Browse Articles

Efficient Electrosynthesis of Hydrogen Peroxide Enabled by a Hierarchical Hollow RE–P–O (RE = Sm, La, Gd) Architecture with Open Channels

AbstractThe electrochemical two‐electron oxygen reduction reaction (2e− ORR) offers a sustainable pathway for the production of H2O2; however, the development of electrocatalysts with exceptional activity, selectivity, and long‐term stability remains a challenging task. Herein, a novel approach is presented to addressing this challenge by synthesizing hierarchical hollow SmPO4 nanospheres with open channels via a two‐step hydrothermal treatment. The produced compound demonstrates remarkable 2e− selectivity, exceeding 93% across a wide potential range of 0.0–0.6 V in 0.1 m KOH, with a peak of 96% at 0.45 V. When employed as the cathode in a flow cell, the synthesized SmPO4 exhibits impressive stability at 100 mA cm−2 for 12 h, consistently achieving a Faradaic efficiency above 90%. Using X‐ray absorption, in situ Raman and Fourier‐transform infrared spectroscopies, theoretical calculations, and post‐ORR assessments, it is found that this hollow compound possesses intrinsic open channels and is characterized by the optimal metal atomic spacing, and exceptional structural and compositional stabilities. These factors significantly enhance the thermodynamics, kinetics, and stability of the 2e− ORR process. Notably, the produced compound also exhibits outstanding 2e− ORR performance in neutral environments. Furthermore, this strategy can be extended to other hollow rare‐earth–P–O compounds, demonstrating excellent 2e− ORR performance under both neutral and alkaline conditions.

Toxicology and clinical protocol development of DUO-207: An ultrasmall nanomedicine co-delivering gemcitabine and paclitaxel for the treatment of metastatic pancreatic cancer.

749 Background: The long-term survival rates for metastatic pancreatic cancer have remained stubbornly low for decades. Most pancreatic cancers have dense, fibrous stroma tissue surrounding their tumors, which contributes to tumor growth and acts as a barrier to many therapies. Nanomedicines have been developed for use in oncology to reduce toxicity and improve efficacy, but a majority are too large (> 100nm) to effectively penetrate dense stroma. DUO-207 is a novel ultrasmall nanomedicine (~ 20nm) composed of copolymer-conjugated gemcitabine that encapsulates paclitaxel. Numerous preclinical efficacy models have demonstrated DUO-207’s ability to penetrate and accumulate in tumor tissue. Here we describe results from toxicology studies performed in canines that assisted in the design of a phase 1b clinical trial using the continual reassessment method (CRM). Methods: A single cycle, bridging toxicology study of DUO-207 with a recovery period was performed in canines. Animal equivalent doses of nano-albumin-bound paclitaxel (nAb-PTX) and gemcitabine were administered as the standard of care (SoC) comparator. Blood was analyzed for hematological toxicity, biomarkers of major organ toxicity, and drug toxicokinetics. Toxicology results from DUO-207 were then used in a statistical model to explore plausible scenarios for clinical dose escalation. Results: DUO-207 treated canines demonstrated improved clinical observations compared to SoC. As expected, hematologic toxicities occurred in a dose dependent fashion in the DUO-207 group but no hepato- or nephrotoxicity was noted. Based on these data, a phase 1b CRM design has been developed with 90% power to detect the maximum tolerated dose in key scenarios with an average sample size of 11 patients per group. Conclusions: In summary, DUO-207 is a novel, ultrasmall nanomedicine that can co-deliver paclitaxel and gemcitabine in a single intravenous infusion to treat stroma-rich cancers. DUO-207 demonstrated dose dependent hematological toxicities but improved clinical observations compared to SoC and lacked signals of renal and hepatoxicity. Toxicokinetic data from canines was used in a statistical model to determine patient numbers for phase 1b dosing using the CRM. Duo Oncology will conduct its clinical trial in 2025.

Risk factors for mortality and financial burdens in patients with colon cancer.

300 Background: Colon cancer remains one of the most common cancers of the digestive system and continues to rank high among the leading causes of cancer-related deaths, despite the increased prevalence of screening. In this study, we aimed to investigate risk factors for mortality and health care costs in hospitalized patients diagnosed with colon cancer. Methods: Patients admitted to the hospital in 2019 and 2020 were identified using the Nationwide Inpatient Sample database and categorized into two groups based on the presence of colon cancer (with relevant ICD-10 codes). To account for confounding factors, multivariate regression analysis was applied to calculate mortality. Statistical analyses were conducted to assess mortality rates, length of stay, and hospital charges. Results: A total of 169,805 patients were admitted with a primary diagnosis of colon cancer, with a mean age of 67.6 years. The majority were White (69.9%), and 50.2% were male. Age over 60 (OR: 1.67, p < 0.001) and sepsis (OR: 16.01, p < 0.001) were associated with increased in-hospital mortality among colon cancer patients, while higher household income (76th to 100th percentile, OR: 0.71, p = 0.011) and treatment at an urban teaching facility (OR: 0.54, p < 0.001) were linked to a lower risk of in-hospital mortality. Female gender (OR: 0.88, p = 0.080) and having inflammatory bowel disease (OR: 0.67, p = 0.055) did not significantly affect in-hospital mortality, nor did Black race (OR: 1.1, p = 0.348) or Hispanic race (OR: 1.15, p = 0.287) compared to White patients. Sepsis (+11.8 days, p<0.001; +$192,699, p< 0.001), age over 60 (+0.99 days, p<0.001; +$6,134, p<0.001), and care at urban teaching hospitals (+0.54 days, p< 0.001; +$32,230, p< 0.001) were associated with longer hospital stays and higher total charges. Conversely, female gender (-0.21 days, p=0.001; -$5,529, p<0.001) and higher income (-0.69 days, p<0.001; -$1,565, p=0.466) were linked to shorter hospital stays and lower total charges. Conclusions: Early recognition of sepsis in colon cancer patients could potentially reduce in-hospital mortality rates, as well as significantly decrease costs and length of stay. The higher mortality rates observed in patients with sepsis may be attributed to the immunocompromised state associated with cancer. Implementing targeted interventions to address the higher risks in older patients and those with sepsis could improve outcomes and reduce the overall burden of colon cancer-related hospitalizations. Impact of patient demographics, socioeconomic factors, and clinical conditions on mortality, length of hospital stay, and total hospital charges. Data Mortality Length of Hospital stay Total Charge Age>60 1.67 (p< 0.001) 0.99 days, p<0.001 $6428, p< 0.001 Race (Hispanic compared to White race) 1.15 (p=0.287) 0.38 days, p= 0.004 $14,127, p<0.001 Race (Black compared to White race) 1.1 (p=0.348) 1.4 days, p< 0.001 $5370, p=0.002 Female gender 0.88 (p=0.08) -0.21 days, p= 0.001 -$5529, p< 0.001 High house hold income 0.71 (p= 0.011) -0.69 days, p<0.001 -$1565, p= 0.466 Treatment at urban teaching facility 0.54 (p<0.001 0.54 days, p<0.001 $32230, p< 0.001 Sepsis 16.01 (p<0.001) 11.8 days, p<0.001 $192699, p< 0.001 IBD 1.05 (p=0.888) 0.67 days, p=0.055 $5348, p=0.293

Clinical-pathological characteristics, follow-up, and survival of patients with early-onset vs late-onset colorectal cancer: Institutional experience in Argentina.

82 Background: The incidence of colorectal cancer (CRC) in young adults aged 50 or younger (Early Onset - EO) is increasing worldwide, while in patients over 50 years old (Late Onset - LO), it is declining. The objective is to compare the clinicopathological characteristics, time to diagnosis, and survival between Early Onset (EO) and Late Onset (LO) patients diagnosed with colorectal cancer (CRC). Methods: The sample was described using measures of central tendency and dispersion for continuous numerical variables and percentages for categorical variables. Clinical characteristics between Early Onset (EO) and Late Onset (LO) groups were compared using the Student’s t-test or Chi-square test. Kaplan-Meier curves and the Log-Rank Test were utilized to analyze mortality time. For multivariable analysis, a Cox regression model was applied. A p-value of less than 0.05 was considered statistically significant. The analysis was performed using RStudio. Results: A total of 460 patients were evaluated, with 343 diagnosed with colon adenocarcinoma and 117 with rectal cancer. Patients were grouped into two categories: the LO group with 408 (88.6%) patients and a mean age of 69.3 (8.60 SD) years, and the EO group with 52 (11.3%) patients and a mean age of 41.9 (6.23 SD) years. The EO group presented a higher percentage of patients with a PS of 0 compared to the LO group. In the EO group, there was a predominance of left-sided colon cancer (40.4% vs. 40.0%) and rectal cancer, especially in the middle and lower regions (30% vs. 18.8%), with disease diagnosed at stage III (26.9% vs. 26.5%) and IV (5.8% vs. 4.4%) compared to the LO group. Molecular testing for KRAS, NRAS, and BRAF mutations was more frequent in the EO group (19.2%, 3.8%, and 3.8%, respectively) compared to the LO group, as well as mismatch repair (MMR) status at 9.6% in the EO group vs. 6.9% in the LO group. The median time to diagnosis was 186 days in the LO group and 341 days in the EO group (p=0.21). Follow-up was 858 days in the LO group and 725 days in the EO group (p=0.18); while mortality was 200 (49.0%) in the LO group and 24 (46.2%) in the EO group, with a median survival of 1193 days for the LO group and 1414 days for the EO group, respectively (p=0.7). PS and stage were the most influential prognostic factors for mortality. Conclusions: In the comparison, the EO group showed a higher incidence of left-sided colon and rectal cancers, more advanced stages, better PS, and a greater number of molecular alterations, with a longer time to diagnosis and shorter follow-up. Although these differences were not statistically significant, they highlight the need to optimize prevention strategies and genetic counseling. Additional studies with a larger number of EO patients in real-life contexts are needed to generate more evidence that can improve clinical decision-making.

Effective in vivo binding energy landscape illustrates kinetic stability of RBPJ-DNA binding

Abstract Transcription factors (TFs) such as RBPJ in Notch signaling bind to specific DNA sequences to regulate transcription. How TF-DNA binding kinetics and cofactor interactions modulate gene regulation is mostly unknown. We determine the binding kinetics, transcriptional activity, and genome-wide chromatin occupation of RBPJ and mutant variants by live-cell single-molecule tracking, reporter assays, and ChIP-Seq. Importantly, the search time of RBPJ exceeds its residence time, indicating kinetic rather than thermodynamic binding stability. Impaired RBPJ-DNA binding as in Adams-Oliver-Syndrome affect both target site association and dissociation, while impaired cofactor binding mainly alters association and unspecific binding. Moreover, our data point to the possibility that cofactor binding contributes to target site specificity. Findings for other TFs comparable to RBPJ indicate that kinetic rather than thermodynamic DNA binding stability might prevail in vivo. We propose an effective in vivo binding energy landscape of TF-DNA interactions as instructive visualization of binding kinetics and mutation-induced changes.

Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC).

586 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report the final efficacy analysis. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, objective response rate (ORR) by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Historically, the mTTP for patients treated with sorafenib is 5.5 mo (SHARP trial). We predicted the addition of HCQ will improve mTTP by 50% to 8.2 months. Results: N=33 completed C1. Median age 64.1 years SD 8.6 (46- 80). 88% Male; 58% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 35%. Etiology of cirrhosis: HCV 68%, ETOH 32%, NASH 11%. BCLC B 19%, C 81%. AFP>400: 43%, PVT: 27%, extrahepatic/metastases: 68%, post-transplant: 27%. N=5 (14%) were in cohort 2 (prior SOR). Reason off study: PD (n=21), toxicity (n=5), lost to f/u (n=1), withdrew (n=3). mTTP is 8.0 months (95% CI: 4.0-19.0). mOS 10.0 months (95% CI: 6.0-22.0). ORR (CR+PR): 27%. Best response: CR n=1 (3%), PR n=8 (24%), SD n=14 (42%). 4+ cycles: n=19 (58%). AE on treatment: grade 1 (68%), 2 (24%), 3 (7%), 4 (0.6%), 5 (0.3%). No Gr 4/5 related to SOR or HCQ. Dose interruption (20%), dose reduction (10%). Conclusions: SOR/HCQ had a better mTTP (8.0 months) than historical control (mTTP=5.5 months, p=0.03), and the trial met its primary endpoint. SOR/HCQ ORR (27%) was higher than historically SOR alone (ORR 2%, SHARP) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis (35%), and was tolerable. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may still have a role in patients with CP B cirrhosis, post-transplant, or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437 .

Short interval circulating tumor DNA (ctDNA) kinetics as a predictor of tumor response in patients with gastrointestinal (GI) cancer receiving immune checkpoint inhibitor (ICI)-based treatment.

836 Background: Circulating tumor DNA (ctDNA) has a short half-life (<2 hours) which may permit real-time monitoring of tumor status. This single-institution study aimed to assess the feasibility of rapid treatment response evaluation through serial short-interval ctDNA testing. Methods: Patients with gastrointestinal (GI) cancer undergoing immune checkpoint inhibitor (ICI)-based therapy were included. A personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.) was used in this study. We collected samples to measure the baseline ctDNA levels on cycle 1, day 1 (C1D1) of treatment or within 14 days prior to C1D1. A second ctDNA sample was obtained after 14-21 days depending on the cycle length of the treatment regimen employed (on cycle 2, day 1 [C2D1]). Changes in ctDNA levels between baseline and C2D1 were recorded, as well as the tumor response at the first radiographic assessment. Patients achieving partial response (PR) or better, or stable disease (SD) with tumor shrinkage supporting continuation of same treatment were considered responders. Results: The study cohort consisted of 14 patients aged 36-89 years (median age 66); 5 patients were female. Tumor types included advanced colorectal (n=5) and gastroesophageal (n=9) cancers. Treatments consisted of pembrolizumab alone (n=5), ICI + chemotherapy combinations (n=8), and regorafenib plus nivolumab (n=1). Baseline ctDNA levels were obtained on C1D1 in 9 patients, with the remaining 5 patients having baseline measurements within 14 days before C1D1. All patients had the second ctDNA level drawn on C2D1. The median interval between C1D1 and the first radiographic response assessment was 61 days (range, 45-84). A reduction in ctDNA levels by 50% or more (range: 66-100%) was observed in 9 patients (64%) after one cycle of treatment. All 9 patients were classified as responders at the time of first radiographic assessment: 7 with PR and 2 with SD but significant tumor shrinkage leading to continuation of the same treatment. In 3 patients (21%), ctDNA levels increased (range: 20-500%), correlating with progressive disease (PD) on first assessment scan. Two patients showed increased ctDNA levels of 82% and 22% after one cycle of treatment but achieved PR and SD, respectively. In both patients, however, the 3rd ctDNA level drawn before the first assessment scan dropped by >90%. Overall, short-interval ctDNA kinetics correlated with treatment response in 12 of 14 patients (86%), with a binomial test p = 0.0065. Conclusions: Short-interval ctDNA kinetics demonstrates a strong correlation with radiographic tumor response and clinical benefit in GI cancer patients receiving ICI-based treatments, providing early signal of tumor response. This approach has the potential to guide treatment decisions if validated in larger prospective studies.

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

A universal and wide-range cytosine base editor via domain-inlaid and fidelity-optimized CRISPR-FrCas9

Ultra‐Flexible High‐Linearity Silicon Nanomembrane Synaptic Transistor Array

AbstractThe increasing demand for mobile artificial intelligence applications has elevated edge computing to a prominent research area. Silicon materials, renowned for their excellent electrical properties, are extensively utilized in traditional electronic devices. However, the development of silicon materials for flexible neuromorphic computing devices encounters great challenges. To address these limitations, ultrasoft silicon nanomembranes have emerged as a focal point due to their capability to preserve the superior electrical properties of silicon while providing substantial mechanical flexibility and interfacial tunability. Despite these advantages, difficulties remain in the transfer process of silicon nanomembranes and their integration for flexible synaptic transistors. In this work, an organic–inorganic hybrid polyimide‐Al2O3 dielectric layer has been designed for synaptic behavior grown by an atomic layer deposition process, and integrated with a silicon nanomembrane to realize highly flexible synaptic transistors. These transistors demonstrate stable electrical performance even after undergoing 10 000 bending cycles at an extreme curvature radius of 2.2 mm. Furthermore, the silicon nanomembrane transistors effectively emulate synaptic functions, exhibiting exceptional linearity in their long‐term characteristics, making them suitable for the application scenarios of detecting subtle signals. When applied to handwritten digit recognition simulations, these synaptic transistors have achieved a high accuracy rate of 93.2%.

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Phase II study of olaparib in patients with advanced pancreatic acinar cell carcinoma.

TPS789 Background: Pancreatic Acinar Cell Carcinoma (PACC) is a rare and biologically distinct subtype of pancreatic cancer, representing 0.5-1% of all pancreatic malignancies, with a median overall survival of 15-20 months. Significant serum CA 19-9 elevation is uncommon, while elevation of serum lipase is observed in at least 50% of patients. Most patients present at advanced stages and treatment with combination chemotherapies extrapolated from other GI malignancies leads to low response rates. No clinical treatment trials specific for PACC have ever been reported. PACC tumors from patients show evidence of high chromosomal instability, a hallmark of DNA repair deficiency. ID3 is ubiquitously downregulated and was recently shown to play a significant role in homologous recombination repair (HRR). Recent genomic profiling of larger PACC patient cohorts has revealed a high prevalence of mutations in HRR genes, including BRCA1, BRCA2, and PALB2. Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved for treatment of BRCA-mutant HRR deficient cancers. We hypothesize that PACC will be sensitive to PARP inhibition with olaparib. Methods: This is an open label, single arm, single center, phase II study of olaparib in patients with advanced previously treated PACC. The primary objective of the trial is to evaluate anti-tumor activity of olaparib (objective response rate). Secondary objectives assess the safety (CTCAE v. 5.0) and alternative measures of efficacy such as clinical outcomes and blood biomarkers (disease control rate, median progression-free survival, median overall survival, best response in serum lipase). Key eligibility criteria include histologic diagnosis of PACC, receipt of at least one line of combination chemotherapy, presence of RECIST measurable disease and adequate organ and bone marrow function. A fixed dose of olaparib at 300 mg will be given orally continuously twice daily during a 28-day cycle, for up to 2 years or until disease progression or intolerable toxicities. In person visits to assess toxicity are required every 4 weeks, and response is determined through serial imaging every 8 weeks (CT or MRI). Exploratory objectives include acquisition of tumor tissue for establishment of new PACC preclinical models, assessment of genetic alterations through genetic mapping technique, assessment of HRR-related gene products as a predictive biomarker, assessment of ID3 protein levels, and assessment of treatment response to tumor profile. Up to 13 evaluable participants will be enrolled. Three participants have been enrolled as of Sep 19, 2024. Clinical trial information: NCT05286827 .

Predictors of late recurrence of colorectal cancer (CRC) among older long-term survivors using claims-based evidence.

66 Background: There are established features that predict early recurrence of CRC in the first 5 years from diagnosis, but predictors of late recurrence 5-10 years after diagnosis are less well understood. Long-term CRC survivors require multidisciplinary follow-up accounting for both cancer and non-cancer related conditions. Identifying predictors of cancer recurrence after 5 years of disease-free survival may help inform survivorship care. Methods: This was a retrospective cohort study of patients aged ≥66 in the SEER-Medicare database with non-metastatic CRC diagnosed between 2003 and 2011. As SEER does not collect recurrence data, we used a validated algorithm to identify treated recurrence in Medicare claims. Patients with early recurrence or a second primary malignancy in years 0-5 were excluded. Demographic and cancer-specific clinical data were collected at time of cancer diagnosis. Comorbidities were identified between 4 -5 years after cancer diagnosis and recurrence was modeled starting at year 5 using restricted mean survival time (RMST) regression. Estimates from RMST models were converted to RMST ratios (ratio <1 indicates shorter time to event). The Fine-Gray model was used to estimate cumulative incidence of CRC recurrence or mortality between 5 and 10 years after cancer diagnosis. Results: 20,255 patients with non-metastatic CRC were included: 16,158 with colon cancer (33.4% stage I, 41.7% stage II, 25.0% stage III), and 4,097 with rectal cancer (43.1% stage I, 30.1% stage II, 26.7% stage III). Mean age at cancer diagnosis was 77 years. In those who remained disease free five years after initial diagnosis, late recurrence developed in 4.8% (973/20,255) of the combined CRC cohort, 4.2% (679/16,158) of those with colon cancer, and 7.2% (294/4,097) of those with rectal cancer. In colon cancer, stage III disease was associated with a shorter time to recurrence (RMST ratio = 0.97, CI = 0.96-0.98). In both colon (RMST ratio = 0.98, 95% CI 0.96-0.99) and rectal cancer (RMST ratio = 0.97, 95% CI 0.94-0.99) having ≥3 comorbidities was associated with a shorter RMST, consistent across disease stages. For colon cancer, the cumulative incidence of CRC-specific mortality vs. all-cause mortality in years 5-10 from diagnosis was 3% (95% CI 2.8-3.0) vs. 35% (95% CI 34.0-36.0), respectively. For rectal cancer, during the same period, the corresponding rates were 6% (95% CI 5.4-7.0) vs. 30% (95% CI 28.4-31.0). Conclusions: Late CRC recurrence is rare in the SEER-Medicare population. Primary risk factors are advanced stage at diagnosis and multiple co-morbidities. Patients who survive 5 years from their diagnosis have a higher risk of all-cause mortality compared to CRC-specific mortality. Interpretation of data is limited by the validated algorithm used to detect recurrence, as it may underestimate recurrence in patients who did not undergo treatment or workup for recurrent disease.

Distal protein-protein interactions contribute to nirmatrelvir resistance

Evaluation of social support, discrimination, and perceived health in patients with gastrointestinal tract cancers.

802 Background: Health-related social conditions affect cancer outcomes. Gastrointestinal cancers (GIC) comprise a large proportion of cancers diagnosed in the United States. We hypothesized that a diagnosis of GIC negatively impacts Social Determinants of Health (SDOH) and perceived health (PH). Methods: Prospectively collected data from The All of Us database was queried for GIC patients who completed SDOH and PH surveys. Healthy, non-cancer (NC) participants were matched to GIC based on age, race, sex, deprivation index, and Charlson Deyo comorbidities using Propensity Score Matching. Regression was used to analyze the relationship between cancer status and survey scores. Results: A total of 231,033 patients met the criteria: 14,032 GIC and 217,001 NC. The majority of patients were white (69%%), female (59.2%), and non-Hispanic (97.2%). Colorectal cancer was most represented (81%), followed by anus (12%), stomach (3%), and pancreatic (1%) cancers. The median time between cancer diagnosis and survey response was 3.4 years (IQR 1.4-6.5 years). With respect to SDOH, GIC patients perceived more social support (β 0.07 [95% CI: 0.04, 0.10]), more neighborhood positivity (β 0.07 [95% CI: 0.05, 0.10]) and less healthcare discrimination (β -0.03 [95% CI: -0.06, -0.01]) (Table, NC is reference). GIC surveyed < 1 year after their diagnosis scored higher on social support than those surveyed > 1 year (β 0.13 [95% CI: 0.05, 0.21]). For PH, GIC were 15% more likely to report better mental health and 33% more likely to report better quality of life (QOL). Those diagnosed < 1 year before their survey had no difference in perceived physical and general health compared to NC, although their QOL (OR 1.3 [95% CI: 1.2-1.4]) and mental health (OR 1.1[95% CI: 1.0-1.2]) were similar to those surveyed > 1 year after the diagnosis. Chemotherapy-treated GIC patients reported better PH in all four domains than those not treated with chemotherapy, including QOL (OR 1.3, [95% CI: 1.2-1.5]) and mental health (OR 1.2, [95% CI: 1.1-1.4]). Conclusions: Findings of this survey study reveal that a GI cancer diagnosis has a favorable impact on SDOH and PH - GIC feel more supported, less discriminated, and perceive better health compared to NC, and time of cancer diagnosis and chemotherapy impact outcomes. A concerted societal effort is required to improve health related social conditions for individuals with and without cancer. Impact of cancer status on perceived health and social determinants of health. Social Determinants of Health* Beta (95% CI) P Value Social Support 0.074 (0.04, 0.10) < 0.001 Neighborhood Positive 0.074 (0.05, 0.10) < 0.001 Healthcare Discrimination -0.034 (-0.06, -0.01) < 0.001 UCLA Loneliness -0.013 (-0.03, 0.01) 0.196 Perceived Health Domain* Odds Ratio (95% CI) P Value Quality of Life 1.32 (1.27, 1.38) < 0.001 Physical Health 1.27 (1.21, 1.32) < 0.001 Mental Health 1.15 (1.10, 1.20) < 0.001 General Health 1.26 (1.21, 1.32) < 0.001 *Comparison is gastrointestinal cancer vs. non-cancer, with non-cancer as the reference group.

Impact of <i>RAS</i> and <i>BRAF</i> heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .

Regorafenib combined with immunotherapy and prognosis of unresectable hepatocellular carcinoma.

541 Background: To investigate the prognosis and influencing factors of patients with unresectable hepatocellular carcinoma (uHCC) receiving regorafenib in different treatment modes. Methods: A total of 227 patients with uHCC who received at least 2 cycles of regorafenib treatment in the Affiliated Hospital of Qingdao University between June 2018 and August 2022 were retrospectively collected through the Hospital Information System (HIS). 204 patients were finally enrolled by inclusion and exclusion criteria after screening. Results: The median follow-up was 25.9 (4.5-69.7) months. The median overall survival (OS) of 204 patients with uHCC was 27.7 (95%CI 21.98-33.42) months. The 1, 2, 3 and 5-year OS were 80.9%, 55.9%, 41.4% and 26.7%, respectively. Univariate analysis showed that combination with immune checkpoint inhibitor (ICI) and metabolic-associated complications were independent factors for survival benefit of regorafenib, while the Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale = 2, undecreased Alpha-fetoprotein (AFP), macrovascular invasion and extrahepatic metastasis were independent risk factors for poor prognosis (P&lt;0.05). Compared with 60 patients receiving regorafenib alone, 144 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 16.9 vs. 31.5 months, respectively, P=0.006). The median OS of 153 patients receiving second-line therapy with regorafenib was 30.3 months. Among 51 patients receiving third or more lines of therapy with regorafenib, compared with 4 patients receiving regorafenib alone, 47 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 9.4 vs. 24.1 months, respectively, P=0.000). Among 148 patients receiving local treatment, the median OS of patients with regorafenib combined with ICI (n=115) or without ICI (n=33) was 33.2 and 16.5 months, respectively (P=0.005). Conclusions: Regorafenib has a good prognosis in second-line treatment of uHCC. The OS of patients with regorafenib combined with ICI were significantly better than that of patients without ICI. The OS benefit of regorafenib combined with ICI was also equivalent in patients with third or more lines. The benefit of regorafenib combined with ICI was better for patients receiving local treatment.

Layer ensemble averaging for fault tolerance in memristive neural networks

Tunable Bicontinuous Macroporous Cell Culture Scaffolds via Kinetically Controlled Phase Separation

Abstract 3D scaffolds enable biological investigations with a more natural cell conformation. However, the porosity of synthetic hydrogels is often limited to the nanometer scale, which confines the movement of 3D encapsulated cells and restricts dynamic cell processes. Precise control of hydrogel porosity across length scales remains a challenge and the development of porous materials that allow cell infiltration, spreading, and migration in a manner more similar to natural ECM environments is desirable. Here, a straightforward and reliable method is presented for generating kinetically‐controlled macroporous biomaterials using liquid–liquid phase separation between poly(ethylene glycol) (PEG) and dextran. Photopolymerization‐induced phase separation resulted in macroporous hydrogels with tunable pore size. Varying light intensity and hydrogel composition controlled polymerization kinetics, time to percolation, and complete gelation, which defined the average pore diameter (Ø = 1–200 µm) and final gel stiffness of the formed hydrogels. Critically, for biological applications, macroporous hydrogels are prepared from aqueous polymer solutions at physiological pH and temperature using visible light, allowing for direct cell encapsulation. Human dermal fibroblasts in a range of macroporous gels are encapsulated with different pore sizes. Porosity improved cell spreading with respect to bulk gels and allowed migration in the porous biomaterials.

A multicenter, phase 2 study of atezolizumab plus bevacizumab (atezo+bev) combination therapy in patients with unresectable hepatocellular carcinoma (HCC) and Child–Pugh class B cirrhosis: CHALLENGE trial final results.

587 Background: The Phase 2 CHALLENGE trial (jRCTs031210355) evaluated the safety and efficacy of atezo+bev combination therapy in patients with advanced HCC with Child–Pugh class B cirrhosis. Results of the trial’s main analysis demonstrated that atezo+bev was well-tolerated. Here, we present the trial’s final safety and efficacy outcomes. Methods: This multicenter, open-label, single-arm, Phase 2 study enrolled patients with advanced HCC and a Child–Pugh score of 7 or 8 who had not received prior systemic therapy. Patients were administered atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the frequency of severe adverse events (SAEs). Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and frequency of adverse events (AEs). Results: A total of 31 patients were enrolled between December 2021 and April 2023. Child–Pugh score was 7 points in 25 patients (80.6%) and 8 points in 6 patients (19.4%). Fourteen patients (45.2%) were classified as having Barcelona Clinic Liver Cancer stage C. We set 30 eligible patients as the population for analysis. The final analysis performed with a median follow-up duration of 517days showed that the frequency of SAEs was 30.0% (95% confidence interval [CI] 14.7–49.4%). ORRs according to RECIST 1.1 and modified RECIST were 40.0% and 46.7%, respectively. Median PFS, TTP, and OS were 240 days (95% CI: 176–526 days), 240 days (95% CI: 176–526 days), and 470 days (95% CI: 256–576 days), respectively. Frequent Grade ≥3 SAEs were blood bilirubin increased (n=3), proteinuria (n=3), hypoalbuminemia (n=2), and hypertension (n=2). Grade ≥3 severe liver-related AEs occurred in 7 patients (23.3%), including blood bilirubin increased (n=3) and esophageal varices hemorrhage (n=2). Grade ≥3 severe immune-related AEs occurred in 2 patients – these were mucositis oral (n=1) and malaise (n=1). The mean Child–Pugh score (±standard deviation) at the start of treatment was 7.2±0.4, and was 7.0±1.0, 7.2±0.9, and 7.6±1.7 at the third and fifth cycles and at the withdrawal study, respectively. Conclusions: Atezo+bev was well-tolerated with demonstrable anti-tumor effects in patients with unresectable HCC and Child–Pugh class B cirrhosis. Additional studies are warranted to confirm the efficacy results of atezo+bev in this patient group. Clinical trial information: jRCTs031210355.