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Co-formulated favezelimab plus pembrolizumab versus standard-of-care in previously treated, PD-L1-positive metastatic colorectal cancer: The phase 3, randomized KEYFORM-007 study.

LBA248 Background: Effective treatment options remain an unmet need for patients (pts) with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). Combination therapy with the anti–lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) and the PD-1 inhibitor pembrolizumab (pembro), has shown promising antitumor activity and manageable safety in PD-L1 CPS ≥1 MSS/pMMR mCRC. The phase 3 KEYFORM-007 study (NCT05064059) evaluated the efficacy and safety of co-formulated fave/pembro vs standard-of-care (SOC) in PD-L1–positive MSS/pMMR mCRC. We present results of the pre-specified final analysis of OS. Methods: Eligible pts with PD-L1 CPS ≥1, MSS/pMMR unresectable mCRC (Stage IV per AJCC 8 th edition), who had progressed on or after, or could not tolerate standard treatment were randomized 1:1 to co-formulated fave 800 mg/pembro 200 mg IV Q3W (Arm A) or SOC (regorafenib 160 mg PO Q4W [QD on days 1-21] or TAS-102 35 mg/m 2 PO Q4W [BID on days 1-5 and 8-12]) (Arm B). Randomization was stratified by geographic region, presence or absence of liver metastases, and time from initial diagnosis of metastatic disease to randomization. Treatment continued for up to 35 cycles or until unacceptable toxicity, progression, confirmed CR (Arm A), or withdrawal. The primary endpoint was OS. The data cut-off was August 15, 2024. Secondary endpoints included PFS, ORR, and DOR (central review, RECIST v1.1 [assessed at interim analysis with data cut-off of August 21, 2023]), and safety. Results: At final analysis, 441 pts (63% male; 59% RAS mutant) were randomized (221 fave/pembro; 220 SOC. Median follow-up was 28 mo (range, 21-32). Median OS was not superior with fave/pembro vs SOC (median 7.3 vs 8.5 mo; HR 0.98; 95% CI, 0.80-1.20; P = 0.4183) in pts with MSS/pMMR mCRC. PFS was not superior with fave/pembro vs SOC (median 2.1 vs 2.6 mo; HR 1.34; 95% CI, 1.09-1.64; nominal P = 0.997). Per protocol, PFS was not tested for statistical significance. A confirmed objective response occurred in 15 (14PR; 1CR [6.8%]) vs 2 (2PR; [0.9%]) pts in the fave/pembro and SOC arms, with best response of PD occurring in 143 (65%) vs 94 (43%) pts, respectively. Median DOR was not reached ([NR] range, 1.8 to 16.8+) among the 15 responders in the fave/pembro arm, and was 6.5+ mo and 12.4 mo, for the 2 responders in the SOC arm. At final analysis, treatment-related adverse events (TRAEs) occurred in 145 (66%) vs 167 (80%) pts, respectively (grade ≥3 in 44 [20%] vs 76 [36%] pts). Adverse events of special interest occurred in 84 (38%) vs 13 (6%) pts, respectively. Conclusion: At final analysis, co-formulated fave/pembro did not improve OS vs SOC in pts with PD-L1-positive MSS/pMMR mCRC. The safety profile was manageable with no new safety signals observed. Clinical trial information: NCT05064059 .

Adjuvant cytokine-induced killer cell immunotherapy in hepatocellular carcinoma: Extended follow-up of a randomized controlled trial and post-treatment immune cell profiling.

518 Background: Notwithstanding the pressing need for adjuvant therapy for hepatocellular carcinoma (HCC), most adjuvant therapies, including atezolizumab/bevacizumab, have failed. Meanwhile, adjuvant immunotherapy utilizing autologous cytokine-induced killer (CIK) cells for HCC improved recurrence-free survival (RFS) in a previously reported randomized controlled trial (RCT) and real-world data. This study aimed to assess the longer-term outcomes of the RCT and elucidate the underlying mechanisms of sustained effects of CIK cell treatment. Methods: This study comprised two parts: a long-term follow-up of the preceding RCT and an analysis of immune cells in patients who received adjuvant CIK cell treatment. In the original RCT, 226 patients who underwent curative treatment for stage I or II HCC were randomly allocated to either the CIK (n=114, 16 injections of 6.4×10 9 CIK cells over an 11-month period) or control group (n=112). The follow-up period was extended to 9 years after the enrollment of the last patient. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included cancer-specific survival (CSS) and overall survival (OS). Parallelly, a prospective study was conducted to investigate post-treatment changes of immune cells in peripheral blood of 7 patients, who received repeated transfer of CIK cells after curative treatment for HCC, using flow cytometry. Results: In the extended follow-up of the RCT (median follow-up=115.7 months, interquartile range=74.2–130.5 months), the CIK group sustained a significantly prolonged RFS (median=43.5 vs 27.4 months; hazard ratio [HR]=0.74, 95% confidence interval [CI]=0.55–0.99, P =0.045) and CSS (median=unreached; HR=0.49, 95% CI=0.25–0.95, P=0.04) compared to the control group. Adjuvant CIK cell therapy reduced the risk of overall death by 30%, although it did not achieve statistical significance (median=unreached; HR=0.70, 95% CI=0.44–1.11, P=0.1). A preliminary analysis of peripheral blood immune cells revealed that the CIK cell treatment tended to increase the frequencies of CD8 + and CD4 + classical memory cells. Conclusions: Adjuvant CIK cell treatment demonstrated significantly enhanced RFS and CSS in the prolonged follow-up of the RCT extending to 9 years in patients who received curative treatment for HCC. The CIK group also demonstrated a consistent trend of improved OS. The increase in memory T cell populations might be linked to the sustained off-treatment anti-tumor efficacy of CIK cell treatment.

Complementary logic-in-memory inverters integrating n-channel and p-channel ferroelectric organic transistors

The emerging logic-in-memory (LIM) technology is a promising strategy to overcome the von Neumann bottleneck in modern computers. For LIM circuits, the complementary structure is desirable for low-power consumption. To date, there have been rare reports on the n-channel organic thin-film transistor nonvolatile memories (OTFT-NVMs), which is indispensable for building the complementary LIM circuits. In this Letter, we demonstrate a route to achieve the low-voltage operatable n-channel OTFT-NVMs, by blade-coating an ultrathin tetratetracontane buffer layer on the oxygen plasma treated ferroelectric terpolymer insulator with a low coercive field. The n-channel OTFT-NVMs exhibit good performances, with a high electron mobility over 0.1 cm2/V s, highly reliable endurance over 1000 cycles, and highly stable retention over 10 000 s. The mechanism for improving device performances is discussed. Moreover, the mechanism and the route for improving performances are also suitable for p-channel OTFT-NVMs. Furthermore, the LIM architecture-based complementary organic inverters are constructed by integrating the n-channel and p-channel OTFT-NVMs, which can well perform logic and memory operations at the low voltage of 10 V. The work laid the foundation for the development of the LIM circuits.

Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A

Sensitizing K-Ras G12D mutant colorectal patient-derived organoids via ferroptosis pathway.

211 Background: Colorectal cancer remains the third most fatal form of cancer for males and females combined, with K-Ras mutations present in approximately 40% of all cases. These mutations drive cancer progression and confer resistance to conventional therapies, underscoring the need for novel treatment strategies. Ferroptosis, a regulated non-apoptotic form of cell death characterized as iron-dependent lipid peroxidation, has emerged as a target for cancer therapy. A study published in 2023 found that K-Ras mutant pancreatic ductal adenocarcinoma and non-small cell lung cancer cells lack ferroptosis induced lipid peroxidation and concurrently upregulated ferroptosis suppressing protein (FSP-1). It is unknown if K-Ras mutant colorectal tumors also evade ferroptosis-induced cell death as a method of cancer progression and therapy resistance. This study aims to measure the effects of inhibiting K-Ras G12D, the most common K-Ras mutation found in CRC, on ferroptosis through a patient derived colorectal cancer organoid (PDO) model. We hypothesize that blocking K-Ras G12D using a MRTX-1133, a K-Ras G12D specific inhibitor, can induce ferroptosis and synergistically work with ferroptosis inducers. Methods: As a pilot study, two patient derived organoid lines were established. Surveillance screening and whole exome sequencing was performed to verify K-Ras mutation. CRC9T has wild-type and CRC30T has mutant K-Ras. Additionally, Columbia Pathology Core confirmed tissues used to generate organoids were moderately differentiated colorectal adenocarcinoma. CTG-3D assays were performed to measure IC50 using ferroptosis inducers RSL3, iFSP, and K-Ras inhibitor MRTX-1133. Organoids were cultured in standard gut media for 72 hours, treated, and collected after 72 hours. After treatment, organoids were imaged and stained with BODIPY-C11, a lipid peroxidation fluorescence dye. Flow cytometry was performed, and results were analyzed using FlowJo to show ferroptosis-induced lipid peroxidation in stained organoids. Results: Inhibiting K-Ras G12D and inducing ferroptosis showed a synergistic effect on ferroptosis-induced lipid peroxidation. CRC9T was more sensitive (IC50 RLS3: 2.96 uM, iFSP 3.46 uM) to ferroptosis inducers than CRC30T (IC50: RSL3: 5.68 uM, iFSP: 8.6 uM). Blocking K-Ras in was only efficacious in CRC30T (IC50: MRTX1133: 9.73 uM). Cells from the mutant line showed greatest lipid peroxidation when combining ferroptosis inducers with K-Ras G12D inhibitors in flow cytometry analysis. Conclusions: These findings demonstrate a synergistic effect when blocking K-Ras G12D and inducing ferroptosis and align with previous studies that showed a connection between ferroptosis suppression and oncogenic KRAS expression. We plan to validate these findings in other patient derived organoid model systems and to assess the effects of pan-KRAS inhibition and ferroptosis inducer on non-K-Ras G12D PDOs.

Clinicopathological factors related to survival in gastroenteropancreatic neuroendocrine tumors (GEP-NET): 20 years experience in the American British Cowdray Medical Center.

656 Background: Neuroendocrine neoplasms (NEN) are a diverse group of tumors originating from neuroendocrine cells found throughout the body. Their “rarity”, heterogeneity, and non-specific presentation contribute to limited reliable epidemiological data, especially in developing countries such as Mexico. This study aims to analyze the clinical and pathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NET) and their association with survival in a third-level center in Mexico. Methods: A retrospective cohort study at the American British Cowdray Medical Center, in Mexico City, was conducted. We included all histopathological confirmed GEP-NET from 2004 to 2024. Clinical, biochemical, and radiological features at diagnosis were analyzed. Survival was estimated using Kaplan-Meier and Log-Rank test. Results: We identified 110 NENs, of which 89% were GEP-NET, 56.1% were female, and the median age was 57.7 (SD 13.8) years. The clinical stage was metastatic (50%), localized (37.7%), and locally advanced (6.1%). The primary sites were the pancreas (49%), small bowel (23.5%), gastric (10.2%), colon (7.1%), rectum (5.1%), appendix (3.1%), and unknown (2%). ECOG performance status were 0-1 in 96.9%. In the metastatic setting, liver involvement was 96.2%, mainly high hepatic burden (59.6%). Symptoms were abdominal pain (34.6%), diarrhea (16.3%), and bowel obstruction (6.1%). Functioning tumors were 26.8%, and carcinoid syndrome was found in 9.2%. Grades 1, 2, and 3 were 62.9%, 34%, and 3.1% respectively. The median of Ki-67 was 6.4%. At diagnosis, Ga-68 PET/CT scan, serum CgA, and urinary 5-HIIA were performed in 98.2%, 39.7%, and 16.3% of patients. Among metastatic patients, 87.1% received at least one line of systemic treatment, primarily with somatostatin analogs (62.9%). In all population, the median follow-up was 42.5 months and the median overall survival (OS) was 164.9 (SD 12.2) months. Univariate analyses showed that primary site (p=0.02), Ki-67 <5% (p=0.02), CgA <700 ng/ml (p=0.03), and low hepatic burden (p=0.01) were statistically significantly associated with OS. Conclusions: This study provides critical insights into GEP-NET characteristics in a Mexican population, highlighting clinical, biochemical, and radiological factors associated with better survival.

Envafolimab in combination with lenvatinib and albumin paclitaxel for previously treated advanced GEJ adenocarcinoma: Latest analysis of a phase II, two-cohort study.

375 Background: The combination of first-line chemotherapy and PD-1 has emerged as a standard treatment, enhancing the efficacy in advanced gastric/gastroesophageal junction (GEJ) cancer. The efficacy of the combination of second-line chemotherapy and PD-1/PD-L1 remains unclear. This study aims to observe the efficacy of Envafolimab (PD-L1 inhibitor ) plus tyrosine kinase inhibitors (TKIs) and second-line chemotherapy in the treatment of patients (pts) with advanced GEJ adenocarcinoma. Methods: Eligible pts with HER2-negative, microsatellite stable (MSS), advanced GEJ adenocarcinoma were enrolled in this study. Pts who never received PD-1 or PD-L1 inhibitors before would assign into Group A. Pts in Group B have failed first-line PD-1 antibody combined chemotherapy, with optimal efficacy as or above stable disease (SD). Pts in both groups received Envafolimab (200mg, hypodermic injection, days 1, 15, Q4W) combined with Lenvatinib (8mg/12mg, po, once a day) and albumin paclitaxel (100mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or pts refusal to continue treatment. The primary endpoint was objective response rate(ORR) per iRECISTv1.1, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: From Oct 2022 to Apr 2024, 32 pts were enrolled. Both groups enrolled 16 pts equally, and 15 pts of each group were evaluable for efficacy analysis. The average ages were 60.07 ± 11.73 y and 50.13 ± 12.18 y in group A and B respectively. In group A, 7 pts had been tested for PD-L1 status, of which 2 (13.3%) was positive and 5 (33.3%) were negative. PD-L1 status was negative in 5(33.3%) pts, positive in 9 (60.0%), and untested in 1(6.7%) in group B. As of Sep 14, 2024, The ORR was 60.0% (9/15) in group A and 46.7% (7/15) in group B. The DCR was 100.0% (15/15) in both groups. After a median follow-up of 17.0 mo (IQR: 8.0-18.8) in group A, the mPFS was 8.2 mo (95% CI = 6.1-10.4), and the mOS was 14.8 mo(95% CI = 7.4-22.2). With median follow-up of 9.0 mo (IQR: 6.1-16.2) in group B, the mPFS was 5.9 mo (95% CI= 3.8-8.1) and the mOS was 11.5 mo (95% CI = 3.1-19.9). Overall incidences of adverse events (AEs) of any grade was 100% (30/30), and 80.0% (24/30) pts had ≥ grade 3 AEs during treatment. Most treatment-related adverse events (TRAEs) of grade ≥3 included decreased neutrophil count (73.3%), decreased leukocyte count (63.33%), Anemia (10%), febrile neutropenia (6.67%). Conclusions: In pts of advanced gastric cancer who have previously received PD-1 inhibitors or not, this second-line combination therapy demonstrates promising preliminary effects. Pts who have not previously received ICIs might benefit more from this combination therapy. Clinical trial information: NCT06030934 .

INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer

PURPOSE Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). METHODS A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). RESULTS INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. CONCLUSION Regorafenib improves survival compared with placebo in refractory AGOC.

A deep convolutional neural network for diffuse correlation tomography

Near-infrared diffuse correlation tomography (DCT) is an emerging technology for tomographic imaging of blood flow index (BFI) in biological tissues through quantifying the light electric field temporal autocorrelation function. With the conventional approaches, proper reconstruction of BFI images is a challenging task from the limited DCT signals due to the severe imbalance between the optical measurements and the voxels to be reconstructed. In this study, we proposed a complete deep learning solution for DCT, including a dataset containing massive prior information for network training, a long short-term memory neural network for DCT signal denoising, as well as a deep convolutional neural network for mapping the DCT signals into the tomographic BFI images. The proposed deep learning solution was comprehensively validated through both computer simulations and phantom experiments, demonstrating its strong superiority over the conventional approach for precise and robustness reconstructions of the target BFI anomalies, with much better performance in reducing errors (i.e., the mean absolute error was reduced by 26.1 times) and preserving fine structure (i.e., the structure similarity index measure was increased by 12.8 times). The proper establishment of a deep learning strategy enables future exploration of the microvasculature blood flow mechanism on pathological tissues even from the limited DCT signals.

The NADH-dependent flavin reductase ThdF follows an ordered sequential mechanism though crystal structures reveal two FAD molecules in the active site

Amivantamab with or without chemotherapy in right-sided metastatic colorectal cancer: Updated results from OrigAMI-1, an open-label, phase 1b/2 study.

197 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity and is FDA approved in EGFR -mutated advanced non-small cell lung cancer. High MET expression is observed in ~68% of patients (pts) with metastatic colorectal cancer (mCRC). Additionally, MET amplification occurs in up to 23% of EGFR-resistant mCRC and is implicated in driving resistance to EGFR-targeting antibodies (EGFRi). Compared to left (L)-sided disease, right (R)-sided disease is less responsive to EGFRi and associated with poorer outcomes. We present longer follow-up data among pts with R-sided mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing ami as monotherapy and combined with chemotherapy in mCRC. All pts were wild-type for KRAS , NRAS , BRAF , and EGFR ectodomain by central ctDNA testing, without ERBB2 / HER2 amplification. One ami monotherapy cohort (Cohort C) enrolled only pts with R-sided disease (all pts must have 2-3 prior lines; prior EGFRi allowed). The ami plus chemotherapy cohorts (Cohorts D [with FOLFOX] and E [with FOLFIRI) enrolled both L- and R-sided disease (1 prior line max; prior EGFRi use was exclusionary). Primary tumor locations of cecum, ascending colon, hepatic flexure, and transverse colon were considered R-sided. Response was assessed by the investigator per RECIST v1.1. Results: As of 26-Aug-2024, 23 pts with R-sided mCRC received ami monotherapy (median follow-up of 8.1 months [mo]). Median number of prior lines was 2, and 43% had prior EGFRi. There were 7 pts with R-sided disease who received ami plus FOLFOX or FOLFIRI (median follow-up of 6.5 mo); all 7 had received 1 prior line. Among pts receiving ami monotherapy, objective response rate (ORR) was 22% (5/23) and disease control rate (DCR) was 78% (18/23), with 1 achieving a complete response. Median duration of response (DoR) is 7.4 mo; response and treatment are ongoing for 3 of the 5 responders. In pts receiving ami plus FOLFOX or FOLFIRI, ORR was 43% (3/7) and DCR was 86% (6/7). Median DoR is 5.8 mo, with all 3 responders on treatment, of which 2 are ongoing response. Additional details are in the Table. Biomarker data will be presented at the meeting. Safety profile among R-sided disease was consistent with prior reports, with the most common ami-related grade 3+ AEs being rash and hypoalbuminemia (2 pts each). Conclusions: Ami monotherapy or combined with FOLFOX or FOLFIRI demonstrated durable antitumor activity in R-sided mCRC. Clinical trial information: NCT05379595 . Efficacy. Ami monotherapy (n=23) Ami + FOLFOX or FOLFIRI (n=7) Median follow-up, mo (range) 8.1 (0.6–17.5) 6.5 (3.2–8.8) Median number prior lines 2 1 Prior EGFRi, n (%) 10 (43) 0 ORR, % (95% CI) 22 (8–44) 43 (10–82) Median DoR, mo (95% CI) 7.4 (3.7–NE) 5.8 (NE–NE) a DCR, % (95% CI) 78 (56–93) 86 (42–100) Median progression-free survival, mo (95% CI) 3.7 (3.4–5.5) 7.4 (1.8–NE) a All 3 responders remain on treatment; 2 of 3 responders are ongoing response.

Disparities in prophylactic tetracycline use among patients with metastatic colorectal cancer undergoing treatment with EGFR inhibitors.

109 Background: Epidermal growth factor receptor (EGFR) inhibitors have been shown to improve survival in metastatic colorectal cancer and are considered a standard of care option for patients with RAS/RAF wild-type disease. However, anti-EGFR agents are associated with an acneiform rash that can lead to decreased quality of life and early discontinuation of treatment. Prophylactic doxycycline has been shown in a randomized clinical trial to decrease any skin toxicity ≥ grade 2 by 50%. In this study we sought to determine the rate of prophylactic tetracycline use in metastatic colorectal cancer patients receiving anti-EGFR therapy in the United States. Methods: The Flatiron Health Electronic Health Record-derived, de-identified database was used to analyze the records of patients who were at least 18 years old, diagnosed with metastatic colorectal cancer, and received treatment with an anti-EGFR agent (cetuximab or panitumumab). Patients were stratified by receipt of prophylactic tetracycline versus not. This was defined by an order for a tetracycline 28 days before to 1 day after initiation of an anti-EGFR agent. Demographic and clinical characteristics were compared via multivariable logistic regression. The change in percentage of patients who received a prophylactic tetracycline over time was assessed and was compared to the rate of anti-emetic prescription which served as a control to ensure drug administration data was accurately captured. Results: The records of 6,713 patients who met inclusion criteria and received an anti-EGFR agent between 2013 and 2023 were included in our analysis. A logistic regression model assessing the association between patient characteristics and the receipt of a prophylactic tetracycline suggested that older age, race (black/African American or Other), presence of RAS mutation, and higher line of therapy were all significantly associated with not receiving prophylactic tetracyclines. Other patient characteristics including gender, ECOG status, mismatch repair status, and RAF mutation status did not appear to impact the likelihood of receiving a prophylactic tetracycline. The rate of prophylactic tetracycline use increased from 10.9% in 2013 to 22.3% in 2023 while the rate of prophylactic anti-emetic remained stable at around 82%. Conclusions: This real-world analysis suggests the use of preemptive treatment for skin toxicity in patients with metastatic colorectal cancer who are treated with an anti-EGFR in US is suboptimal. Disparities in cancer care are also evidenced by lower use of tetracyclines in elderly and African Americans. Randomized controlled trials support the use of prophylactic tetracycline in these patients; thus, further research into the reason for this practice gap is necessary. Educational efforts should be undertaken to improve tetracycline prescribing rates in this population.

Optical coherence tomography and elastography for the visualization of architecture and stiffness differences in gastric cancer and dysplasia.

382 Background: Individuals at high risk for gastric cancer may be recommended to undergo risk-reducing gastrectomy, which leads to life-long morbidity. Surveillance with endoscopy can be an appropriate and effective option for avoiding unnecessary surgery. Gastric cancer is commonly characterized by changes in tissue architecture and increased tissue stiffness, but visualization of these alterations is challenging for white light endoscopy methods. We utilized optical coherence tomography (OCT), a non-destructive imaging modality that uses reflected near-infrared light to generate cross-sectional images of tissue, to visualize microstructure and relative tissue stiffness. Methods: We utilized two modes of OCT for visualization of ex vivo tissue samples collected from patients undergoing gastrectomy for gastric cancer, endoscopic mucosal resection, or endoscopic biopsy. Images were collected with a benchtop OCT system (Thorlabs Telesto TEL221). Structural OCT was used to visualize changes in tissue architecture including thickened mucosa and irregular put structure of the mucosa. Optical coherence elastography (OCE) was used to extract relative measures of tissue stiffness using an optical palpation method. A phantom of known mechanical properties was placed on the tissue and an axial force was applied. The resulting deformation (strain) of the phantom provided relative measurements of tissue stiffness. Classification of normal and cancerous tissue was confirmed by histology. Results: Structural OCT imaged architectural features of tissue with high resolution (<10 um) and depth of imaging up to 1.5 mm. Strain maps generated with OCE data showed that normal gastric tissue had relatively consistent stiffness, whereas stomach cancer and dysplasia exhibited increased tissue stiffness compared to normal. Conclusions: Structural OCT and OCE captured changes in tissue architecture and increased stiffness in patient samples of gastric cancer and dysplasia. These tissue features are classic characteristics of cancer, making this technique a useful screening tool for several cancer types. Future work aims to implement endoscopic OCT and OCE to detect cancer at early stages in vivo .

Nivolumab plus ipilimumab in advanced hepatocellular carcinoma with Child-Pugh B: A multicenter retrospective study.

551 Background: The phase 3 CheckMate 9DW trial proposed that nivolumab plus ipilimumab (Nivo/Ipi) significantly improved the survival of patients with advanced hepatocellular carcinoma (aHCC) compared with sorafenib or lenvatinib as first-line treatment, but it only included patients with Child-Pugh A. Given the limited treatment options for patients with poor liver function, we aimed to assess the efficacy and safety of Nivo/Ipi in aHCC patients, stratified by liver function. Methods: This study included patients with aHCC who received Nivo/Ipi treatment at three referral hospitals between March 2020 and September 2023. Patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (four doses), followed by nivolumab (240 mg) every 2 weeks. Results: Of 106 patients treated with Nivo/Ipi, 96 evaluable patients were included in the final analysis. Among them, 76 patients had Child-Pugh A, while 20 had Child-Pugh B. The baseline characteristics were generally comparable between the two groups, except for a significantly higher rate of extrahepatic metastasis in patients with Child-Pugh A (86.8% vs. 65.0%, p = 0.043) and a higher incidence of macrovascular invasion in patients with Child-Pugh B (55.0% vs. 27.6%, p = 0.032). The objective response rate (ORR) was 28.9% (22/76, 4 complete responses [CR] and 18 partial responses [PR]) in the Child-Pugh A group and 10.0% (2/20; 0 CR and 2 PR) in the Child-Pugh B group. Disease control rates were 42.1% in the Child-Pugh A group and 25.0% in the Child-Pugh B group. In a median follow-up duration of 29.3 months (95% confidence interval [CI], 28.8-29.8), the median overall survival (OS) was 8.9 months (95% CI, 5.5-17.6) in the Child-Pugh A group and 3.9 months (95% CI, 2.1-4.8) in the Child-Pugh B group (p < 0.001). The median progression-free survival (PFS) was 1.6 months (95% CI, 1.2-3.5) in the Child-Pugh A group and 1.2 months (95% CI, 0.8-2.1) in the Child-Pugh B group (p = 0.003). Adverse events of any grade occurred at a comparable rate between the two groups, although immune-related adverse events were significantly more frequent in the Child-Pugh A group. Multivariable analysis indicated that Child-Pugh B was consistently associated with a worse PFS and OS, while prior exposure to immune checkpoint inhibitors (ICIs) was associated with a poorer PFS. Notably, both responders with Child-Pugh B were both ICI naïve. Conclusions: While Nivo/Ipi treatment showed reduced efficacy in patients with Child-Pugh B, identifying potential responders beyond the current clinical trial criteria may offer opportunities to improve outcomes in this challenging population.

Enhanced thermoelectric performance in AgSbTe2 with extremely low thermal conductivity via grain boundary defects

A delicate balance between high electrical conductivity and ultra-low glass-like thermal conductivity is critical for enhancing thermoelectric performance. Here, by introducing grain boundary trapping states into the AgSbTe2 matrix, the thermally activated release of carriers at elevated temperatures enhances electrical conductivity, while the increased barrier potential induces an energy filtering effect that sustains a high Seebeck coefficient. This synergistic optimization of electrical conductivity and Seebeck coefficient significantly enhances the power factor. Additionally, numerous point defects and a higher density of grain boundaries further enhance phonon scattering, resulting in a 33% reduction in glass-like thermal conductivity compared to the pristine sample. With enhanced power factor and reduced lattice thermal conductivity, Fe-doped AgSbTe2 achieves a remarkable peak zT of 1.8 at 623 K and an impressive zTavg of 1.4 over the temperature range of 323–623 K, showcasing its leading performance in the field. By selecting proper contact layer materials with matched thermal expansion coefficients, low interfacial resistivity was achieved, enabling a single-leg thermoelectric device with ∼10% efficiency under a 323 K temperature difference.

Lipid droplet targeting of the lipase coactivator ABHD5 and the fatty liver disease-causing variant PNPLA3 I148M is required to promote liver steatosis

Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study.

19 Background: Neoadjuvant treatment with immune checkpoint inhibitors has shown remarkable responses in patients with deficient mismatch repair (dMMR) colorectal cancer. However, the optimal choice and duration of treatment have yet to be established. Methods: RESET-C (NCT05662527) was an investigator-initiated, phase II, single-arm, multicenter study investigating the efficacy and safety of single-cycle neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. Additional inclusion criteria were ≥ 18 years of age, no indication for neoadjuvant therapy, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. After inclusion, patients received one cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery within three to five weeks. A tumor-response evaluation was done before surgery, including blood samples, a computed tomography scan of the chest and abdomen, and a colonoscopy. The primary endpoint was the pathological complete response (pCR) rate according to Mandard tumor regression grading (Clopper-Pearson method). Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (Mandard tumor regression grade 1 or 2), and disease-free survival. Results: Between February 2023 and March 2024, 85 patients were included. The median age was 74 years (IQR, 68-79), 72% were women, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients proceeded to surgery. One patient with stage I disease decided not to undergo surgery. A pCR rate of 44% (37/84; 95% CI, 33-55) and a major pathological response rate of 57% (48/84; 95% CI, 46-68) were found. A significantly higher pCR rate was seen in patients with stage I-II (20/33) versus stage III (17/51) disease (61% vs 33%; p=0.02). A total of 41 surgical complications were seen in 31 patients (37%; 95% CI, 27-48). Of these, eight complications were Clavien-Dindo grade 3a or above, including three patients with anastomotic leakages and two deaths within 30 days. The patients who died were aged 80 and 81, had ECOG performance status 1, and clinical stage IIIB and IIIC disease, respectively. Seven out of 85 patients (8%; 95% CI, 3-16) experienced grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were registered. Finally, data on the association between endoscopically evaluated clinical complete response and pCR, along with the 1-year disease-free survival rate expected in January 2025, will be reported. Conclusions: A single cycle of neoadjuvant pembrolizumab was efficacious and safe in patients with localized dMMR colon cancer. For most patients with clinical stage I-II disease, a single cycle sufficed to achieve pCR. Clinical trial information: NCT05662527 .

Trajectories of premorbid healthcare contact days in veterans with pancreatic cancer.

706 Background: Early detection of pancreatic cancer is a key clinical priority. Although prior work has evaluated machine learning models to identify at-risk patients for pancreatic cancer screening, this is limited by complexity and cost. "Contact days’’— days spent receiving healthcare outside the home for any reason or length of time—have previously been used to measure the ‘’time toxicity’’ of cancer care post-diagnosis. We sought to characterize trajectories of premorbid contact days, alongside standardized risk scores and healthcare costs to explore their use as potential markers for early pancreatic cancer diagnosis. Methods: We identified decedents with pancreatic adenocarcinoma diagnosed between 2012 and 2022 who had at least one primary care visit in the Veterans Affairs (VA) system in each of the two years prior to diagnosis using the VA Clinical Cancer Registry (VACCR) and the Corporate Data Warehouse (CDW). We grouped patients into two cohorts: (1) surgical (receipt of curative intent surgery), and (2) non-surgical and collected sociodemographic and clinical characteristics. During a 2-year premorbid period we calculated monthly contact days (24 data points) and plotted them as percentages (e.g., 3 contact days in a month=10%) and visualized their trajectory using cubic smoothing splines. We plotted trajectories for each sociodemographic and clinical subgroup and visually evaluated differences. We similarly plotted monthly Care Assessment Need (CAN) scores, a validated VA risk score identifying patients at high risk of hospitalization/death, and monthly VA healthcare costs. Results: We included 8,654 patients (649 surgical - median age 69 years, 74% white, 78% stage 1-2 and 8,005 non-surgical - median age 71 years, 72% white, 21% stage 1-2). For both groups, trajectories of contact days were similar. Baseline contact days (-24 to -12 months) were 7-8% (≈2 days/month). Contact days started to rise on average 9 months prior to diagnosis at an approximate rate of 1% per month, reaching 15-20% at diagnosis (≈5-6 days/month). In the surgical group, patients with a Charlson comorbidity score of ≥2, urban residence, and Black race had higher baseline contact days. Those <65 years and rural residence had a steeper slope of rise in contact days. CAN score trajectories closely mirrored contact day trajectories in both groups. Cost trajectories were similar in both groups (≈$1000/month at baseline), rose gradually to ≈$2000/month by -3 months, and then rose sharply to >$6000/month 2 months before diagnosis. Conclusions: In this decade-long national study of Veterans diagnosed with pancreatic cancer, we found that contact days and CAN scores, but not costs, start to rise 9 months prior to diagnosis. These data provide the first evidence supporting their further evaluation in pancreatic cancer risk models which may aid early diagnosis. The similar trajectories in patients who go on to receive curative-intent surgery or not may imply they may be markers for pancreas cancer diagnosis but perhaps not outcomes.

Impact of COVID-19 on colorectal cancer screening using Medicare Centers for Medicare and Medicaid Services (CMS) claims data.

91 Background: When COVID-19 pandemic started in 2020 in the US, the Centers for Medicare and Medicaid Services (CMS) recommended that all non-urgent procedures, including screening colonoscopies, be delayed until pandemic stabilization. This was done to prevent the spread of the virus via colonoscopy since the presence of the virus in fecal samples has been reported in infected patients. Little is known of the impact of COVID-19 on the number of colorectal cancer (CRC) screening performed in the US. Methods: We utilized the Centers for Medicare & Medicaid Services Database which provides Medicare claims data for 2013-2022. We searched “Medicare Physician & Other Practitioners - by Geography and Service” using CPT code for colonoscopy(G0121, G0105), fecal occult blood test (FOBT; G0328, 82270), stool-based gene analysis (81528), sigmoidoscopy (G0104), and barium enema (G0120) and collected the number of CRC screening claims at national level and calculated the year-over-year (YOY) change. Results: The number of CRC screening claims in the US from 2013 to 2022 is listed (Table). The total number of CRC screening claims increased an average of 0.5% YOY from 2014 to 2019 then decreased 23.4% in 2020. From 2014 to 2019, the average YOY change in colonoscopy, FOBT, stool-based gene analysis, sigmoidoscopy, and barium enema claims were -0.5%, -6.0%, 58.7%, 8.1%, and -6.0%, respectively whereas in 2020, the rates were -27.5%, -25.0%, -14.4%, -25.3%, and -1.7%, respectively. The total number of CRC screening claims in year 2021 and 2022 increased from 2020, however, was still lower than 2019. Conclusions: CRC screening claims decreased in the US in 2020 likely due to COVID-19 and not yet returned to pre-pandemic levels. Number of CRC screening claims in the US from 2013 to 2022. Screening test 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 　 Colonoscopy 759,883 736,400 743,873 765,974 767,063 755,806 736,247 533,972 685,439 707,672 　 FOBT 1,307,054 1,263,602 1,161,214 1,130,130 1,085,777 996,016 897,993 673,614 646,550 556,950 　 Stool-Based Gene analysis 　 　 　 123,748 231,765 335,459 482,761 413,224 497,748 536,348 　 Sigmoidoscopy 2,666 2,316 3,254 3,390 3,835 3,784 3,975 2,968 3,893 3,680 　 Barium enema 107 93 80 116 128 97 58 57 44 65 　 Total CRC screening 2,069,710 2,002,411 1,908,421 2,023,358 2,088,568 2,091,162 2,121,034 1,623,835 1,833,674 1,804,715 　 Data are expressed in numbers (N). CRC; colorectal cancer; FOBT; fecal occult blood test.

Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC).

722 Background: PDAC is the third leading cause of cancer mortality, with limited treatment options. Even with multi-agent chemotherapy, patients with second-line (2L) PDAC have a median progression-free survival (PFS) of ≈2–3.5 months and median overall survival (OS) of ≈6–7 months. RAS mutations occur in >90% of patients with PDAC, mainly KRAS G12X (G12X = non-synonymous mutations in KRAS codon 12 [G12]). RMC-6236 is an oral, RAS(ON), multi-selective, tri-complex inhibitor of the active GTP-bound state of both mutant and wild-type RAS. In a Phase 1 study, RMC-6236 demonstrated efficacy and manageable safety in patients with PDAC harboring KRAS G12X or other RAS mutations (NCT05379985). Data on ctDNA reduction with targeted therapy in PDAC are sparse. We report safety, updated efficacy, and exploratory analyses of early ctDNA reduction with clinically active doses of RMC-6236 in patients with RAS mutant PDAC. Methods: Escalating doses of RMC-6236 were administered orally to patients with previously treated RAS mutant PDAC. Additional patients were enrolled for dose optimization and expansion. Patients receiving clinically active doses (160–300 mg QD) of RMC-6236 ≥14 weeks before the July 23, 2024 data cutoff were included. Plasma samples were collected for ctDNA analysis of change in RAS mutant variant allele fraction at baseline (BL; cycle 1, day 1 [C1D1]), and on treatment (C2D1 or C3D1). Results: As of July 23, 2024, 127 patients with RAS mutant PDAC had received RMC-6236 160–300 mg QD. The most common (≥10% of patients) any-grade treatment-related adverse events were rash (91%), diarrhea (48%), nausea (43%), vomiting (31%), stomatitis (31%), fatigue (20%), paronychia (13%), mucosal inflammation (13%), decreased appetite (11%), and peripheral edema (10%). The Table shows objective response rate (ORR), PFS, and OS with 2L RMC-6236. Paired plasma samples were tested in 106/127 patients. Of these, 68 patients with RAS mutant allele ctDNA at BL were evaluable for ctDNA response (Table). Conclusions: RMC-6236 showed a manageable safety profile and encouraging efficacy in patients with previously treated RAS mutant PDAC, and early and deep reductions in RAS mutant ctDNA. RASolute 302, a global, randomized, Phase 3 trial evaluating RMC-6236 as 2L treatment vs chemotherapy in patients with metastatic PDAC, is ongoing. Clinical trial information: NCT05379985 . KRAS G12X RAS mutant Efficacy with 2L RMC-6236 (n=42) (n=57) ORR, % (95% CI)[confirmed + pending confirmation] 29 (16–45) 25 (14–38) Median PFS, months (95% CI) 8.5 (5.3–11.7) 7.6 (5.9–11.1) Median OS, months (95% CI) 14.5 (8.8–not evaluable) 14.5 (8.8–not evaluable) ctDNA Response with 2L+ RMC-6236 (n=56) (n=68) >50% decrease from BL, n (%) 53 (95) 63 (93) 100% decrease from BL, n (%) 28 (50) 32 (47)