Browse Articles

Real-world clinical outcomes of patients (Pts) with metastatic colorectal cancer (mCRC) who received trifluridine-tipiracil (FTD-TPI) monotherapy or FTD-TPI + bevacizumab (FTD-TPI+bev) combination therapy.

79 Background: FTD-TPI+bev has shown survival benefit when compared to FTD-TPI alone in pts with mCRC and was approved in the U.S. in 2023. However, there is a lack of real-world data on outcomes for pts who received FTD-TPI+bev as compared to pts who received FTD-TPI. Methods: This retrospective study used data abstracted from electronic medical records and claims in the ConcertAI RWD360 dataset. Adult pts with a diagnosis of mCRC and exposure to FTD-TPI were included. Pts were categorized as having received FTD-TPI or FTD-TPI+bev based on first exposure to FTD-TPI (index date). Kaplan-Meier analyses were used to describe the overall survival (rwOS), real-world time to discontinuation (rwTTD), and time to next treatment or death (rwTTNTD) from the index date. Multivariate Cox regression analyses were used to control for patient characteristics, including demographics, ECOG performance status (PS), comorbidities, sites of metastatic disease, time from mCRC to index date, lab results, and receipt of prior regorafenib. Results: This study included 3,680 pts. The FTD-TPI cohort included 3,151 pts (median age 62 years; male 56.3%; White 63.3%; any comorbidities 40.6%; ECOG PS 0-1 34.8%; 2+ metastatic sites 25.4%; median time from mCRC diagnosis to index date 699 days). The FTD-TPI+bev cohort included 529 pts (median age 60 years; male 53.9%; White 68.1%; any comorbidities 34.4%; ECOG PS 0-1 51.4%; 2+ metastatic sites 25.1%; median time from mCRC diagnosis to index date 609 days). Prior to index date, 18.5% and 6.9% of pts had been exposed to regorafenib in the FTD-TPI and FTD-TPI+bev cohorts, respectively. FTD-TPI+bev significantly increased rwOS (median 9.4 [95% CI 8.0-10.1] vs 6.4 [95% CI 6.1-6.6] months; p<0.0001) and significantly decreased the risk of death (HR=0.68; p<0.0001) in the adjusted model. Other significant factors for rwOS included 2+ metastatic sites (vs.1 site, HR=1.16; p=0.002) and no receipt of regorafenib prior to index date of FTD-TPI (HR=0.80; p<0.0001). FTD-TPI+bev also significantly prolonged rwTTD as compared to FTD-TPI (median 3.5 [95% CI: 3.3-3.8] vs 2.4 [95% CI: 2.3-2.6] months; p<0.0001) and decreased risk of discontinuation (HR=0.65; p<0.0001) after adjusting for patient demographic and clinical characteristics. Additionally, the FTD-TPI+bev cohort had a significantly longer rwTTNTD as compared to the FTD-TPI cohort (median 5.0 [95% CI: 4.6-5.5] vs 3.9 [95%CI: 3.8-4.1] months; p<0.0001) in the adjusted model (HR=0.73; p<0.0001). Conclusions: This is the largest study to compare the clinical outcomes of pts receiving FTD-TPI and FTD-TPI+bev in the real-world setting. FTD-TPI+bev improved clinical outcomes including rwOS, rwTTD, and rwTTNTD, as compared to FTD-TPI in pts with mCRC. These findings align with the results of the SUNLIGHT trial.

Exploring the role of bispecific and CAR-T cell therapies in gastric cancer: A systematic review and meta-analysis.

465 Background: Gastric cancer (GC) is associated with significant mortality due to the limited efficacy of current conventional treatments, necessitating the need for novel therapies. In this systematic review and meta-analysis, we aim to explore the potential role and outcomes of bi-specific antibodies and chimeric antigen receptor T-cell (CAR-T) immunotherapy in treating GC. Methods: Using PRISMA guidelines, searches were conducted on PubMed, Cochrane, and Clinicaltrial.gov for 'Gastric cancers', 'bispecific antibodies', and 'CAR-T therapy' as of March 30, 2024. Out of 35 studies, 9 were selected for pooled analysis in R (v4.3.3) using the Der Simonian-Laird Estimator, calculating inter-study variance and extracting data with 95% CI. Results: 138 gastric cancer (GC) patients from 2 phase I (22.22%), 3 phase Ib (33.33%), 3 phase II (33.33%), and 1 case report (11.11%). Median age was 57 (28-77) years, and 76% (31/41) were male. Bispecific antibodies were MCLA-128 (25/138), catumaxomab (15/138), AK104 PD-1/CTLA-4 (16/138), ABL 001 DLL4VEGFA (19/138), and KN026 (25/138) while CART therapy was CT041 (38/138). The pooled overall response (OR), partial response (PR), and complete response (CR) for bispecific antibodies was 37% (95% CI, 0.12-0.71, I2=76%, n=100, p <0.01), 21% (95% CI,0.05-0.55, I2=73%, n=85, p<0.01), and 11%(95% CI, 0.02-0.38, I2=63%, n=85, p=0.03) respectively, while the pooled OR, PR, and CR for CART was 56% (95% CI, 0.40-0.71, I2=0%, n=38, p=0.41), 53%(95% CI, 0.36-0.69, I2=0%, n=38, p=0.38, ), and 12% (95% CI, 0.02-0.42, I2=38%, n=38 p=0.2), respectively. The pooled disease control rate was 75% (95%CI,0.46-0.92, I2=79%, n=80, p < 0.01) for bispecific antibodies and 27% (95% CI,0.16-0.40, I2=0%, n=65, p=0.37) had the stable disease while pooled incidence of progressive disease was 18% (95% CI,0.09-0.31, I2=0%, n=55, p=0.53). The median progressive free survival was 6.74 months, with a median overall survival of 14.75 months. Common adverse effects included anemia, diarrhea, fatigue, and cytokine release syndrome grades 1 or 2. Conclusions: This analysis shows promising results in GC patients using bi-specific antibodies and CAR-T cell therapy. However, further clinical trials are needed to fully explore their potential.

Advances in lignocellulosic feedstocks for bioenergy and bioproducts

Realizing C–C Coupling via Accumulation of C1 Intermediates within Dual‐Vacancy‐Induced Dipole‐Limited Domain Field to Propel Photoreduction of CO₂‐to‐C2 Fuel

AbstractPhotocatalytic conversion of CO2 and H2O into high‐value‐added C2 fuels remains a tough challenge, mainly due to the insufficient concentration of photogenerated electrons for the instability of C1 intermediates, which often tend to desorb easily and disable to form C─C bonds. In this work, photoreduction of CO2‐to‐C2H6 is successfully achieved by introducing adjacent C, N dual‐vacancy sites within the heptazine rings of ultrathin g‐C3N4, which results in the opening of two neighboring heptazine rings and forms a distinctive dipole‐limited domain field (DLDF) structure. In situ X‐ray photoelectron spectra and in situ fourier transform infrared spectra provide direct evidence of the rapid accumulation and transformation of C1 intermediates, especially CO* and CHO*, within the DLDF. Ab initio molecular dynamics further substantiates the role of DLDF in promoting C–C coupling between CO* and CHO*, through the analysis of interaction trajectories and energy changes of their central atoms, ultimately achieving a high yield of C2H6 up to 57.86 µmol g−1 h−1. It is for the first time to propose the concept of DLDF for significant advancement in photoreduction of CO2‐to‐C2 fuel with the evident breakthrough to address the challenge of coupling carbon‐containing intermediates between active sites, offering new insights for the design of C–C coupling sites in single‐component photocatalysts.

HLX22 plus trastuzumab and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer (G/GEJC): Updated results with additional patients.

440 Background: Approximately 12–23% G/GEJC patients have human epidermal growth factor receptor 2 (HER2)-positive disease. Despite survival benefit from combination therapy with trastuzumab and chemotherapy, the prognosis remains unsatisfactory; more effective treatments are needed. This phase 2 study is evaluating the combination of HLX22 (an anti-HER2 monoclonal antibody targeting a different epitope than trastuzumab), trastuzumab, and XELOX chemotherapy as first-line treatment for patients with advanced/metastatic G/GEJC. Following the most recent report of 17 to 18 patients in each group at ASCO 2024 Annual Meeting, herein we present the updated efficacy and safety results with 31 patients in each group. Methods: Patients with locally advanced or metastatic HER2-positive G/GEJC and no prior systemic antitumor therapy were enrolled. Herein reported are results from Stage 2 of the study. Eligible patients were randomized to receive either HLX22 + trastuzumab + XELOX or placebo + trastuzumab + XELOX in 3-week cycles. Primary endpoints were independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included other efficacy and safety endpoints. Results: As of June 30, 2024, 62 patients were randomized to the respective groups (31 vs 31), of whom 51 (82.3%) patients were male. Median follow-up duration was 20.3 and 24.0 months for the respective groups. The efficacy results are shown in the table. Treatment-emergent adverse events (TEAEs) were reported in 30 (96.8%) and 31 (100%) patients, and HLX22- or placebo-related TEAEs of grade 3 or higher were reported in 9 (29.0%) and 6 (19.4%) patients in the respective groups. One patient (3.2%) in the placebo + trastuzumab + XELOX group had a grade 5 HLX22-/placebo-related TEAE. Conclusions: With a manageable safety profile, the addition of HLX22 to first-line treatment with trastuzumab plus XELOX conferred survival benefit for HER2-positive G/GEJC patients. Clinical trial information: NCT04908813 . Updated efficacy, IRRC-assessed. HLX22 + trastuzumab + XELOX (n=31) placebo + trastuzumab + XELOX (n=31) Median PFS, months (95% CI) NR (23.49, NE) 8.3 (5.7, 12.7) HR (95% CI) 0.2 (0.06, 0.45) - 12-month PFS rate (95% CI) 73.8 (50.3, 87.4) 34.2 (12.0, 58.1) 24-month PFS rate (95% CI) 61.5 (30.4, 82.0) 24.0 (10.3, 27.3) Confirmed ORR, % (95% CI) 87.1 (70.2, 96.4) 80.6 (62.5, 92.5) Week 48 ORR, % (95% CI) 38.7 (21.8, 57.8) 9.7 (2.0, 25.8) Median OS, months (95% CI) NR (17.6, NE) 22.0 (10.6, NE) HR (95% CI) 0.5 (0.20, 1.21) - Median DOR, months (95% CI) NR (22.1, NE) 9.7 (4.6, 20.0) HR (95% CI) 0.1 (0.04, 0.41) - CI, confidence interval. NE, not evaluable. NR, not reached.

Distribution of lymph node metastasis and prognosis in duodenal bulb tumors: A multicenter retrospective study.

797 Background: Duodenal tumors, especially duodenal bulb tumors, is a relatively rare malignancy of the gastrointestinal tract. The optimal surgical procedure for primary duodenal tumors has not been established because of its low incidence. The purpose of this study was to examine the distribution of lymph node (LN) metastasis in duodenal bulb tumors. Specifically, in T1a and T1b tumors, we aimed to evaluate the feasibility of distal gastrectomy with duodenal bulb resection combined with lymphadenectomy of regional gastric LNs. Methods: Data from patients who underwent surgery for either adenocarcinoma or neuroendocrine tumor located in the duodenal bulb between 2000 and 2020 were retrospectively analyzed from five high-volume centers in Japan. Patient background, clinicopathological factors, type of surgery, distribution of LN metastasis, and long-term outcomes were evaluated. Results: Of the 128 patients evaluated, LN metastasis was observed in 36%. The frequency of LN metastasis in T1b was 18%. Metastatic LNs were identified in #3, #5, #6, #8a, #8p, #12a, and #13 in T1b. The distribution of LN metastasis in T1b was similar between adenocarcinoma and neuroendocrine tumors. The 3 years overall survival rate in T1a, T1b, and T2–4 was 100%, 93%, and 64%, respectively. ln T1b, while there were three patients with a recurrence, two cases were observed in distant organs without regional LNs, and one patient who underwent pancreaticoduodenectomy had metastasis in the gastric regional LNs. Conclusions: Based on the distribution of LN metastasis with pT1, distal gastrectomy with duodenal bulb resection and regional LN dissection is considered a curative treatment. Conversely, pancreaticoduodenectomy is recommended in tumors with T2 or deeper.

Blood TCTP as a biomarker associated with immunosuppressive features and resistance to immunotherapy in metastatic gastric cancer.

474 Background: Cancer biomarkers are essential for determining the prognosis of the disease and/or predicting its response to specific treatments. However, established biomarkers representing specific myeloid cell populations and representative biomarkers in gastric cancer remain unavailable. Therefore, this study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with immune checkpoint inhibitor (ICI) and cytotoxic chemotherapy. Methods: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer who were treated with 1 st line fluoropyrimidine plus platinum chemotherapy (n = 143, cohort 1) and 3 rd line nivolumab (n = 165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. An external single-cell RNA sequencing (scRNA-seq) dataset was employed to validate the findings. Results: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor survival outcomes with 1 st line chemotherapy compared to those with low levels (TCTP-low group) in cohort 1. In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/NK cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. The scRNA-seq analyses of myeloid cells revealed that TCTP pathway-associated genes (i.e., TLR2 , CXCL1, and CXCL2 ) were specifically expressed in immunosuppressive APOE + macrophages, THBS1 + macrophages, and CD1C + conventional type 2 dendritic cells. In the TCTP-high group, patients treated with nivolumab (cohort 2) also experienced poor survival outcomes. Conclusions: Plasma TCTP is a readily measurable prognostic biomarker, reflecting immunosuppressive signals of myeloid cells in patients with gastric cancer treated with ICI and chemotherapy.

Bidirectional relationship between epigenetic age and stroke, dementia, and late-life depression

Dynamic Redox Induced Localized Charge Accumulation Accelerating Proton Exchange Membrane Electrolysis

AbstractThe sluggish anodic oxygen evolution reaction (OER) in proton exchange membrane (PEM) electrolysis necessitates applied bias to facilitate electron transfer as well as bond cleavage and formation. Traditional electrocatalysis focuses on analyzing the effects of electron transfer, while the role of charge accumulation induced by the applied overpotential has not been thoroughly investigated. To explore the influence mechanism of bias‐driven charge accumulation, capacitive Mn is incorporated into IrO2 to regulate the local electronic structure and the adsorption behavior. The applied bias triggers dynamic redox reactions at the active sites, which introduce local charge accumulation on the surface of electrocatalyst. Under bias, Mn oxidation induced a noticeable pseudocapacitance in the pre‐OER region, promoting the OER kinetics of iridium sites. Meanwhile, the increased oxygen vacancy formation energy further prevents the lattice oxygen activation. The PEM electrolyzer, equipped with optimal materials as an anode, operates at a low driving voltage of 1.637 V under 2.0 A cm−2, maintaining stable performance for over 800 h with a low degradation rate (19.4 µV h−1). This work provides insights into the performance of metal oxide catalysts in acidic environments and offers forward‐looking strategies for enhancing the catalytic performance through dynamic redox induced capacitive behavior.

Deep learning–powered analysis of tumor-infiltrating lymphocytes (TILs) in colorectal cancer.

288 Background: TILs are a promising biomarker in various cancers, including colorectal cancer (CRC). Advances in deep learning enable objective and efficient TIL assessment. This study applies a novel deep learning model to quantify TIL density in a large cohort of CRC tumors, examining its relationship with clinicopathologic factors and survival. Methods: We applied a deep learning model (Deep-ICP) to H&E-stained images from CRC patients treated at Dana-Farber Cancer Center to quantify TIL density (immune cells/mm²). Kruskal-Wallis and Wilcoxon tests were used to compare categories. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Cox proportional hazards models analyzed the association between TIL density tertiles (lower, middle, upper) and OS, adjusting for age, sex, stage, biopsy site, tumor mutational burden (TMB, mutations/megabase), and mismatch repair (MMR) status. Results: Of 1,477 tumor specimens tested, 1,039 (70%) were primary and 438 were metastatic. The most common sites of metastasis were liver (n=205), lung (n=86), and soft tissue (n=35). The median age at diagnosis was 56 (range 19–91) years and 706 were female (48%). Most tumors (1,214/1,300; 93%) were MMR proficient (MMRp); 86 were MMR deficient (MMRd). Median TIL density was 664 (interquartile range; 469–934) cells/mm² in primary tumors, 478 (358–685) cells/mm² in liver metastases, 415 (251–645) cells/mm2 in soft tissue (p<0.001). MMRd tumors had higher median TIL density than MMRp (881 vs. 620 cells/mm²; p<0.001). After adjusting for covariates, patients with highest TIL tertile had significantly longer OS than patients with lowest TIL tertile (median OS: 75.4 [95%CI 67.4-87] months; 100.5 [83.9-116] months and 99.1 [92.4-157] months for lower, middle and upper TIL tertiles respectively; Table). In the MMRp subset, higher TIL density was still predictive of improved OS (p adj=0.010). Conclusions: This study demonstrates the feasibility of deep learning powered TIL quantification in CRC, potentially informing differences in tumor microenvironment and prognostication. Future prospective studies are needed to validate the results and explore their therapeutic implications in personalized CRC management. Variable Hazard Ratio (95% CI) P-value TIL upper tertile (vs. lower) 0.70 (0.50-0.99) 0.04 TIL middle tertile (vs. lower) 1.04 (0.77-1.39) 0.80 Age (continuous) 1.02 (1.00-1.03) 0.008 Male (vs. female) 1.13 (0.86-1.47) 0.38 Stage II (vs. stage I) 4.8 (0.59-40) 0.14 Stage III (vs. stage I) 9.4 (1.20-73) 0.03 Stage IVA (vs. stage I) 23 (2.94-178) 0.003 Stage IVB (vs. stage I) 46 (5.6-369) 0.0003 Liver specimen (vs. primary) 1.39 (1.00-1.92) 0.050 Lung specimen (vs. primary) 0.78 (0.47-1.29) 0.33 Lymph node specimen (vs. primary) 0.77 (0.27-2.17) 0.62 Other metastasis (vs. primary) 1.23 (0.78-1.93) 0.37 TMB≥10 (vs. <10) 1.17 (0.82-1.68) 0.38 MMRd (vs. MMRp) 0.65 (0.29-1.46) 0.30

Use of gene expression profiling to examine association between MUC1 and claudin 18 in gastrointestinal cancers: Implications for targeted therapies.

838 Background: Gastrointestinal tract cancers exhibit considerable molecular heterogeneity, which requires a detailed understanding of their distinct genetic profiles. Understanding the gene expression of other genes along with Claudin 18 (CLDN18) could provide insights into their interactions. Methods: We conducted a retrospective analysis of NGS profiling on 1,043 GI cancer tissue samples from three cohorts: Upper and Lower Gastrointestinal Cancer Cohort (GICC; n=651), Pancreaticobiliary Cancer Cohort (PBCC; n=316), and Hepatocellular Carcinoma Cohort (HCC; n=76). Immunohistochemistry data for PD-L1, Her2 and MMR proteins, NGS based Tumor mutation burden (TMB) and gene expression profiling (GEP) of 20,802 genes including CLDN18 was examined in a subset by targeted transcriptome profiling. We explored associations of these biomarkers with expression of CLDN18. Results: In GICC, frequent mutations were seen in TP53 (68%; 442), APC (33.5%; 218) and KRAS (33.3%; 217). PBCC, showed mutations in TP53 (62%; 197), KRAS (47%; 149) and CDKN2A (16%; 51). HCC showed mutations in TP53 (42%; 32), ARID1A (18%; 14) and KRAS (9%; 7). Amplifications were predominantly observed in MYC (13%; 120), ERBB2 (5%; 49) and CCND1 (5%; 44). Fusions were infrequent. All MSI-H cases (11/462; 2.4%) were observed in GICC. High TMB (≥10 muts/mb) was seen in 23% (111/481), stratified as 28% (90/318) in GICC, 13% (18/139) in PBCC and 10% (3/30) in HCC. Out of 321 samples analyzed for gene expression profiling, CLDN18 was significantly upregulated in 65 (20%) samples. The expression of CLDN18 did not show statistically significant correlation with Her2 (n=184), PD-L1 (n=231), TMB (n=228), or MSI (n=229); (p>0.05). In subset where both CLDN18 and MUC1 expression were analyzed (n=118), all the CLDN18 positive tumors showed overexpression of MUC1. This finding was statistically significant (p<0.05). Increased expression of MUC1 promotes cancer cell mobility promoting metastases. Expression of MUC1 can play an important role in the development of resistance to chemotherapy. MUC1 expression in cancer cells is associated with avoidance of immune defenses. Thus, this finding of CLDN18 and MUC1 association is especially relevant as the CLDN18 targeted therapies may be the potential avenue for the aggressive and chemo-resistant MUC1 expressing tumors. Conclusions: This study identifies potential association between MUC1 and CLDN18. GEP could enhance biomarker detection and support personalized treatment approaches. Future research should integrate these findings with clinical data to improve precision in GI cancer care.

Clinical and molecular characterization of <i>FAP</i> and <i>SPP1</i> in colorectal cancer (CRC), CALGB (Alliance)/SWOG 80405 and real-world data.

276 Background: FAP and SPP1 contribute to immune modulation in the CRC tumor microenvironment (TME). FAP is expressed by cancer associated fibroblasts, aiding in tissue remodeling and tumor invasion. SPP1 is an integrin-binding protein expressed by tumor associated macrophages that promotes tumor growth, adhesion, and metastasis. We present a clinical and molecular characterization of FAP and SPP1 in CRC. Methods: We analyzed 24,257 CRC samples tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq), NextGen DNA sequencing (NextSeq), and PD-L1 expression (SP142, positive ≥ 2+, 5%). RNA deconvolution analysis estimated cell infiltration in the TME. Data from the phase 3 CALGB/SWOG 80405 trial (NCT00265850) on 433 metastatic CRC patients treated with bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207) in combination with first-line chemotherapy were also evaluated. RNA isolated from FFPE tumor samples were sequenced with HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared using Cox regression in categorical gene expression tertiles (high (T3), medium (T2), and low (T1)) for FAP and SPP1 . Results: FAP -T3 and SPP1 -T3 had increased PD-L1 positivity (q&lt;0.05), while SPP1 -T3 also demonstrated increased MSI-H (8.4% vs 5.3%) and TMB-H(&gt;10 mt/mb, 15.0% vs 10.1%) status relative SPP1 -T1 (all q&lt;0.001). T3 of both genes of correlated with increased M1/M2 macrophages, NK cells and T cell inflamed score (q&lt;0.001); dendritic cells and neutrophils were increased in SPP1 -T3 and FAP -T1 tumors (q&lt;0.05). FAP -T3 and SPP1 -T3 had increased pathway activation of epithelial-mesenchymal transition (EMT), inflammatory response, TNF-a signaling, angiogenesis and KRAS signaling (all q &lt; .005). In Caris cohorts, FAP -T3 demonstrated worse OS in Cet/panitumumab treated CRC (T3: 23.6 vs T1: 21.0 months [mo], P = .005; HR 0.85, 95% CI [0.77-0.95]), but SPP1 did not correlate with OS. In 80405, FAP -T3 showed shorter PFS (T3: 9.5 vs T2: 11.5 vs T1: 12.6 mo, T3 vs T1 (reference) adjusted HR 1.27 [1.07-1.51]) and OS (25.2 vs 29.4 vs 35.5 mo, adjusted HR 1.31 [1.10-1.57]). Similarly, SPP1 -T3 demonstrated worse PFS (9.0 vs 12.7 vs 14.0 mo, adjusted HR 1.29 [1.12-1.48]) and OS (20.9 vs 34.0 vs 36.3 mo, HR 1.24 [1.07-1.44], P &lt; 0.001). Treatment interaction tests noted FAP -T1 CRC benefited from Cet over Bev with respect to PFS ( P = 0.003) and OS ( P = 0.044), while SPP1-T1 tumors demonstrated a PFS benefit with Cet ( P = 0.009). Conclusions: Our results indicate that increased FAP and SPP1 expression is associated with immune cell infiltration, EMT, and inflammatory signaling. Additionally, their expression may be prognostic and predictive of targeted therapy. These data support the evaluation of FAP and SPP1 as predictive markers and therapeutic targets in CRC.

INSTINCT: Multi-sample integration of spatial chromatin accessibility sequencing data via stochastic domain translation

Nanoparticle‐Mediated Explosive Anti‐PD‐L1 Factory Built in Tumor for Advanced Immunotherapy

AbstractImmunotherapy, particularly immune checkpoint blockade (ICB) therapies, has revolutionized oncology. However, it encounters challenges such as inadequate drug accumulation and limited efficacy against “cold” tumors characterized by lack of T cell infiltration and immunosuppressive microenvironments. Here, a controlled antibody production and releasing nanoparticle (CAPRN) is introduced, designed to augment ICB efficacy by facilitating tumor‐targeted antibody production and inducing photodynamic cell death. CAPRN achieves tumor‐specific accumulation via pH‐responsive PEG detachment, enabling efficient intracellular gene delivery encoding anti‐PD‐L1 antibody. Laser‐induced photodynamic therapy (PDT) not only triggers cancer cell death but also facilitates targeted antibody release from dying tumor cells. CAPRN demonstrates significant anti‐tumor efficacy, attributed to multiple effects including enhanced antibody release, dendritic cell (DC) maturation, and T cell activation. Moreover, CAPRN exhibits substantial tumor suppression in both primary and bilateral tumor models, accompanied by activated T cell infiltration and enhanced immune responses. This study presents a novel strategy for priming robust immunotherapy, offering targeted antibody release through laser‐assisted photodynamic nanoparticles.

Individual patient data (IPD) pooled analysis on the optimal therapeutic management of patients with microsatellite instability-high (MSI) resectable gastroesophageal adenocarcinoma (GEA).

455 Background: Patients with resectable MSI/dMMR GEA showed improved survival and modest if any benefit from chemotherapy. Preoperative treatment with immune checkpoint inhibition (ICI) showed high rate of major-complete pathologic response in single arm trials possibly allowing the design of chemotherapy/surgery-free approaches. Methods: This was a multinational IPD analysis including patients with resectable GEA with MSI/dMMR status enrolled in INFINITY and NEONIPIGA phase II trials, with dual CTLA-4/PD-(L)1 ICI followed by surgery +/- adjuvant ICI; PROSECCO retrospective study, with perioperative FLOT chemotherapy and surgery, and the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials of patients treated with surgery alone or plus older perioperative/adjuvant chemo(radio)therapy regimen. Primary endpoint was the evaluation of rates of pathologic complete response (pCR) defined as TRG1a Becker and major-complete pathologic response (pCR/MPR) defined as TRG1a/b Becker according to preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to the therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed. Results: The IPD included 197 patients. Of these, 49 received ICI +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care treatment, ICI demonstrated a higher rate of pathologic response compared to chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; pCR/MPR 78.6% vs 10%, OR 39.3 p&lt;0.001). In ITT population, no significant difference in OS and EFS was shown in patients treated with ICI, FLOT plus surgery, old chemo(radio)therapy plus surgery or surgery alone. Conclusions: In resectable MSI/dMMR GEA, upfront ICI showed comparable survival outcomes to surgery alone, with limitations of study design and sample size. The impact on survival of ICI versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. The high rate of major-complete pathologic response may allow to study or perform organ sparing surgery procedures or non-operative management to reduce surgical morbidity/mortality and improve quality of life. OS EFS HR 2.5-97.5% CI p HR 2.5-97.5% CI p Ref: Surgery only - - - - - - Chemo+surgery 1.16 0.27-4.98 0.84 1.10 0.39-3.07 0.85 FLOT+surgery 1.10 0.19-6.22 0.92 2.38 0.90-6.27 0.08 ICI +/- surgery 1.97 0.43-8.96 0.38 1.39 0.51-3.77 0.52

Oncomine panel testing in the clinical management of colorectal cancer: An Irish experience.

212 Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. It has been hypothesized that the molecular signatures of EOCRC could differ from those of late onset CRC (LOCRC). Next Generation Sequencing (NGS) using the Oncomine Precision Assay is a useful tool to guide treatment decisions based on the presence or absence of oncogene drivers. While not all of these mutations currently influence the clinical management of CRC patients, ongoing research on the function of these genes and the development of new drugs could offer insights into patient prognosis, treatment choices and prediction of therapy resistance. Methods: Of &gt;1500 CRC identified between 2010 and 2024, we investigated the clinical and genetic characteristics of 38 EOCRC and 41 LOCRC cases. All cases were microsatellite stable and staged I-III. NGS was performed with the Ion Torrent Genexus integrated platform using the Oncomine 45-gene Precision Assay panel. DNA hotspot mutations and copy number variations (CNVs) were assessed, followed by the classification of clinically relevant mutations using the genetic variant OncoKB database. Results: There were 38 EOCRC and 41 LOCRC cases. The age range was 27 to 49 and 50 to 91, with median ages of 44 and 72, in the EOCRC and LOCRC groups, respectively. Based on the stratification of NGS mutation levels as per the OncoKB classification, all patients in both groups (100%) had level 1 actionable mutations. NRAS wild type (WT) status was present in 100% of patients in both groups. However, differences were observed in KRAS status: 84% (32/38) of EOCRC were KRAS WT, while only 65% (27/41) of LOCRC were KRAS WT. While 3 % (n=1) of the EOCRC cohort had an ERBB2 amplification, none were detected in the LOCRC group. BRAF V600E mutations were present in 11% (4/38) of EOCRC and 12% (5/41) of LOCRC. Level 4 mutations were detected in 18% (n=7) of EOCRC, all of which were PIK3CA mutations, while these were seen in 24% (n=10) of the LOCRC group, including 9 PIK3CA mutations and 1 FGFR1 mutation. Regarding concurrent mutations, 2 patients in the EOCRC group had two mutations each: one with concurrent KRAS and PIK3CA mutations, and another with concurrent JAK2 and KRAS mutations. The LOCRC group had a higher incidence of concurrent mutations, with 8 patients affected: 6 had concurrent KRAS and PIK3CA mutations, and 2 had concurrent BRAF and PIK3CA mutations. Conclusions: Our study demonstrates that EOCRC have higher KRAS WT status and fewer concurrent mutations compared to LOCRC, who exhibit more frequent KRAS non-G12C oncogenic mutations. It also underscores the importance of routine NGS mutation panel analysis in CRC management. Additionally, identifying specific mutations in patients that relapse can guide targeted therapies, potentially improving outcomes and offering personalized treatment options.

Prompt initiation of durvalumab and tremelimumab treatment for unresectable hepatocellular carcinoma in patients with chronic active hepatitis B.

568 Background: Chronic hepatitis B virus (HBV) infection is a common etiology of HCC, especially in East Asia. Clinical trials using immune checkpoint inhibitors (ICIs) usually exclude patients with chronic active hepatitis B (serum HBV viral load &gt; 2000 IU/mL) or require the HBV viral load to be below a certain level using anti-HBV medications. This study examines the safety and efficacy of concurrently administering the STRIDE regimen (durvalumab with a single dose of tremelimumab) or durvalumab alone with anti-HBV medications in this patient population. Methods: We enrolled patients with advanced HCC, Child-Pugh A liver function reserve, and untreated chronic active hepatitis B. Initially, only patients naïve to ICIs were eligible, and patients received 1500mg of durvalumab intravenously every four weeks for up to two years except for disease progression or occurrence of unacceptable toxicities. After the positive results of the HIMALAYA study, we shifted to the STRIDE (single tremelimumab regular interval durvalumab) regimen, adding one dose of 300mg tremelimumab on the first day to regular durvalumab treatment, and allowed patients who had received prior programmed cell death-1 blockade therapy to be enrolled. Anti-HBV treatment with entecavir was initiated within seven days before starting ICI therapy. The primary endpoint was the rate of HBV reactivation (defined as a ≥2 log increase in serum HBV DNA from baseline) during the first six months. Results: Following the protocol design, 30 patients were enrolled. Two patients were female, and the mean age was 66.9 years. Ten patients received durvalumab alone, and 20 received the STRIDE regimen. Macrovascular invasion and extrahepatic spread were present in 16 (53.3%) and 20 (66.7%) patients, respectively; 18 (60%) patients had alpha-fetoprotein level ≥ 400 ng/mL. More than half (60.0%) of the patients had received prior systemic therapy for HCC, including 2 patients who had received PD-1 blockade therapy. Seven patients received the study treatment as the 3 rd or later line of systemic therapy. The mean±standard deviation baseline HBV viral load was 771.0±354.1 KIU/mL. No patients experienced HBV reactivation or HBV-associated hepatitis. Hepatitis flare was noted in 8 (26.7%) patients, but none of them were associated with HBV reactivation. The objective tumor response rate was 10% and 25% for the durvalumab treatment alone and the STRIDE regimen, respectively. No unexpected toxicities were identified in this study. The most common treatment-related adverse events were skin rash and liver function test abnormalities. Conclusions: For patients with chronic active hepatitis B, ICI therapy could be promptly initiated as long as anti-HBV medications were administered simultaneously. This study was partially supported by AstraZeneca. Clinical trial information: NCT04294498 .

KAI2-dependent signaling controls vegetative reproduction in Marchantia polymorpha through activation of LOG-mediated cytokinin synthesis

3D‐Printed Electrohydrodynamic Pump and Development of Anti‐Swelling Organohydrogel for Soft Robotics

Abstract This study introduces advancements in electrohydrodynamic (EHD) pumps and the development of a 3D‐printable anti‐swelling organohydrogel for soft robotics. Using digital light processing (DLP)technology, precise components with less than 1% size variation are fabricated, enabling a unique manifold pump array. This design achieves an output pressure of 90.2 kPa—18 times higher than traditional configurations—and a flow rate of 800 mL min −1 , surpassing previous EHD pumps. To address swelling issues in dielectric liquids, a novel organohydrogel is developed with Young's modulus of 0.33 MPa, 300% stretchability, and a swelling ratio under 10%. Its low swelling is attributed to the shield effect and edge length confinement effect. This durable material ensures consistent pump performance under mechanical stresses like bending and twisting, crucial for dynamic soft robotic environments. These innovations significantly improve EHD pump efficiency and reliability, expanding their potential applications in soft robotics, bioengineering, and vertical farming.

CLARITY-Gastric 01: A randomized phase 3 study of AZD0901, a Claudin18.2 (CLDN18.2)-targeted antibody-drug conjugate, in second- or later-line (2L+) advanced gastric or gastroesophageal junction cancer (GC/GEJC).

TPS507 Background: GC/GEJC is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide (Sung H, et al. CA Cancer J Clin 2021). Prognosis is poor in GC/GEJC; median overall survival (OS) is less than 10 months in the 2L setting and less than 6 months in the 3L+ setting (Wilke H, et al. Lancet Oncol 2014; Shitara K, et al. Lancet Oncol 2018). New treatment options are needed. CLDN18.2 has emerged as a new therapeutic target in GC/GEJC. AZD0901, a potential first-in-class CLDN18.2-targeted antibody conjugated to monomethyl auristatin E via a protease cleavable linker, has demonstrated clinical activity in a Phase 1 study in advanced GC/GEJC (Xu R-H, et al, J Clin Oncol 2023). CLARITY-Gastric 01 (NCT06346392) is a randomized, open-label, sponsor-blinded, global Phase 3 study that will assess the efficacy and safety of AZD0901 versus investigator’s (INV) choice of therapy after ≥1 prior therapy for advanced GC/GEJC expressing CLDN18.2. Methods: Participants (pts) will be randomized 1:1:1 to AZD0901 dose level 1 intravenous (IV) every three weeks (Q3W; Arm 1), AZD0901 dose level 2 IV Q3W (Arm 2), or INV choice of therapy (2L: ramucirumab [ram] + paclitaxel [PTX], PTX, or docetaxel [for pts with contraindication to ram only]; 3L+: irinotecan, TAS-102 [excluding China], or apatinib [China only]; Arm 3). One AZD0901 arm (Arm 1 or Arm 2) will stop enrollment after a pre-planned dose selection decision. Randomization will continue in a 1:1 ratio to the two remaining arms (selected AZD0901 dose arm and Arm 3). Eligible pts must have histologically confirmed, unresectable, locally advanced or metastatic GC/GEJC (non-HER2+, CLDN18.2 expression). Pts must have disease progression on/after ≥1 prior regimen (including platinum-fluoropyrimidine) and have an ECOG performance status of 0 or 1. Pts previously treated with CLDN18.2-targeting therapy (other than naked monoclonal antibody) are excluded. Recruitment has begun and pts are planned to be enrolled across 16 countries in Asia, Europe, and North America. Dual primary endpoints are progression-free survival (PFS; intent-to-treat [ITT] pts) and OS (3L+ pts). The secondary endpoints include OS (ITT pts), PFS (3L+ pts), objective response rate and duration of response (ITT and 3L+ pts), and safety/tolerability. Efficacy data will be summarized and analyzed in the ITT population. All efficacy endpoints will assess the selected AZD0901 dose arm versus Arm 3. Safety and tolerability will be assessed in all pts who receive ≥1 dose of study treatment. Previously presented at European Society for Medical Oncology - Gastrointestinal Cancers Congress 2024, Final Publication Number: 495TiP, Kohei Shitara et al. Reused with permission. Clinical trial information: NCT06346392 .