EGC models. BBI-355 alone and in combination with erlotinib/futibatinib was well tolerated. Clinical testing in patients with EGFR and FGFR2 oncogene amplifications is ongoing with a strong rational for EGC. Clinical trial information: NCT05827614 .

Efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) vs percutaneous transhepatic biliary drainage (PTBD) for cholangiocarcinoma biliary obstruction: An updated systematic review and meta analysis.

557 Background: Perioperative and/or palliative biliary drainage for the management of cholangiocarcinoma biliary obstruction has been part of the backbone of the multidisciplinary approach that this condition requires. For both intrahepatic and perihilar cholangiocarcinoma, ERCP and PTBD are the two main techniques available. There has yet to be consensus favoring one approach over the other. Methods: Following the PRISMA guidelines, a systematic review and meta-analysis were performed to determine if there was a difference in efficacy and safety of ERCP compared to PTBD for Cholangiocarcinoma Biliary Obstruction. Primary outcomes were successful biliary drainage, mean number of needed procedures, length of stay and overall adverse events rate. Data were analyzed using R version 4.2.2. The risk of bias was assessed by the Robins-I and RoB 2 tool. The quality of evidence was graded using the GRADE scale and Newcastle-Ottawa guidelines. Results: Three randomized clinical trials and two observational studies described the successful biliary drainage rate of ERCP vs PTBD for cholangiocarcinoma associated biliary obstruction, totaling 340 patients. Meta-analysis test for overall effect, showed no statistical difference between groups (RR = 0.88; 95% CI = [0.69; 1.13]; p = 0.23; Fig. 1). Similarly, in terms of the mean number of needed procedures per patient, a total of three randomized clinical trials and two observational studies, totaling 340 patients were included, no statistically significant difference was found (SMD = 0.64; 95% CI = [- 9.36; 10.63]; p = 0.57; Fig. 2). Likewise, one randomized clinical trial and two observational studies showed no statistically significant difference on the length of stay (days) mean between groups (SMD = 0.06; 95% CI = [- 1.57; 1.68]; p = 0.73; Fig. 3). Although, the three clinical trials and three observational studies showed a mild decreased adverse event and death (within 3 months) rate in the ERCP group, after undergoing statistical analysis, meta-analysis test for overall effect, showed no statistical difference (RR = 0.99; 95% CI = [0.55; 1.77]; p = 0.97; Fig. 4 and RR = 0.61; 95% CI = [0.10; 3.87]; p = 0.22; Fig. 5, respectively). The risk of bias was low with moderate-to-high quality of evidence amongst the included studies. Conclusions: Our updated systematic review and meta-analysis demonstrated no statistically significant difference in the successful biliary drainage rate, mean number of needed procedures, length of stay, death within 3 months and adverse event rate between ERCP vs PTBD for management of cholangiocarcinoma biliary obstruction. Further randomized studies are needed to confirm these findings.

Chidamide plus envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer (P-henomS/SCOG-P002): A single-arm, exploratory, multicenter, phase 2 trial—Interim report.

740 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with poor prognosis worldwide. Chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, has significant anti-tumor effects and extensive synergistic effects with immunotherapy. Envafolimab is a light-chain deficient PD-L1 antibody. Here we conducted a single-arm, multicenter, prospective phase Ⅱ clinical study (ChiCTR2200058431) to evaluate the efficacy and safety of Chidamide plus Envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer. Methods: Patients with metastatic PDAC receive Envafolimab (400 mg, on day 1), Chidamide (20 mg orally twice weekly, on days 0, 3, 7, and 10), and S-1 (40-60 mg according to body surface area, orally twice daily from day 1 to 14) every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary end points are safety and ORR. The secondary endpoints were PFS, OS, DCR, QoL and nutrition score. Results: Recruitment completed with 16 patients as of September 2023 and the data cut-off for analysis was August 2024, 13 were evaluable. Median age was 66 (range 59 - 80), with 5 males and 11 females. After a median follow-up of 8.5 months, the ORR and DCR by RECIST v1.1 were 30.77% and 76.92%, respectively. Median PFS was 5.83 months (95%CI 2.592-9.068) and median OS was not reached. No new safety signals were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 31.25% of patients. The most common TRAEs were anemia (12.5%), decreased platelet count (6.25%) and neutropenia (12.5%). No treatment-related deaths occurred. Conclusions: Preliminary data suggest that Chidamide and Envafolimab in combination with S-1 may be an effective second-line treatment with a manageable safety profile for patients with PDAC. Clinical trial information: ChiCTR2200058431 . Efficacy evaluation. Efficacy Evaluation AII (N = 13) n(%) Best efficacy evaluation Partial Response (PR) 4（30.77%） Stable Disease (SD) 6（46.15%） Progressive Disease (PD) 3（23.08%） Objective response rate (ORR) 30.77% 95%CI 9.09-61.43 Disease control rate (DCR) 76.92% 95%CI 46.19-94.96 mPFS（95%CI） 5.83（2.592-9.068） mOS（95%CI） -（NR）

An atlas of metabolites driving chemotaxis in prokaryotes

Unveiling the Oxidation Mechanisms of High‐entropy Carbides Through Atomic‐scale Dynamic Observation

Abstract Understanding the behavior of high‐entropy carbides (HECs) under oxygen‐containing environments is of particular importance for their promising applications in structural components, catalysis, and energy‐related fields. Herein, the structural evolution of (Ta, Ti, Cr, Nb)C (HEC‐1) nanoparticles (NPs) is tracked in situ during the oxidation at the atomic scale by using an open‐cell environmental aberration‐corrected scanning transmission electron microscope. Three key stages are clearly discerned during the oxidation of HEC‐1 NPs at the atomic level below 900 °C: i) increased amorphization of HEC‐1 NPs from 300 to 500 °C due to the energetically favorable formation of carbon vacancies and substitution of carbon with oxygen atoms; ii) nucleation and subsequent growth of locally ordered nanocluster intermediates within the generated amorphous oxides from 500 to 800 °C; and iii) final one‐step crystallization of non‐equimolar MeO 2 and Me 2 O 5 (Me = metallic elements, Ta, Ti, Cr, and Nb) high‐entropy oxides above 800 °C, accompanied with the reduction in atomic defects. This result is further confirmed by theoretical calculations that these observed high‐entropy oxide phases are thermodynamically preferable to generate above 830 °C. The study provides direct evidence of the ordered–disordered–ordered structural transition of HECs during oxidation.

FOLFIRI-ramucirumab (FOLFIRI-Ram) versus ramucirumab-paclitaxel (Ram-Pac) in the second line (2L) for patients with advanced upper gastrointestinal (UGI) cancer: A real-world propensity-score matched analysis of survival.

377 Background: The approach to 2L treatment of advanced UGI (gastric, esophageal, and gastroesophageal junction) cancers is guided primarily by the results of the RAINBOW trial, a global randomized phase III trial that demonstrated the benefit of Ram-Pac over paclitaxel. However, the onset of peripheral neuropathy limits its use in the palliative-intent setting. The RAMIRIS trial demonstrated the feasibility of 2L FOLFIRI-Ram compared to Ram-Pac, however it failed to meet the prespecified endpoint of ≥ 65% 6-month overall survival (OS). Despite this, FOLFIRI-Ram has emerged as an alternative 2L regimen and now endorsed in major society guidelines. Yet, comparative outcomes between FOLFIRI-Ram and Ram-Pac therapy in the real world are lacking. Methods: This study used the nationwide Flatiron Health electronic health record-derived deidentified database. During the study period (January 2011-June 2024), longitudinal patient-level data were derived from approximately 280 cancer clinics. Patients were eligible for inclusion if they had advanced unresectable or metastatic UGI cancer and received 2L treatment with either FOLFIRI-Ram or Ram-Pac. Demographics and lab values at the time of 2L initiation were extracted. Given anticipated imbalances in sample size, patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) for inclusion into the analytic dataset using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics. The primary endpoint was OS from the start of 2L therapy, analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model. Results: A total of 15,908 patients were included in the database, of whom 5189 received a 2L treatment. Of these, 631 patients received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, the final sample size was 240 patients who received Ram-Pac and 40 who received FOLFIRI-Ram. Baseline clinical and laboratory characteristics were well-balanced. The median OS from initiation of 2L FOLFIRI-Ram was 9.7 months (95% CI 6.9-12.3) and 7.6 months with 2L Ram-Pac (95% CI 6.3-9.2 months). The hazard ratio (HR) for death with FOLFIRI-Ram was 0.77 (95% CI 0.52-1.15, log-rank P=0.20) in reference to Ram-Pac. The adjusted HR death for FOLFIRI-Ram after adjustment for baseline albumin and white blood cell count was 0.87 (95% CI 0.58-1.30, p=0.49) in the final multivariate model. Conclusions: This real-world propensity-score matched analysis of patients with advanced UGI cancers receiving FOLFIRI-Ram or Ram-Pac supports the ongoing use of FOLFIRI-Ram in the 2L as an alternative to Ram-Pac. These data are consistent with results from the RAMIRIS study, however further prospective study is needed.

Real-world treatment patterns, healthcare resource utilization (HCRU), and costs in newly diagnosed patients with rectal cancer (RC) in the United States (US).

295 Background: RC constitutes 30% of colorectal cancer cases, the fourth most common cancer in the US, and is associated with a substantial economic burden. This retrospective claims analysis examined patient (pt) characteristics, all-cause and RC-related HCRU, and costs in pts who received surgery, radiotherapy (RT), or systemic therapy (ST) for RC. Methods: Medicare Fee-for-Service and MORE 2 Registry claims data were used to select pts with RC (RC cohort) and matched, non-RC controls (non-RC cohort). Pts with RC were required to have a diagnosis of RC in the primary position of ≥1 inpatient claim or in any position of ≥2 outpatient claims between Jan 1, 2016, and Dec 1, 2021, and ≥1 claim for an RC surgery, RT, or ST after diagnosis. Pts (aged ≥18 y) also needed to have continuous enrollment for 12 months preceding and minimum 30 days following the treatment index date (earliest RC treatment claim). Non-RC controls were matched to pts with RC on birth year, sex, payer type, and Deyo-Charlson Comorbidity Index (DCI). All-cause HCRU and costs (per pt per month [PPPM]) were compared for the RC and non-RC cohorts. Results: A total of 20,953 pts were included in each cohort (median age, 70 y; 52.5% male; median DCI, 1.0 in both cohorts). Median follow-up time was 24 months. In the RC cohort, 88.5% of pts underwent ≥1 surgery after RC diagnosis and 51.3% had ≥4 surgeries during follow-up. Colonoscopy and biopsies (59.4%), total mesorectal excision (47.7%), and proctectomy (45.2%) were the most frequent surgeries/procedures. RT was used as neoadjuvant and adjuvant therapies in 21% and 15.7% of pts, respectively; 5-fluorouracil was the most common neoadjuvant (12.7%) and adjuvant (20.9%) ST. Among nonsurgical pts (11.5%), 72.8% were treated with RT and 49.9% with 5-fluorouracil; a small proportion received immunotherapy (pembrolizumab, 1.2%; nivolumab, 0.7%). All-cause HCRU was significantly greater ( P &lt;0.001) in the RC cohort vs the non-RC cohort (proportion of pts with ≥1 claim for physician office/clinic visit, 81.3% vs 73.6%; emergency room visits, 68.7% vs 45.3%; hospitalization, 71.1% vs 25.9%). The mean all-cause costs PPPM were $6043 for the RC cohort vs $1538 for the non-RC cohort ( P &lt;0.001); mean RC-related costs PPPM were $3119. Outpatient and inpatient services were the main cost drivers in the RC cohort, accounting for 57.1% and 36.6% of all-cause expenditure, respectively, and 58.1% and 40.5% of RC-related expenditure. Conclusions: Most pts newly diagnosed with RC received standard of care surgical treatment, often with neoadjuvant or adjuvant RT or ST. All-cause HCRU was significantly greater for pts with RC vs those without RC; all-cause costs were almost 4 times higher, with about half of these costs related to RC and driven by outpatient services and hospitalizations. These results show a high economic burden and a need for additional treatments for pts with RC.

Effects of targeting CTMP on immunogenicity of MSI-L colon adenocarcinoma cells by metabolism and cell cycle modulation.

246 Background: Regimen of metastatic colon cancer (mCOAD) is moving towards combination of immune checkpoint inhibitors (ICBs) and targeted therapy, however ICBs are rarely effective in MSI-L metastatic colon cancers, limiting options for backline treatments, new targeted therapy is on demand to improve immunogenicity of MSI-L mCOAD. As targeting fatty acid metabolism or cell cycle has shown potential in improving the efficacy of ICBs, our team focused on CTMP, a thioesterase (ACOT) family member, mainly modulates fatty acid β oxidation, meanwhile it binds to phosphorylation sites of AKT thus intervenes cell cycle, currently its role on immunogenicity of COAD is not clear. Methods: Correlation between CTMP and OS in MSI-L colon cancer patients was assessed by KM plotter in GEO database.11 Clinical samples of MSI-L colon cancer, who received a third-line treatment regimen of anti-PD-1 and fruquintinib, were collected then applied in immunofluorescence and western blot analyses to evaluate CTMP and MHC-I expression. In vitro, Lentiviral transfection of targeted genes were stably established,then applied in RNA-seq and metabolic assays. Proteomic analysis and co-IP were applied to explore CTMP-modulating pathway. In vitro, IFNγ was intratumorally injected. Results: KM curve showed CTMP was negatively correlated with OS in MSI-L COAD in GEO database. In clinical samples, lower CTMP expression and higher MHC-I expression were observed in partial response (PR) than progressive disease (PD) group. In vitro, CTMP-OE reduced MHC-I, increased AKT phosphorylation and immune checkpoints (PD-L1, IDO-1), promoted clone formation. Seahorse assay showed increased capacity of glycolysis and oxidative phosphorylation in CTMP-OE than vector. RNA-seq showed CTMP-OE reduced MHC-I augmentation under IFN-γ treatment, meanwhile glucose metabolism genes, ACOT family ,immune checkpoints were also up-regulated, indicating ACOT family related metabolism promotion and immunogenicity suppression of COAD. Proteomic analysis and co-IP assay indicated CTMP interacts REV7, a key mitotic regulatory protein. Enzyme activity assay showed REV7 negatively regulates CDK1. Furthermore, REV7-OE alone is capable to induce MHC I augmentation and G2 arrest, accordingly CTMP-KD enhanced REV7's negative modulation on CDK1,contributing to G2 arrest, that also augmented MHC I . In homologous mice tumor-bearing model, tumor shrinkage was observed in CTMP-KD/ REV7-OE group. CTMP-KD/ REV7-OE increases MHC I expression,CD8+ T cell infiltration under IFN γ intra-tumoral injection. Conclusions: In summary, our studies suggested that CTMP regulates the metabolism of colorectal cancer and intervenes MHC-I molecules expression, and targeting CTMP is potential in suppressing tumor cell cycle and promoting immunogenicity through its modulation on REV7.

Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism

Slide‐Ring Structured Stress‐Electric Coupling Hydrogel Microspheres for Low‐Loss Transduction Between Tissues

Abstract High transductive loss at tissue injury sites impedes repair. The high dissipation characteristics in the electromechanical conversion of piezoelectric biomaterials pose a challenge. Therefore, supramolecular engineering and microfluidic technology is utilized to introduce slide‐ring polyrotaxane and conductive polypyrrole to construct stress‐electric coupling hydrogel microspheres. The molecular slippage mechanism of slide‐ring structure stores and releases mechanical energy, reducing mechanical loss, the piezoelectric barium titanate enables stress‐electricity conversion, and conjugated π‐electron movement in conductive network improves the internal electron transfer efficiency of microspheres, thereby reducing the loss in stress‐electricity conversion for the first time. Compared to traditional piezoelectric hydrogel microspheres, the stress‐electric coupling efficiency of low‐dissipation microspheres increased by 2.3 times, and the energy dissipation decreased to 43%. At cellular level, electrical signals generated by the microspheres triggered Ca 2+ influx into stem cells and upregulated the cAMP signaling pathways, promoting chondrogenic differentiation. Enhanced electrical signals induced macrophage polarization to the M2 phenotype, reshaping inflammation and promoting tissue repair. In vivo, the low‐dissipation microspheres restored low‐loss transduction between tissues, alleviated cartilage damage, improved behavioral outcomes, and promoted the treatment of osteoarthritis in rats. Therefore, this study proposes a new strategy for restoring low‐loss transduction between tissues, particularly in mechanically sensitive tissues.

Pan-cancer microsatellite instability testing using a multiplex assay including long mononucleotide repeats.

290 Background: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) testing is a critical component of molecular testing for gastrointestinal cancers, among others. These analyses are important for the identification of patients with lynch syndrome and eligibility for treatment with immunotherapy. The current standard of care testing can identify most cases, however improved identification of MSI-H status is needed for non-colorectal cancers and for cancers with alterations outside MLH1/PMS2. A recent analysis indicated the potential for improved MSI-H detection with a multiplex assay including long mononucleotide repeats (LMR). Methods: Patients were selected based on MSI status, MMR gene variants, or the presence of a high tumor mutation burden and consented for participation as part of an IRB-approved protocol (UW15068). Formalin-fixed tissue slides were annotated by a pathologist for tumor and normal tissue. Slides were scraped and DNA isolated. The LMR MSI Analysis System (Promega, Madison, WI) and the OncoMate MSI Dx Analysis System (Promega) were performed on cancer DNA and normal tissue DNA when available per the manufacturer’s protocols. Instability of microsatellites and the MSI score were reported and correlated with clinical MMR immunohistochemistry (IHC) and commercial next-generation sequencing (NGS). Results: A total of 96 cancer samples were tested across 94 patients with over 20 different cancer types, including lung, colon, rectal, gynecologic, and esophagogastric cancers. Tumors from 20 patients were known to have microsatellite instability based on clinical NGS testing. 27 cases were found to be MSI-H based on the OncoMate assay. All of these cases were also MSI-H per the LMR assay and an additional 3 cases were found to be MSI-H using only the LMR assay. Of these 3 cases all were microsatellite stable by NGS. This number includes 1 colorectal and 2 esophagogastric cancer cases. One of the cases was found to have loss of MSH6 by IHC with an MSH6 mutation (MSH6 L1061fs). One of the cases was MMR intact by IHC, though did have a MSH6 exon 7 splice acceptor alteration that failed NGS calling quality control. The last case did not have MMR IHC performed, no detected MMR gene alterations, and a tumor mutation burden of 6.3 mutations per megabase. Conclusions: In this limited dataset, the utility of various methods for determination of MSI, dMMR, and TMB including PCR, IHC, and NGS were demonstrated using a patient cohort spanning solid tumor types. Promising results were observed with the LMR MSI Analysis System. These findings need to be further validated in a larger dataset and correlated with the response to immunotherapeutics.