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Predicting the Mechanical Properties of Supramolecular Gels

AbstractThe prediction of gelation is an important target, yet current models do not predict any post‐gel properties. Gels can be formed through the self‐assembly of many molecules, but close analogs often do not form gels. There has been success using a number of computational approaches to understand and predict gelation from molecular structures. However, these approaches focus on whether or not a gel will form, not on the properties of the resulting gels. Critically, it is the properties of the gels that are important for a specific application, not simply whether a gel will be formed. Supramolecular gels are often kinetically trapped, meaning that predicting gel properties is inherently a difficult challenge. Here, the first successful a priori prediction of gel properties for such self‐assembled, supramolecular systems is reported.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in <i>BRCA1</i> and <i>BRCA2</i>

PURPOSE It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. METHODS Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. RESULTS Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and &gt;10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). CONCLUSION Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Association between skeletal muscle morphometrics and overall survival among older adults with gastrointestinal cancers.

808 Background: Older adults with gastrointestinal (GI) cancers face a higher risk of treatment toxicities and adverse survival outcomes. However, the variability in these outcomes remains poorly understood. Age-related changes, including the progressive loss of skeletal muscle and gain in adipose tissue, contribute to this heterogeneity. Recent studies highlight an association between skeletal muscle gauge (SMG) and overall survival (OS) in older cancer patients, but its relevance among those with GI cancers is unclear. Methods: We included adults aged ≥ 60 years with newly diagnosed GI cancers, enrolled in the University of Alabama at Birmingham (UAB) Cancer and Aging Resilience Evaluation (CARE) registry between October 2017 and April 2024. Skeletal muscle index (SMI; skeletal muscle area in m²/height in cm) and skeletal muscle radiodensity (SMD; Hounsfield units) were derived from single-slice computed tomography (CT) staging scans at the third lumbar vertebra (L3) using validated methods. SMG was calculated as the product of SMI and SMD, reported in arbitrary units (AU). Participants were followed until death or the study cutoff date of July 10, 2024. Kaplan-Meier survival analysis was used to estimate OS by SMG status (low: &lt; median; high: ≥ median). Cox proportional hazards models were employed to assess the relationship between SMG and OS, adjusting for age, sex, race/ethnicity, and cancer stage. Results: A total of 568 patients were included in the study, with a median age at diagnosis of 68 years (interquartile range, IQR: 64-74), 55% male, 73% non-Hispanic White, and 43% were diagnosed with Stage IV disease. Colorectal (33%) and pancreatic (27%) cancers were the most common diagnoses. The median SMG was 1,529 AU (IQR: 1,151–1,967). Over a median follow-up of 60 months, 367 patients (64%) died. Median OS was 19 months for those with low SMG and 26 months for those with high SMG (log-rank test, p &lt; .05). After adjustment for confounders, SMG remained independently associated with OS (adjusted Hazard Ratio: 0.678 per IQR increase; 95% CI: 0.57– 0.807; p &lt; .001), indicating that each IQR increase in SMG is associated with a decrease in all-cause mortality risk by 32.2%. Conclusions: Skeletal muscle gauge, an integrated measure of SMI and SMD, is significantly associated with improved survival among older adults with GI cancers. Further research is needed to determine whether SMG has a causal impact on survival in this population.

The prognostic impact of <i>SLFN11</i> gene expression in metastatic colorectal cancer (mCRC).

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.

Imine‐Linked 3D Covalent Organic Framework Membrane Featuring Highly Charged Sub‐1 nm Channels for Exceptional Lithium‐Ion Sieving

AbstractCoupling ion exclusion and interaction screening within sub‐nanoconfinement channels in novel porous material membranes hold great potential to realize highly efficient ion sieving, particularly for high‐performance lithium‐ion extraction. Diverse kinds of advanced membranes have been previously reported to realize this goal but with moderate performance and complex operations gained. Herein, these issues are circumvented by preparing the consecutive and intact imine‐linked three‐dimensional covalent organic framework (i.e., COF‐300) membranes via a simple solvothermal approach and employing the intrinsically interconnected sub‐1 nm one‐dimensional channels for exceptional lithium‐ion sieving. The synthesized membranes with highly charged angstrom scale channels of ≈0.78 nm achieve an excellent Li+ permeance (0.123 mol m−2 h−1) with an ultrahigh Li+/Mg2+ of 36 in the binary system. The experimental measurement and theoretical calculation reveal that a channel size right exactly between Li+ and Mg2+ enables restricted Mg2+ penetration. Meanwhile, the ion affinity interaction screening with imine groups further strengthens the fast Li+ permeability but severely suppresses the Mg2+ passage. In particular, the synthesized three‐dimensional covalent organic framwork membranes also have a remarkable separation performance during a long‐term operation test without sacrificing trade‐off, demonstrating chemistry stability and mechanical integrity under the high‐salinity aqueous environment.

A systematic review of the impact of artificial intelligence in pancreatic cancer detection.

685 Background: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, and early detection remains a significant challenge. Screening the general population is not feasible, but the rise of artificial intelligence (AI) has introduced new possibilities for improving early diagnosis and patient outcomes. Methods: A systematic literature search was conducted using PubMed, Google Scholar, and MEDLINE using MeSH terms Artificial intelligence or AI, and diagnosis and pancreatic carcinoma or pancreatic adenocarcinoma. Prisma guidelines were adhered to, and a total of 19 studies resulted, 6 of them were retrospective studies, 4 of them were literature reviews, and 4 of them were randomized trials. The rest were duplicates. The inclusion criteria for this study is AI being used in the diagnosis, only in pancreatic cancer, within the last 5 years, only in English, and only retrospective studies were included. Results: One study used Digital Imaging Processing (DIP) for analyzing Endoscopic ultrasound (EUS) images from 153 pancreatic cancer patients, yielding a sensitivity of 97.98% and a specificity of 94.32%. Two studies explored Computer Aided Diagnosis (CAD) models applied to PET/CT and EUS images, achieving a sensitivity of 95.23% and specificity of 97.51% in PET/CT scans and 83.3% and 93.3% in EUS images, respectively. Another study used a Faster R-CNN model to analyze CT images from 338 pancreatic cancer patients showed high diagnostic accuracy in much less time. Additionally, two studies utilized Natural Language Processing (NLP) for identifying family histories of pancreatic cancer and detecting pancreatic cysts, with the latter achieving sensitivity and specificity rates of 99.9% and 98.8%. Conclusions: The current strategies for early diagnosis of pancreatic cancer focus on serum biomarkers and EUS-guided Fine Needle Aspiration (EUS-FNA) and sensitivity varies but depends on the physician's expertise. AI is showing promise in improving pancreatic cancer diagnosis by enhancing early detection and accuracy. Techniques like deep learning, NLP-based models, Faster R-CNN, and CAD systems analyze medical data and images more effectively than manual methods. AI holds the potential to shape the future of pancreatic cancer diagnosis and improve patient outcomes.

Combination of Osimertinib and Vascular Endothelial Growth Factor Receptor Inhibitors for <i>EGFR</i> -Mutated Non–Small Cell Lung Cancer: Old or New Regimen?

Association between ctDNA levels, timing of blood collection, and overall survival in metastatic colorectal cancer.

245 Background: While circulating tumor DNA (ctDNA) detection is influenced by various factors, the impact of blood collection timing remains understudied. This study investigated the relationship between ctDNA detection, and blood collection timing and prognosis in patients with metastatic colorectal cancer (mCRC) from the GOZILA study. Methods: GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. This study evaluated the association of ctDNA levels with blood collection timing and prognosis in patients with mCRC. ctDNA levels were determined by the maximum variant allele frequency. Blood collection timing was categorized into five groups: naive (before initiation of 1st line treatment), after treatment initiation (days 1-14 of treatment), during treatment (between “after treatment initiation” and “before progression disease [PD]”), before PD (from 28 days before PD to PD), and after PD (after disease progression but before the next line of treatment). Overall survival (OS) was compared across treatment lines using ctDNA level cutoff of 10. Results: We analyzed 2,398 blood samples from 1,994 patients with mCRC enrolled in the GOZILA between February 2018 and July 2023. ctDNA levels were significantly lower during treatment compared to the naive (median, 13.2 vs. 5.7, p &lt; 0.001). No significant differences were observed between naive and other blood collection timing. Compared to blood collection before 1st line treatment, ctDNA levels significantly decreased before 2nd line (median, 13.5 vs. 8.3, p = 0.02) and 3rd line treatments (median, 13.5 vs. 7.6, p = 0.01). Patients with ctDNA levels&lt;10 demonstrated significantly better OS across all treatment lines, including 1st line (median, NA vs. 23.9 months, HR 0.49, 95% CI, 0.34-0.72), 2nd line (median, 22.1 vs. 10.3 months, HR 0.42, 95% CI, 0.33-0.55), and later line treatments (FTD/TPI: median, 12.7 vs. 5.7 months, HR 0.51, 95% CI, 0.26-0.99; FTD/TPI+Bev: median, 9.3 vs. 6.5 months, HR 0.55, 95% CI, 0.37-0.82; Regorafenib: median, 13.5 vs. 7.4 months, HR 0.45, 95% CI, 0.26-0.80). Conclusions: In mCRC, blood collection during treatment is suboptimal due to decreased ctDNA levels. Patients with ctDNA levels &lt;10 showed significantly better OS across all treatment lines. Optimal timing of blood collection can enhance ctDNA levels, enabling more accurate gene mutation assessment and stratifying outcomes.

Light‐Induced Hysteresis of Electronic Polarization in Anti‐Ferromagnet FePS₃

AbstractResearch on manipulating materials using light has garnered significant interest, yet examples of controlling electronic polarization in magnetic materials remain scarce. Here, the hysteresis of electronic polarization in the anti‐ferromagnetic semiconductor FePS3 is demonstrated via light. Below the Néel temperature, linear dichroism (i.e., optical anisotropy) without structural symmetry breaking is observed. Light‐induced net polarization aligns along the a‐axis (zigzag direction) at 1.6 eV due to the dipolar polarization and along the b‐axis (armchair direction) at 2.0 eV due to the combined effects of dipolar and octupolar polarizations, resulting from charge transfer from the armchair to the zigzag direction by light. Unexpected hysteresis of the electronic polarization occurs at 2.0 eV due to the octupolar polarization, in contrast to the absence of such hysteresis at 1.6 eV. This is attributed to a symmetry breaking of the light‐induced phase of FePS3 involving electronic polarization within the spin lattice. Here a new mechanism is suggested for generating and controlling electronic polarization in magnetic materials using light, with implications for future device applications.

Organ-specific responses to nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma: A multicenter, retrospective study.

543 Background: The Check-Mate 9DW trial demonstrated that combining ipilimumab with nivolumab (Ipi/Nivo) improved survival outcomes compared with sorafenib or lenvatinib in advanced hepatocellular carcinoma (aHCC). Accumulated evidence suggests that immune checkpoint inhibitor (ICI) monotherapy elicits limited intrahepatic responses in patients with aHCC. Here, we aimed to examine the organ-specific objective response rate (OSORR) of Ipi/Nivo compared with that of nivolumab monotherapy (Nivo) and to evaluate the OSORR of Ipi/Nivo based on the prior use of ICI treatment. Methods: We conducted a retrospective assessment of 69 Ipi/Nivo-treated patients and 164 nivolumab-treated patients for aHCC at five referral hospitals in Korea. Only patients classified as Child-Pugh Class A were included. Organ-specific response criteria were adopted from RECIST 1.1, according to the indicated primary sites, including the liver, lungs, lymph nodes and other sites of metastasis. Results: Baseline characteristics of the Ipi/Nivo and Nivo groups were comparable. However, 65.2% of patients in the Ipi/Nivo group had prior ICI exposure, compared with only 4.3% in the Nivo group. The objective response rate (ORR) of Ipi/Nivo was 29.0%. The Ipi/Nivo combination therapy elicited OSORRs for 204 individual lesions: 18.0% in the liver, 17.7% in the lungs, 30.0% in the lymph nodes, and 12.5% in other sites. Within the Ipi/Nivo group, the ORR was 45.8% for patients without prior ICI exposure and 20.0% for those with prior ICI exposure. Patients without prior ICI exposure demonstrated OSORRs for 72 individual lesions: 29.0% in the liver, 31.3% in the lungs, 33.3% in the lymph nodes, and 23.1% at other sites. Conversely, patients with prior ICI exposure exhibited OSORRs for 132 individual lesions: 11.5% in the liver, 11.4% in the lungs, 27.8% in the lymph nodes, and 7.4% at other sites. Patients who exhibited a response in one organ were more likely to demonstrate responses in other organs irrespective of the organ type, with only two patients exhibiting variable responses across different organs. Furthermore, these responders had improved survival outcomes, including longer progression-free survival and overall survival, compared with non-responders. In terms of nivolumab monotherapy, the ORR was 21.3%. Nivo yielded OSORRs for 305 individual lesions: 13.5% in the liver, 25.3% in the lungs, 39.3% in the lymph nodes, and 18.4% at other sites. Conclusions: In contrast to lesions of patients who received Nivo, intrahepatic lesions of Ipi/Nivo-treated patients without prior ICI exposure exhibited favorable responses, comparable with treatment responses of extrahepatic lesions. Conversely, Ipi/Nivo-treated patients with prior ICI exposure had reduced organ-specific responses across all organs when compared with those without prior ICI exposure.

Safety and tolerability of different total neoadjuvant therapy strategies in patients with locally advanced rectal cancer.

121 Background: Total neoadjuvant therapy (TNT) leads to improved local control and organ preservation for locally advanced rectal cancer (LARC). The chemotherapy part of TNT may play a critical role in achieving local control and in improving OS. Few studies have focused on the toxicity associated with the chemotherapy of TNT. Furthermore, the differences in safety and tolerability between radiotherapy-first and chemotherapy-first strategies remain unclear. Methods: LARC patients treated with TNT between June 2020 and July 2023 at a single cancer institute were retrospectively enrolled. TNT consisted of induction chemotherapy followed by long-course chemoradiotherapy (INCT-LC-CRT) or long-course chemoradiotherapy/short-course radiotherapy followed by consolidation chemotherapy (LC-CRT-CNCT/SC-RT-CNCT). Concurrent chemotherapy in LC-CRT was capecitabine (825 mg/m 2 oral twice daily). INCT/CNCT consisted of six cycles of CAPOX (capecitabine 1000 mg/m² oral twice daily on days 1–14 and oxaliplatin 130 mg/m² intravenously on day 1 every 21 days). INCT allowed the addition of bevacizumab (7.5 mg/kg intravenously on day 1). We compared adverse events (AEs) and treatment exposure between INCT-LC-CRT, LC-CRT-CNCT and SC-RT-CNCT. Results: A total of 93 patients were included. Patients with INCT-LC-CRT and LC-CRT-CNCT/SC-RT-CNCT were 28 (30.1%) and 45 (48.4%)/20 (21.5%), respectively. Patients who were treated with INCT-LC-CRT (53.6%) had more N2 stage than those with LC-CRT-CNCT/SC-RT-CNCT (21.6%). Grade 3–4 AEs during chemotherapy were significantly more frequent in LC-CRT-CNCT/ SC-RT-CNCT group than in INCT-LC-CRT group (50.8% vs. 21.4%; p = 0.02). Neutropenia was the most common Grade 3–4 AEs during chemotherapy in INCT-LC-CRT group (7.4%) and LC-CRT-CNCT/SC-RT-CNCT group (27.7%). Grade 3–4 AEs during chemotherapy were not significantly different between the LC-CRT-CNCT and SC-RT-CNCT groups (36.9% vs. 40.0%; p = 0.42). All patients underwent the full radiation dose. The completion rate of six cycles of chemotherapy was no significant difference between INCT-LC-CRT group and LC-CRT-CNCT/SC-RT-CNCT group (92.9% vs. 84.6%; p = 0.37). However, LC-CRT-CNCT/SC-RT-CNCT group required significantly more dose modification during chemotherapy than INCT-LC-CRT group (75.4% vs. 46.4%; p &lt; 0.01). Dose modification during chemotherapy between LC-CRT-CNCT and SC-RT-CNCT group was no significant difference (modification rate 77.8% vs. 70.0%; p = 0.54). Chemotherapy discontinuations due to AEs in INCT-LC-CRT group and LC-CRT-CNCT/SC-RT-CNCT group were 1(3.6%) and 6 (9.2%), respectively. Conclusions: Grade 3–4 AEs during chemotherapy were more frequent and required dose modification of chemotherapy in a radiotherapy-first strategy. Safety and tolerability of chemotherapy part of TNT may differ between radiotherapy-first and chemotherapy-first strategies.

Phase 1/2 study of the trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) as monotherapy or combination therapy in gastrointestinal cancers: LIGHTBEAM-02A.

TPS846 Background: There is a significant need for new tolerable and effective therapeutic options for colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC) that can provide survival benefit. TROP2 is expressed broadly in several cancers, including CRC, PDAC, and BTC. Sac-TMT (formerly MK-2870/SKB264) is an ADC consisting of a humanized antihuman TROP2 monoclonal antibody, a linker, and a cytotoxic belotecan–derivative topoisomerase I inhibitor. The nonrandomized, open-label, phase 1/2 LIGHTBEAM-02A study (NCT06428409) is being conducted to examine the safety and efficacy of sac-TMT in gastrointestinal cancers. Methods: Approximately 130 patients will be assigned to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n ≤ 50) must have previously treated locally advanced or metastatic colorectal adenocarcinoma; patients in cohort 2 (PDAC; n ≅ 40) must have previously treated locally advanced or metastatic PDAC; patients in cohort 3 (BTC; n ≅ 40) must have previously treated locally advanced or metastatic BTC. Cohort 1 is included in a dose-escalation phase to determine the recommended phase 2 dose of sac-TMT when used in combination with fluorouracil and leucovorin and an efficacy phase. In the dose-escalation phase, patients will receive sac-TMT 3 mg/kg or 4 mg/kg intravenously (IV) every 2 weeks (Q2W) on days 1 and 15 of each 4-week cycle plus 2400 mg/m 2 fluorouracil IV infused over 46-48 hours Q2W and 400 mg/m 2 leucovorin IV Q2W; in the efficacy phase, patients will receive the recommended phase 2 dose of sac-TMT with the same chemotherapy regimen as the dose-escalation phase. Patients in cohorts 2 and 3 will receive sac-TMT 4 mg/kg IV monotherapy Q2W on days 1 and 15 of each 4-week cycle. The primary objectives are to evaluate safety and tolerability and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival. Enrollment is ongoing. Clinical trial information: NCT06428409 .

Programmable Magnetic Hysteresis in Orthogonally‐Twisted 2D CrSBr Magnets via Stacking Engineering.

Abstract Twisting 2D van der Waals magnets allows the formation and control of different spin‐textures, as skyrmions or magnetic domains. Beyond the rotation angle, different spin reversal processes can be engineered by increasing the number of magnetic layers forming the twisted van der Waals heterostructure. Here, pristine monolayers and bilayers of the A‐type antiferromagnet CrSBr are considered as building blocks. By rotating 90 degrees these units, symmetric (monolayer/monolayer and bilayer/bilayer) and asymmetric (monolayer/bilayer) heterostructures are fabricated. The magneto‐transport properties reveal the appearance of magnetic hysteresis, which is highly dependent upon the magnitude and direction of the applied magnetic field and is determined not only by the twist‐angle but also by the number of layers forming the stack. This high tunability allows switching between volatile and non‐volatile magnetic memory at zero‐field and controlling the appearance of abrupt magnetic reversal processes at either negative or positive field values on demand. The phenomenology is rationalized based on the different spin‐switching processes occurring in the layers, as supported by micromagnetic simulations. The results highlight the combination between twist‐angle and number of layers as key elements for engineering spin‐switching reversals in twisted magnets, of interest toward the miniaturization of spintronic devices and realizing novel spin textures.

Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.

Updated results from the trastuzumab deruxtecan (T-DXd) 5.4 mg/kg triplet combination of DESTINY-Gastric03 (DG-03): First-line (1L) T-DXd with fluoropyrimidine (FP) and pembrolizumab in advanced/metastatic HER2-positive (HER2+) esophageal adenocarcinoma, gastric cancer (GC), or gastroesophageal junction adenocarcinoma (GEJA).

448 Background: T-DXd is a HER2-directed antibody-drug conjugate; T-DXd 6.4 mg/kg monotherapy is approved for patients with metastatic HER2+ GC/GEJA who have received a prior trastuzumab-based regimen. Preliminary results from DG-03 Part 2 showed feasibility and promising antitumor activity with 1L T-DXd 6.4 mg/kg (arm D) or 5.4 mg/kg (arm F) with FP and pembrolizumab in patients with esophageal adenocarcinoma/GC/GEJA. T-DXd 6.4 mg/kg and FP with pembrolizumab was associated with higher than expected toxicity; alternatively, early safety data from T-DXd 5.4 mg/kg triplet combination showed a manageable safety profile. We report updated results for arm F from DG-03 Part 2 with an approximate time-matched analysis with arm D. Methods: DG-03 (NCT04379596) is a Phase 1b/2 multicenter, open-label, dose-escalation (Part 1) and -expansion (Parts 2, 3, and 4) study. In Part 2, patients with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization–positive by local testing) esophageal adenocarcinoma/GC/GEJA, irrespective of programmed cell death ligand 1 status, and no prior treatment for metastatic disease were enrolled. In arm D, patients received T-DXd 6.4 mg/kg intravenous (IV) infusion every 3 weeks (Q3W) and FP (5-fluorouracil [5-FU] 600 mg/m 2 continuous IV or capecitabine [cape] 1000 mg/m 2 twice daily [BID]) with pembrolizumab 200 mg IV Q3W; in arm F, patients received T-DXd 5.4 mg/kg IV Q3W and FP (5-FU 600 mg/m 2 continuous IV or cape 750 mg/m 2 BID) with pembrolizumab 200 mg IV Q3W.Primary endpoint was confirmed objective response rate by investigator assessment (INV) per RECIST 1.1. Secondary endpoints included duration of response by INV and progression-free survival by INV. Safety and tolerability were also assessed. Results: A time matched analysis was performed to compare the efficacy of arm D (n=43), data cut-off (DCO) October 27, 2022, and arm F (n=32), DCO May 6, 2024, given the limited follow up of the 5.4mg/kg. The median duration of follow up for the two cohorts was 4.1 months and 4.6 months for arm D and arm F, respectively. Objective response rate for arm D was 41.9% and 59.4% for arm F. Median PFS was 6.4 months (95% CI: 5.0, NC) for arm D and 5.8 months (95% CI: 5.6, NE) for arm F. At DCO, the median overall survival in both arms was not reached. Updated time matched safety and efficacy data will be provided at the time of presentation. Conclusion: The time matched analysis shows that lowering the dose of T-DXd to 5.4 mg/kg from 6.4 mg/kg and lowering the starting dose of capecitabine, did not result in decrease in efficacy of the combination of T-DXd + FP + pembrolizumab. Funding: This study is sponsored by AstraZeneca in collaboration with Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201). Editorial acknowledgment: Under guidance of the authors and in accordance with Good Publication Practice, medical writing and editorial support was provided by Carmen Grimaldos, PhD, of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca. Clinical trial information: NCT04379596 .

Therapeutic value of para-aortic lymph node dissection in gastric cancer with extensive lymph node metastasis: Integrated analysis of three phase II trials (JCOG2212A).

419 Background: Gastric cancer (GC) sometimes forms metastatic bulky nodes around celiac artery or its branches (Bulky N), or metastasizes to para-aortic node (PAN) without any other distant metastasis. These severe nodal metastases are seldom cured by surgery alone. Japan Clinical Oncology Group (JCOG) defined these tumors as an extensive lymph node metastasis (ELM), and has developed multidisciplinary treatment through 3 phase II trials (JCOG0001, 0405, and 1002). JCOG0405 and 1002 reported the efficacy of D2 gastrectomy and PAN dissection (PAND) after neoadjuvant chemotherapy for GC with ELM with favorable survival outcomes. However, it remains unclear whether PAND truly contributed to the survival. The aim of this study was to clarify an optimal lymph node dissection area for GC with ELM. Methods: Therapeutic value index (TI) was investigated using an integrated dataset of JCOG0001, 0405, and 1002. Irinotecan and cisplatin, S-1 and cisplatin, or docetaxel, cisplatin and S-1 were used as neoadjuvant chemotherapy in JCOG0001, 0405, or 1002, respectively. Patients were classified into Bulky N group (only bulky N without PAN) and PAN group (PAN regardless of bulky N). TI was calculated by the following formula: proportion of metastasis (%) × 5-year relapse-free survival (5y-RFS, %) of patients with metastasis in the respective lymph node area / 100. Subgroup analysis by pathological response was also examined using the Japanese Classification of Gastric Carcinoma (JCGC) criteria. Grade ≥ 2a in JCGC criteria was defined as major pathological response (MPR). Results: A total of 122 patients were analyzed (Bulky N group: 68, PAN group: 54). Proportion of metastasis in peri-gastric (PG), supra-pancreatic (SP), and PAN areas were 80.9%, 54.4%, and 15.2% in Bulky N group, and 79.6%, 51.9%, and 44.4% in PAN group, respectively. 5y-RFS of patients with metastasis in PG, SP, and PAN areas were 38.2%, 29.7%, and 30% in Bulky N group and 23.3%, 7.1%, and 4.2% in PAN group, respectively. 30.9% of Bulky N group and 27.8% of PAN group showed MPR.TIs in each lymph node area are shown in the table. Conclusions: TI of PAN was extremely low in PAN group, especially in recent 2 trials (JCOG0405 and 1002) and when neoadjuvant chemotherapy was effective. These results suggest that advances in chemotherapy may make PAND unnecessary for GC with PAN metastasis in the future. Therapeutic value index in each lymph node area. PG area SP area PAN area Population N Bulky N group PAN group Bulky N group PAN group Bulky N group PAN group Overall 122 30.9 18.5 15.0 3.7 5.6 1.9 JCOG0001 36 25.0 12.5 18.2 12.5 4.5 6.3 JCOG0405 42 40.9 25.0 15.4 0.0 3.8 0.0 JCOG1002 44 26.9 16.7 16.2 0.0 4.5 0.0 MPR 36 19.0 33.3 4.8 0.0 4.8 0.0 PG, peri-gastric; SP, supra-pancreatic; PAN, para-aortic node; MPR, major pathological response.

Interfacial Water Regulation for Nitrate Electroreduction to Ammonia at Ultralow Overpotentials

Abstract Nitrate electroreduction is promising for achieving effluent waste‐water treatment and ammonia production with respect to the global nitrogen balance. However, due to the impeded hydrogenation process, high overpotentials need to be surmounted during nitrate electroreduction, causing intensive energy consumption. Herein, a hydroxide regulation strategy is developed to optimize the interfacial H 2 O behavior for accelerating the hydrogenation conversion of nitrate to ammonia at ultralow overpotentials. The well‐designed Ru─Ni(OH) 2 electrocatalyst shows a remarkable energy efficiency of 44.6% at +0.1 V versus RHE and a nearly 100% Faradaic efficiency for NH 3 synthesis at 0 V versus RHE. In situ characterizations and theoretical calculations indicate that Ni(OH) 2 can regulate the interfacial H 2 O structure with a promoted H 2 O dissociation process and contribute to the spontaneous hydrogen spillover process for boosting NO 3 − electroreduction to NH 3 at Ru sites. Furthermore, the assembled rechargeable Zn‐NO 3 − /ethanol battery system exhibits an outstanding long‐term cycling stability during the charge–discharge tests with the production of high‐value‐added ammonium acetate, showing great potential for simultaneously achieving nitrate removal, energy conversion, and chemical synthesis. This work can not only provide a guidance for interfacial H 2 O regulation in extensive hydrogenation reactions but also inspire the design of a novel hybrid flow battery with multiple functions.

Investigating the real-world outcomes of single- versus multi-agent preoperative chemoradiotherapy for locally advanced rectal cancer: NCDB analysis from 2004-2020.

61 Background: Fluorouracil-based chemoradiotherapy is the standard initial treatment for locally advanced rectal cancer, demonstrating improved pathological response and reduced local recurrences compared to radiation alone. Fluorouracil-based chemo-radiation therapy has no impact on distant recurrences. Oxaliplatin was tested in addition to fluorouracil-based chemo-radiotherapy in clinical trials to improve pathological complete response (pCR), distant recurrence-free survival, and overall survival. The trial results are conflicting. In this study, we aim to compare single-agent (SA) versus multi-agent (MA) chemotherapy using real-world data from the National Cancer Database (NCDB). Methods: The NCDB was used to identify 39,667 patients with rectal cancer who received concurrent chemoradiotherapy between 2004 and 2020. We compared patients who received SA chemotherapy with those who received MA concurrent chemotherapy. The primary outcomes of interest were overall survival and pCR. The groups were compared using univariate analysis and Cox proportional hazard models to adjust for potential confounding factors. Results: Of 39,667 patients with rectal cancer, 24,452 received single-agent (SA) chemotherapy and 14,215 received multi-agent (MA) chemotherapy. Patients in the SA group were of advanced age, had a greater number of comorbidities (as calculated by the Charleson-Dayo score), were treated within community facilities, had a higher income status, were covered by government insurance, were situated on the east coast, and had lower educational attainment compared to those in the MA group (p&lt;0.05). SA group had higher T4 and N1 disease, however MA group had more N2 disease. Upon survival analysis, patient in MA group had higher survival (41.2 vs 38.9 months, p=0.005), however pCR was significantly higher in SA group (10.4% vs 6.4%, p&lt;0.001). Conclusions: MA chemoradiotherapy for rectal cancer improves survival, with the SA regimen showing enhanced complete pathological response. Differences in baseline characteristics may explain the outcomes. While MA chemotherapy offers modest overall survival benefits, potential toxicity needs to be considered and confirmed in future studies. Comparison between single agent vs multi-agent chemo-radiotherapy group. Outcome Single-agent chemotherapy Multiagent chemotherapy Chi Squared p-value No readmission within 30 days of surgical discharge 22,727 (89.3 %) 12,921 (90.9 %) &lt;0.001 30-day mortality after surgery 360 (1.5 %) 59 (0.5 %) &lt;0.001 90-day mortality after surgery 716 (3.0 %) 158 (1.3%) &lt;0.001 Median duration of surgical admission 6.0 5.0 &lt;0.001 Median survival-vital = deceased (months) 38.9 41.2 0.005 Median survival-vital = alive (months) 66.9 52.0 &lt;0.001 Pathological complete response (pCR) 2,644 (10.4%) 904 (6.4%) &lt;0.001

Incidence trends of early-onset colorectal cancer (EOCRC) in the United States, by age, sex, race and ethnicity, and urbanicity (2000-2021).

26 Background: Research is needed to understand the extent to which the incidence of early onset colorectal cancer (EOCRC)is rising across population sub-groups, including by age, sex, race/ethnicity, and urbanicity, to inform hypotheses regarding its causes and strategies for screening and prevention. Methods: We used data on colorectal cancer cases diagnosed among adults 20-49 years (yr) between 2000-2021 in the delay-adjusted Surveillance, Epidemiology, and End Results (SEER) database (April 2024). We calculated delay- and age-adjusted annual incidence rates (IR) per 100,000, overall and by age, sex, race/ethnicity, and urbanicity. Urbanicity was defined using USDA Rural-Urban Continuum Codes for county; 1-3 were classified as urban and 4-9, 98, and 99 were classified as non-urban. We used NCI’s Joinpoint regression models (Joinpoint version 5.2.0.0) to estimate annual percent change (APC) and 95% confidence intervals (CI). We also calculated IRs for the most recent 5-year period (2017-2021) and used incidence rate ratios (IRR) to compare across groups; IRs and IRRs were calculated using SEER*Stat version 8.4.3. Results: Analyses included 155,500 cases of EOCRC. Most cases (72%) occurred among adults 40-49 yr; 22% occurred among those 30–39 yr and 6% in people 20-29 yr. Among adults 40-49 yr, the incidence of EOCRC increased 4.4% / yr on average between 2018-2021 (95%CI: 2.5, 5.6). Among adults 30-39 yr, incidence of EOCRC increased 3.0% / yr, on average, starting in 2010 (95%CI: 2.4, 4.5). For adults ages 20-29 yr, there were large increases in incidence from 2000-2016 (2000-2013, APC: 3.5; 95%CI: 2.4, 4.1; 2013-2016, APC: 11.2; 95%CI: 6.8, 13.5) but no change from 2016-2021. For the most recent 5-yr period (2017-2021), females had lower IR compared to males (IRR: 0.90; 95%CI: 0.88, 0.91), but trends over time were similar by sex. The incidence of EOCRC increased across races and ethnicities between 2000-2021, albeit at different rates. In the most recent period (2017-2021), the IR per 100,000 was 22.0 for Non-Hispanic American Indian and Alaskan Native (AIAN), 15.0 for Non-Hispanic White, 14.9 for Non-Hispanic Black, 12.4 for Hispanic or Latino, and 11.2 for Non-Hispanic Asian American or Pacific Islander adults. People in non-urban areas had a higher incidence of EOCRC compared to those in urban areas (IRR: 1.18; 95%CI: 1.14, 1.22), with similar trends over time. Conclusions: The incidence of EOCRC is highest among adults 40-49 yr, males, Non-Hispanic AIAN adults, and in non-urban areas. Trend analyses generally showed similar increases in incidence (3-5%/yr) in recent periods across sex, race/ethnicity, and urbanicity.

Perioperative versus adjuvant therapy in resectable pancreas cancer.

703 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer death in the United States with a 5-year survival rate of 13%. Recurrence rates are high following resection and optimization of neoadjuvant and adjuvant therapy remains under investigation, with the hypothesis that neoadjuvant/perioperative therapy may convert borderline resectable tumors to resectable and prevent progression of micro-metastases in the postoperative setting. Our study evaluates patient outcomes and models predictive and prognostic markers to assist with clinical decision-making in consideration of neoadjuvant therapy for resectable and borderline resectable pancreatic cancers. Methods: We performed a single-institution retrospective analysis of patients who underwent pancreatic resection between January 1, 2016 and December 31, 2020 (n=532). We excluded patients with unresectable disease or a non-PDAC diagnosis. Analysis of the remaining patients (n=175) was performed using automated and manual chart review, basic statistical comparisons with T-tests or Chi-squared tests, Kaplan-Meier Survival analyses, and Cox Proportional Hazard Testing using intention to treat analysis. Results: There were no significant differences (p&gt;0.05) the presenting demographics between the adjuvant (AJ, n=97) and neoadjuvant/perioperative (NP, n=76) groups. Patients were more likely to have a history of pancreatitis, a risk factor for PDAC development, in the NP group (p=0.0153). Patients in the AJ group included patients who ultimately did not receive the recommended adjuvant therapy for various reasons (n=25) and had overall worse performance status (p=0.004) and received less chemotherapy overall compared to the NP cohort (p=0.0003). Adjuvant therapy was more likely to be gemcitabine with capecitabine (n=37, p=0.0007) in the AJ group and gemcitabine with nab-paclitaxel (n=11, p=0.0018) in the NP group. In the neoadjuvant setting, 62% of patients received FOLFIRINOX and 28% received gemcitabine with nab-paclitaxel. Patients in the NP group were more likely to receive radiation (p=0016), including 6 patients who received neoadjuvant radiation. Median overall survival (33.9 [28.8-43.8] versus 38.2 [28.2-47.8] months) and progression free survival (21.1 [18.1-34.2] versus 16.6 [11.7-23.6] months) were not significantly different between the AJ and NP groups, respectively. Conclusions: These results demonstrate similar presenting characteristics between patients with resectable PDAC treated in a period when general practice shifted from adjuvant therapy to a neoadjuvant/perioperative approach. Although patients treated neoadjuvantly received more chemotherapy overall and the chemotherapy regimens differed between the groups, patients had similar outcomes in the two groups.