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Machine learning assisted composition design of high-entropy Pb-free relaxors with giant energy-storage
Abstract The high-entropy strategy has emerged as a prevalent approach to boost capacitive energy-storage performance of relaxors for advanced electrical and electronic systems. However, exploring high-performance high-entropy systems poses challenges due to the extensive compositional space. Herein, with the assistance of machine learning screening, we demonstrated a high energy-storage density of 20.7 J cm-3 with a high efficiency of 86% in a high-entropy Pb-free relaxor ceramic. A random forest regression model with key descriptors based on limited reported experimental data were developed to predict and screen the elements and chemical compositions of high-entropy systems. Following basic experiments, a (Bi0.5Na0.5)TiO3-based high-entropy relaxor characterized by fine grains, weakly-coupled and small-sized polar clusters was identified. This resulted in a near-linear polarization behavior and an ultrahigh breakdown strength of 95 kV mm-1. Further, this high-entropy realxor presented a high discharge energy density of 7.7 J cm-3 under discharge rate of about 27 ns, along with superior temperature and fatigue stability. Our results present the data-driven model for efficiently exploring high-performance high-entropy relaxors, demonstrating the potential of machine learning in developing relaxors.
Selective Recycling of Mixed Polyesters via Heterogeneous Photothermal Catalysis
AbstractThe selective recycling of mixed plastic wastes with similar structural units is challenging. While heterogeneous catalysis shows potential for selective recycling, challenges such as complex mass transfer at multiphase interfaces and unclear catalytic mechanisms have slowed progress. In this study, a breakthrough in recycling mixed polyester wastes is introduced using heterogeneous photothermal catalysis. By adding co‐solvents, the difficulties associated with multiphase interfacial mass transfer are overcome. Grain boundary (GB)‐rich CeO2 photothermal catalysts are used to selectively glycolyze mixed poly(ethylene terephthalate) (PET) and poly(bisphenol A carbonate) (PC) plastics into bisphenol A (BPA) and bis(2‐hydroxyethyl) terephthalate (BHET), achieving yields of 97.8% and 93.4%, respectively. The high concentration of oxygen vacancies in GB‐rich CeO2 catalysts adjusts the adsorption energy of intermediates, leading to more selective and efficient depolymerization compared to GB‐poor CeO2 catalysts. The economic and environmental analysis demonstrates that this process, which utilizes heterogeneous photothermal catalysis, provides significant energy savings and carbon reduction, representing a major advancement in mixed plastic waste recycling.
Neoadjuvant immunotherapy and nonoperative management of dMMR gastroesophageal adenocarcinoma (GEA): A retrospective case series.
451 Background: Perioperative chemotherapy with surgery is the standard of care for patients (pts) with resectable gastric or gastroesophageal junction adenocarcinoma (GEA). However, recent studies have shown more favorable responses after neoadjuvant immunotherapy (NIO) in patients with mismatch repair deficient (dMMR) cancers. Herein, we present the outcomes of 10 cases with dMMR GEA. Methods: We retrospectively reviewed patients with GEA at Mayo Clinic Arizona who met the following criteria: have dMMR disease by IHC, nonmetastatic operable disease, and received NIO +/- chemotherapy. Patient demographics, disease characteristics, and clinical outcomes were extracted. The primary endpoint was clinical complete response (cCR) in patients treated with non-operative management (NOM) defined as complete radiological response and no residual disease on endoscopic ultrasound (EUS) and biopsy. Results: 10 pts with dMMR GEA with a median age of 70 (43-85) were identified. 6 pts had T2N0, 1 had T4N0, 3 had N+ disease. 8 pts received NIO monotherapy upfront, 1 received NIO after progressing on chemotherapy, and 1 concurrently with chemotherapy. No grade 3/4 toxicities were reported, however, 2 pts discontinued therapy due to arthralgia and colitis. After NIO, 9/10 pts had significant or complete resolution of FGD avidity on PET/CT, while 1/10 had stable disease. 3/10 pts underwent surgical resection, with 2 achieving pathological complete response (pCR) and the third showing T1N0 disease with no recurrence 1 year after surgery. Notably, one of the pts with pCR passed away due to surgical complications. 7/10 patients had NOM, of whom, 4 had cCR and 3 had radiological response only, as no EUS data was available. 4/7 NOM pts had follow up data at 6 months with no evidence of progression, of whom one pt remained progression-free at 33 months. ctDNA testing was performed in 6/10 pts: 2 had undetectable ctDNA at baseline, while 3 became MRD-negative after NIO, consistent with radiological and/or pathological response, and 1 had persistent ctDNA both before and after NIO, despite cCR. Conclusions: This study demonstrates exceptional and prolonged response, along with good tolerability to NIO in pts with dMMR GEA, supporting the feasibility of non-operative management in such patients.
Phase 1/2 study of the HER3-directed antibody-drug conjugate patritumab deruxtecan (MK-1022) as monotherapy in patients with gastrointestinal cancers.
TPS321 Background: A significant medical need exists for more effective and tolerable therapeutic options for patients with advanced gastrointestinal cancers (colorectal cancer [CRC], biliary tract cancer [BTC], and hepatocellular carcinoma [HCC]). Human epidermal growth factor receptor (HER3) expression is high in CRC and BTC, and low-to-intermediate in HCC. Patritumab deruxtecan (HER3-DXd; U3-1402/MK-1022) is a HER3-directed antibody-drug conjugate (ADC) comprising a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab), which includes a plasma-stable, selectively cleavable linker, and a potent topoisomerase I inhibitor payload (DXd; released payload) that leverages the clinically validated deruxtecan (a derivative of exatecan) technology. DXd is cell membrane permeable and enables a bystander antitumor effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring tumor cells. Patritumab deruxtecan has shown antitumor activity in phase 1 and 2 studies of EGFR-mutated advanced non–small cell lung cancer and advanced breast cancer and in preclinical studies of CRC. This nonrandomized, open-label, phase 1/2 study (NCT06596694) will examine the safety and efficacy of patritumab deruxtecan in select gastrointestinal cancers. Methods: Approximately 130 adults (aged ≥18 years) will be allocated to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n = 40) must have previously treated unresectable or metastatic colorectal adenocarcinoma. Patients in cohort 2 (BTC; n = 40) must have previously treated locally advanced or metastatic BTC. Patients in cohort 3 (HCC; n ≤50) must have previously treated advanced HCC. Prior topoisomerase I inhibitor therapy is not allowed. Patients in cohorts 1 and 2 will receive patritumab deruxtecan intravenously (IV) as monotherapy. Cohort 3 includes a dose-escalation phase to determine the recommended phase 2 dose of patritumab deruxtecan monotherapy and an efficacy phase. In the efficacy phase, patients will receive the recommended phase 2 dose of patritumab deruxtecan. The primary objectives are to evaluate safety and tolerability of patritumab deruxtecan and to evaluate the confirmed objective response rate per RECIST v1.1 assessed by blinded independent central review (BICR) for each cohort. Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival, and to characterize the pharmacokinetics of patritumab deruxtecan. Clinical trial information: NCT06596694 .
Peak part 1 summary: A phase 3, randomized, open-label, multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST).
826 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2 nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2 nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .
Propensity score matching analysis of valve-sparing versus aortic root replacement in type A aortic dissection patients
Uncovering the role of oncogenic <i>HER2</i> variants as drivers of pancreatic cancer.
772 Background: The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) to conventional cytotoxic therapy underscores the need for advances in targeted molecular therapeutics. Previous studies have reported approximately 2% of PDAC patients with HER2 gene amplification. While anti- HER2 cancer therapy has yielded success in other disease sites, it has had minimal reported benefit in PDAC. Multiple HER2 isoforms exist that are generated either by loss of exon 16 ( d16 HER2 ), or through N-terminal truncations ( p95 HER2 ). These isoforms are implicated in differential tumor behavior and response to anti-HER2 therapy in the breast but have not been investigated in PDAC. Herein, we hypothesize that these isoforms may underlie the observed resistance to HER2 therapy in PDAC. Methods: To test for the presence of HER2 structural variants within human PDAC, a tissue microarray was constructed of fifty-one primary tumor samples and two metastatic samples. Multiplex immunohistochemistry (mIHC) was performed for staining of the extracellular N-terminal and intracellular C-terminal HER2 domains. We then utilized our previously described HER2 + cancer rainbow (Crainbow) mouse model in which human wild-type HER2 ( WT HER2 ), d16 HER2 , and p95 HER2 were expressed in the same mouse along with fluorescent protein reporters. HER2 Crainbow mice were crossed with PDX1-Cre recombinase to initiate recombination and expression of each fluorescently labelled HER2 isoform during pancreas development. PDX1-Cre / HER2 Crainbow mice were followed for up to one year and sacrificed to lineage trace each isoform and register HER2 lineages with histopathology. Results: In our human data, four of fifty-three patient samples (three primary and one metastatic) had moderate-to-strong HER2 staining. All samples identified on mIHC as HER2 positive stained primarily for the p95 variant of HER2 , with absence of the N-terminal domain and preservation of the intracellular domain. In our transgenic mice, 65% of the mouse cohort developed pre-malignant low grade pancreatic intraepithelial neoplasia (PanIN) by eight weeks. At one year, 58.3% of mice demonstrated advanced high grade PanIN, and 25% developed invasive disease. Lineage tracing revealed that while early low grade PanIN began as polyclonal lesions, comprised of WT- , d16- , and p95 HER2 expressing cells, advanced PanIN and invasive disease were unanimously monoclonal with one dominant isoform arising. WT HER2 was represented abundantly in low grade disease, but high grade and invasive disease were predominantly driven by d16- and p95-HER2. Conclusions: Our data implicates the oncogenic d16- and p95 HER2 variants, rather than WT HER2 , as the primary drivers of HER2+ PDAC tumorigenesis. In breast p95 HER2 has been described as a known cause of Trastuzumab resistance. Therefore, future efforts will be aimed at characterizing the mechanisms driving therapeutic resistance in p95-HER2 PDAC tumors.
Total neoadjuvant therapy followed by total mesorectal excision and selective lateral lymph node dissection for locoregionally advanced low rectal cancer: A phase III randomized controlled trial (JCOG2207).
TPS312 Background: For locally advanced low rectal cancer (RC), total neoadjuvant therapy (TNT) followed by total mesorectal excision (TME) confers a survival advantage compared with neoadjuvant chemoradiotherapy (nCRT) in the West, even though the local control rate was similar between TNT and nCRT. The Japan Clinical Oncology Group (JCOG) Colorectal Cancer Study Group has been developing therapies for RC based on recurrence risk according to presence/absence of clinical lateral lymph node metastasis (cLLNM). Our previous study in Japan showed that the standard of care (SOC) for RC is TME with lateral lymph node dissection (LLND) plus adjuvant chemotherapy (CTx). However, the prognosis for cStage III low RC remains poor regardless of cLLNM status. Therefore, new treatment strategies are needed for this population. In cLLNM-positive cStage III low RC patients, previous research suggests that adding nCRT to LLND would reduce local recurrence and improve survival. TNT and LLND may further improve outcomes. In cLLNM-negative cStage III low RC, several reports have suggested that nCRT as an alternative addition to LLND has comparable efficacy in terms of local control. Thus, in these populations, if TNT can replace LLND, adverse events due to LLND can be avoided while improving prognosis. We hypothesize that TNT + TME + selective LLND would be the most promising strategy for cLLNM-positive and -negative cStage III low RC. Methods: Eligibility criteria include low rectal adenocarcinoma or adenosquamous carcinoma, cT2-cT4 tumor depth, clinically positive lymph node metastasis, no distant metastasis, no history of pelvic irradiation or rectal surgery, age 18-75 years, and sufficient organ function. Eligible patients are randomized (1:1) with adjustment factors of institution, sex, and cLLNM status. The experimental treatment arm receives TNT, short-course radiotherapy (25 Gy/5 fractions to whole pelvis), and consolidation chemotherapy consisting of 6 courses of CAPOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 2000 mg/m2/day on days 1-14). After completing TNT, TME + selective LLND are performed for cLLNM-positive cases or TME alone for cLLNM-negative cases. The SOC arm receives TME + LLND followed by adjuvant chemotherapy with 8 cycles of CAPOX (same as above). The primary endpoint is overall survival (OS) in the intention-to-treat population. To detect an increase in 5-year OS from 76% to 84%, corresponding to a target hazard ratio of 0.64, 408 patients (108 events) would achieve 75% power at a one-sided α of 0.05, an expected accrual period of 4 years, and a follow-up period of 5 years. The total sample size was set at 420 patients to account for patients lost to follow-up. Accrual in JCOG2207 began in October 2023. Clinical trial information: s031230415 .
MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with <i>KRAS</i> G12R alteration.
725 Background: Pancreatic ductal adenocarcinoma (PDAC) is largely driven by oncogenic alterations in the KRAS , TP53 , CDKN2A/B , and SMAD4 genes. KRAS G12R accounts for nearly 20% of KRAS alterations in PDAC, is biologically unique, and offers the potential for improved response to MEK inhibitor (MEK-inh)-based therapy. As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the efficacy of MEK-inh-based therapy matched to the unique molecular alterations in the tumor of each patient as recommended by the molecular tumor board. Methods: From March 2022 to December 2023, 8 patients with metastatic PDAC were treated with MEK-inh-based therapy. Molecular profiling was performed by Tempus (648 genes) in 7 patients, and FoundationOne (324 genes) in 1 patient. Description of molecular alterations, matched therapies, and efficacy of treatment are provided. Results: The median age of patients starting MEK inhibitor-based therapy was 69 years, with 62% of them being female. The molecular characteristics and matched therapies are summarized (Table). MEK-inh-based therapy was administered to 3 (37.5%) patients as a first or second-line treatment, and to 5 (62.5%) patients as a third to fifth-line treatment for metastatic PDAC. The overall survival and progression free survival (PFS) on MEK-inh-based therapy was 8.4 and 4.9 months, respectively. Four patients had PFS beyond 4 months (4.9, 5.5, 5.6 and 6.9 months). Conclusions: Individualized MEK-inh-based therapy demonstrated efficacy in late-line treatment of metastatic PDAC with KRAS G12R alterations. Using this approach earlier in the treatment course and in combination with RAS inhibitors or cytotoxic systemic therapies may further enhance outcomes. Tumor alterations and matched therapies. Gene altered Number of patients (%) Number of patients matched (%) Drug family matched KRAS G12R 8 (100) 8/8 (100) MEK inhibitor TP53 7 (87.5) 4/7 (57) VEGF/VEGR inhibitor* CDKN2A 4 (50) 4/4 (100) CDK4/6 inhibitor** SMAD4 2 (25) 2/2 (100) MEK inhibitor + (EGFR or Pan-HER inhibitor)*** *PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091.
Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies
Abstract Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for treating myeloid malignancies, but challenges remain in bone marrow (BM) infiltration and targeting BM-resident malignant cells. Current autologous CAR-T therapies also face manufacturing and patient selection issues, underscoring the need for off-the-shelf products. In this study, we characterize primary patient samples and identify a unique therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cells. Using stem cell gene engineering and a clinically guided culture method, we generate allogeneic CD33-directed CAR-NKT cells with high yield, purity, and robustness. In preclinical mouse models, CAR-NKT cells exhibit strong BM homing and effectively target BM-resident malignant blast cells, including CD33-low/negative leukemia stem and progenitor cells. Furthermore, CAR-NKT cells synergize with hypomethylating agents, enhancing tumor-killing efficacy. These cells also show minimal off-tumor toxicity, reduced graft-versus-host disease and cytokine release syndrome risks, and resistance to allorejection, highlighting their substantial therapeutic potential for treating myeloid malignancies.
Toward Fast‐Charging and Dendritic‐Free Li Growth on Natural Graphite Through Intercalation/Conversion on MoS <sub>2</sub> Nanosheets
Abstract During fast‐charging, uneven lithium plating on the surface of commercial graphite anode impedes the electrochemical performance of lithium‐ion batteries, causing a safety issue. The formation of a passivation layer, the solid‐electrolyte interphase (SEI), due to side reactions with the organic electrolyte, correlates with long‐term cycling performance under fast‐charging conditions, necessitating comprehensive analysis. Herein, it is demonstrated that a molybdenum disulfide (MoS 2 ) coating on natural graphite (NG) modulates the properties of the SEI layer, enabling reduction of the charging time and the enhancement of long‐term cycling performance. MoS 2 spontaneously transforms into Li 2 S and Mo nanoclusters through intercalation and conversion with Li + , altering the chemical composition and stability of the SEI layer on the NG, promoting faster Li + transport, and reducing interfacial resistance. The MoS 2 ‐NG anode shows improved fast‐charging capability and cycling performance under 3.0 C‐charging and 1.0 C‐discharging over 300 cycles without compromising energy density. In the full‐cell configuration, a charging time of 14.7 min at 80% state of charge is achieved, making it suitable for electric vehicle applications.
Updated results of ALTER-H006: A phase II study of benmelstobart (PD-L1 inhibitor) plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.
601 Background: Although radical resection offers one of the most favorable prognosis for hepatocellular carcinoma (HCC), the rate of postoperative recurrence remains high, which is the primary cause of mortality in HCC patients. The optimal adjuvant treatment strategy for patients is still under active investigation. Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus benmelstobart, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This study enrolled patients diagnosed with HCC confirmed through histological or cytological examination, whose age was 18-75, with ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Enrolled patients received anlotinib (12 mg, p.o., qd, d1-14, q3w) plus benmelstobart (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurred first. Tumor assessment was performed at the end of the second cycle and every four cycles thereafter, according to RECIST v1.1. The predefined sample size was 37. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints included RFS, 1-year overall survival (OS) rate, and safety. Results: As the cutoff date of September 13,2024, a total of 38 patients (pts) were enrolled and 35 pts included in per-protocol set analysis. The majority of the 38 pts were male (94.7%, n = 36), and the median age was 56.5 years (range: 33-75). 18 pts (47.3%) had CNLC Stage IIb and 20 (52.6%) had CNLC Stage IIIa HCC. Among them, 35 pts received at least once tumor assessment. According to RECIST 1.1, of the 35 pts, 18 had no recurrence, 15 experienced relapse, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 59.97% (95%CI: 39.12-79.68) and the primary median RFS was 16.89m(95%CI: 6.82-26.96). The 1-year OS rate was 91.47% (95%CI: 69.23-97.86). 34 of 38 pts (89.5%) experienced treatment-related adverse events (TRAEs). The most common grade 3 TRAEs occurred in 17 pts (44.7%) including hypertension (32%) and neutropenia(5.3%). No grade 4 or 5 TRAEs were observed. Conclusions: The present study indicated that anlotinib plus benmelstobart as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited promising efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366 .
Adherence to multi-target stool DNA test in the US Asian population from 2017-2024.
101 Background: In 2024, incidence and mortality cases related to colorectal cancer (CRC) in the US are estimated to reach 152,810 and 53,010, respectively. CRC screening can help identify malignant lesions at earlier stages; however, in 2021, only 48% of Asian American persons between the ages of 45-75 were up-to-date. Multi-target stool DNA test (mt-sDNA), a highly sensitive and guideline recommended CRC screening modality, may improve screening adherence in average-risk individuals within this population. Herein, we examined CRC screening adherence with mt-sDNA in Asian Americans using national claims data. Methods: A large claims database of over 165 million individuals linked with Exact Sciences Laboratories data, was used to source mt-sDNA orders for Asian Americans from 2017 to 2024. Eligible individuals were aged ≥45 years, new to mt-sDNA and average risk for CRC during the baseline period of 12 months. Primary outcome was adherence to mt-sDNA, defined as return of mt-sDNA kit within 365-days from shipment. The secondary outcome was time to kit return in days. All individuals received a standard mailed letter along with additional digital outreach through the accompanying mt-sDNA patient navigation program, according to their desired mode of communication. Baseline demographic measures included age, sex, ordering provider, residential geography, payor, and outreach preference. Association of adherence with patient characteristics was evaluated using multivariable regression. Results: Of the 182,259 eligible mt-sDNA orders shipped during the study period, overall adherence was 68.9%. Average time to test return was 27.1 days. The cohort was comprised mostly of women (56.7%), aged 50-64 years (58.42%), primary care provider (74.7%), and preferred ‘Digital SMS’ outreach (50.9%). Average adherence for all age groups, 45-49 years, 50-64 years, 65-75 years, and 76+ years, exceeded 65%, at 67.2%, 68.8%, 69.7%, and 72%, respectively. Medicare recipients demonstrated the highest adherence by payor type (71%, p < 0.0001), and persons who opted for ‘Digital SMS + Email’ communication were most adherent (70.9%; p < 0.0001). Of all provider specialties, individuals having their tests ordered by gastroenterologists produced the shortest time to adherence (21.8 days). Multivariable regression revealed that age, digital outreach (compared to none), micropolitan residence, and ordering provider were independent predictors of increased mt-sDNA adherence. Conclusions: The results of this large cohort and nationally representative analysis demonstrated high mt-sDNA adherence amongst Asian American persons, despite a low percentage of this population being current with CRC screening overall. The use of mt-sDNA, in concordance with its included patient navigation, is a viable modality to encourage test completion through screening engagement – which has the potential to reduce screening barriers in this population.
Predicting mortality in upper gastrointestinal tract cancer using long short-term memory neural networks.
340 Background: Upper gastrointestinal (GI) tract cancers represent a significant global health burden, characterized by high morbidity and mortality rates, with an increasing incidence among aging populations and varying outcomes based on gender and ethnicity. Early prediction of mortality rates in upper gastrointestinal cancer can significantly enhance treatment strategies and patient outcomes. This study describes current trends in upper gastrointestinal cancer and proposes a predictive model, developed using Long Short-Term Memory (LSTM) neural networks to project future trends using demographic data. Methods: We extracted mortality data from the Center for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiological Research (WONDER) Database spanning 1999, normalized it and encoded categorical variables such as age, sex, ethnicity, and race numerically. Using Studio R to analyze mortality trends, we developed an LSTM model known for its ability to capture and utilize long term data patterns. The model, trained with a sequence length of 20, predicted future data points based on the previous 20. We then assessed its accuracy and generalization with a test set. Ultimately, our model is able to utilize demographic variables to forecast annual mortality and survival rates. Results: The mortality rates for upper GI tract cancers are notably higher among elderly individuals, particularly those aged 80 and above, with males and certain ethnic groups, such as Hispanics. The accuracy of the trained model was evaluated by calculating the Mean Squared Error (MSE), a measure of the difference between the predicted and actual value, with zero indicating no difference between the two. Our LSTM model achieved a training MSE of 0.00085 and a validation MSE of 0.0016, indicating good reliability and accuracy. Conclusions: Our analysis highlighted clear mortality trends and demonstrated the model’s effectiveness in improving mortality predictions in upper gastrointestinal cancer. However, limitations due to the dataset’s lack of clinical variables (such as comorbidities, cancer stage, and prior treatments) and its reliance on a single dataset may affect external validity. Future research is needed to determine if the model can be applied for clinical prognosis or strategic planning. We ultimately created and validated an LSTM neural network model with the CDC WONDER dataset, showing promising results. Future development will aim to include clinical characteristics to create a more personalized predictive tool.
Electrosynthesis of NH3 from NO with ampere-level current density in a pressurized electrolyzer
Understanding the Dynamic Evolution of Active Sites among Single Atoms, Clusters, and Nanoparticles
Abstract Catalysis remains a cornerstone of chemical research, with the active sites of catalysts being crucial for their functionality. Identifying active sites, particularly during the reaction process, is crucial for elucidating the relationship between a catalyst's structure and its catalytic property. However, the dynamic evolution of active sites within heterogeneous metal catalysts presents a substantial challenge for accurately pinpointing the real active sites. The advent of in situ and operando characterization techniques has illuminated the path toward understanding the dynamic changes of active sites, offering robust scientific evidence to support the rational design of catalysts. There is a pressing need for a comprehensive review that systematically explores the dynamic evolution among single atoms, clusters, and nanoparticles as active sites during the reaction process, utilizing in situ and operando characterization techniques. This review aims to delineate the effects of various reaction factors on dynamic evolution of active sites among single atoms, clusters, and nanoparticles. Moreover, several in situ and operando techniques are elaborated with emphases on tracking the dynamic evolution of active sites, linking them to catalytic properties. Finally, it discusses challenges and future perspectives in identifying active sites during the reaction process and advancing in situ and operando characterization techniques.
Racial, gender and socioeconomic disparities in survival outcomes of hepatocellular carcinoma.
526 Background: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer worldwide, with mortality rates increasing globally, particularly in the Western world. The 5‐year survival rate of persons with HCC is less than 20%. It is, therefore, essential to investigate the extent to which social determinants of health influence survival outcomes. In this study, we explored the effect of gender, race/ethnicity and socioeconomic factors on survival outcomes among patients with HCC in the United States. Methods: We extracted data on patients with a histologic diagnosis of hepatocellular carcinoma from the Surveillance, Epidemiology and End Result (SEER) Registry from 2000-2021. The primary outcome of interest was the cause-specific survival of these patients. According to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) system, the histological code of HCC is 8170/3. We excluded patients of missing or unknown race, income, location, and patients outside the years of study. Cox proportional hazard regression (SPSS) was utilized to determine the association between patients' race/ethnicity, gender, annual median income, location and cause-specific survival. Results: 80,445 met the criteria and were included in our study. Gender proved to be a predictor of survival; compared to females, males had worse outcomes, with males HR 1.040 (95% CI; 1.020-1.060, p = <0.001). Race was a predictor of survival outcomes. Using American Indian/Alaska Native as our reference, Asian/Pacific Islander HR 0.847 (95% CI; 0.790-0.90, p = <0.001), Black HR 1.019 (95% CI; 0.950-1.093, p = 0.603), White HR 0.955 (95% CI; 0.893-1.023, p = 0.186). We also analyzed the effects of socioeconomic factors on survival. Patients with higher annual median income had better outcomes. >$120000 HR 0.817 (95% CI; 0.783-0.851, p = <0.001) while patients with lower annual median income had worse outcomes < $40000 HR 1.217 (95% CI; 1.134-1.305, p < 0.001). The effect of location on survival was not significant. Compared to non-metropolitan areas, metropolitan areas HR 0.988 (95% CI; 0.971–1.004, p = 0.138). Conclusions: Race/ethnicity, income and gender disparities all played a significant role in cause-specific survival in patients with HCC, with improved survival observed in females, Asians and patients with higher annual median income. More efforts are needed to bridge these survival disparities.
Development of a methylation-based, tissue-agnostic test for the detection of molecular residual disease by circulating tumor DNA.
266 Background: Clinical validation studies support tumor-informed molecular residual disease (MRD) as a prognostic biomarker for disease recurrence across multiple solid tumor types. However, these tests are not always feasible due to the occasional lack of tumor tissue. Here, we discuss the design of a test for tissue-agnostic MRD detection and its application to a cohort of patients with colorectal cancer (CRC). Methods: A targeted panel composed of differentially methylated regions was developed. A machine-learning model was trained on differential methylation patterns in order to classify plasma samples as MRD-positive or MRD-negative. Performance of the independently trained classifier was assessed in a cohort of 247 patients enrolled in the Bespoke CRC trial (NCT04264702). These patients had MRD results available using a tumor-informed circulating tumor DNA (ctDNA) assay (Signatera), of whom 163 were persistently MRD-negative without clinical progression and 84 had MRD-positive results. Tissue-agnostic MRD results were compared to the tumor-informed results by calculating the percent positive agreement (PPA). Additionally, the differentially methylated allele fraction (DMAF) from the tissue-agnostic test was compared with variant allele frequencies (VAFs) from the tumor-informed test. Results: In the Bespoke CRC clinical cohort (72% non-Hispanic White, 54% male, mean age 61.4±12.3 years), 71 (28%) patients had stage II CRC, and 147 (60%) had stage III CRC. Overall, PPA was 86% (95% CI: 70-100%) and specificity was 97% (95% CI: 93-100%). When categorizing based on tumor-informed MRD VAF levels, PPA was 97% for VAF >0.2%, 100% for VAF 0.1-0.2%, 89% for VAF 0.04-0.1%, and 68% for VAF <0.04%. The DMAFs strongly correlated with the VAFs from the tumor-informed test and the correlation was independent of disease stage, histology, age, and sex. Conclusions: This is the first study of its kind demonstrating high concordance between a tissue-agnostic MRD test and a clinically validated tumor-informed ctDNA assay. These findings demonstrate that in cases where tissue is not available or of inadequate quality, a methylation-based tissue-agnostic assay may serve as a potential alternative for MRD detection.
Pembrolizumab or placebo plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: An updated analysis of KEYNOTE-859 for patients enrolled in Asia.
464 Background: After a median follow-up of 41.6 months, data from the global phase 3 KEYNOTE-859 study (NCT03675737; N = 1579) continued to show that use of pembrolizumab (pembro) plus chemotherapy (chemo) improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), with manageable safety, versus placebo (pbo) plus chemo for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma. Here, we report updated results from the subgroup analysis of pts enrolled in Asia after an additional 11 months of follow-up from the first interim analysis. Methods: Eligible pts aged ≥18 years with locally advanced unresectable or metastatic HER2-negative G/GEJ adenocarcinoma, an ECOG performance status (PS) of 0 or 1, and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles; all pts received investigator’s choice of chemo (FP or CAPOX). The primary end point was OS. Secondary end points included PFS, ORR, and DOR per RECIST v1.1 by blinded independent central review, and safety. Efficacy end points were evaluated in all randomly assigned pts (intention to treat). Results: A total of 525 pts (263, pembro plus chemo; 262, pbo plus chemo) were enrolled in KEYNOTE-859 in Asia. The median time from randomization to database cutoff (August 22, 2023) was 39.2 months (range, 26.0-56.8). The median OS was 17.3 months (95% CI, 14.8-19.5) for pembro plus chemo versus 13.0 months (95% CI, 11.8-14.4) for pbo plus chemo (HR, 0.75; 95% CI, 0.62-0.91). The median PFS was 8.4 months (95% CI, 7.1-9.6) for pembro plus chemo versus 5.8 months (95% CI, 5.6-6.9) for pbo plus chemo (HR, 0.72; 95% CI, 0.58-0.89). The ORR was 61.2% (95% CI, 55.0-67.1; 36, complete response [CR]; 125, partial response [PR]) for pembro plus chemo and 48.5% (95% CI, 42.3-54.7; 24, CR; 103, PR;) for pbo plus chemo. The median DOR was 10.0 months (range, 1.2+ to 50.8+) for pembro plus chemo and 5.8 months (range, 1.3+ to 44.3+) for pbo plus chemo; 28.9% and 23.3% of pts, respectively, had a response lasting ≥24 months. Grade 3-5 treatment-related adverse events (AEs) occurred in 155 pts (59.2%) in the pembro plus chemo group and 119 pts (45.4%) in the pbo plus chemo group. Treatment-related AEs led to death in 1 pt (0.4%) in the pembro plus chemo group (unknown cause) and 2 pts (0.8%) in the pbo plus chemo group (cerebral hemorrhage and abnormal liver function). Immune-mediated AEs and infusion reactions occurred in 85 pts (32.4%) in the pembro plus chemo group and 35 pts (13.4%) in the pbo plus chemo group. Conclusions: The addition of pembro to chemo improved OS, PFS, and ORR in pts with advanced HER2-negative G/GEJ adenocarcinoma from Asia enrolled in KEYNOTE-859, with no new safety signals. These results further support first-line pembro plus chemo as a treatment option for this population. Clinical trial information: NCT03675737 .