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A Bioinspired Virus‐Like Mechano–Bactericidal Nanomotor for Ocular Multidrug‐Resistant Bacterial Infection Treatment

AbstractMultidrug‐resistant (MDR) bacteria and their associated biofilms are major causative factors in eye infections, often resulting in blindness and presenting considerable global health challenges. Presently, mechano–bactericidal systems, which combine distinct topological geometries with mechanical forces to physically induce bacterial apoptosis, show promising potential. However, the physical interaction process between current mechano–bactericidal systems and bacteria is generally based on passive diffusion or Brownian motion and lacks the force required for biofilm penetration; thus, featuring low antibacterial efficacy. Here, a biomimetic mechano–bactericidal nanomotor (VMSNT) is synthesized by functionalizing COOH‐PEG‐phenylboronic acid (PBA) on virus‐like mesoporous silica, with subsequent partial coating of Au caps. Enhanced by self‐thermophoresis capabilities and virus‐like topological shapes, VMSNT significantly improves mechanical antibacterial effects and biofilm penetration. In addition, scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM) analyses demonstrate that VMSNT can precisely target bacteria within the infection microenvironment, facilitated by PBA's ability to recognize and bind to the peptidoglycan on bacterial surfaces. Remarkably, VMSNT is also effective in eliminating MDR bacteria and reducing inflammation in mice models of methicillin‐resistant Staphylococcus aureus (MRSA)‐infected keratitis and endophthalmitis, with minimal adverse effects. Overall, such a nanomotor presents a promising approach for addressing the challenges of ocular MDR bacterial infections.

Safety and preliminary efficacy of ivaltinostat, an HDAC inhibitor, plus capecitabine in patients with pretreated metastatic pancreatic adenocarcinoma (mPDAC): Results of a phase Ib study.

742 Background: Front-line chemotherapy for patients (pts) with mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses cell proliferation, and promotes apoptosis. Preclinical data demonstrated synergy with 5-FU/capecitabine (cape) in mouse models. We report here results of the Phase Ib portion of a Ib/2 trial evaluating the safety and recommended phase 2 dose (RP2D) of this combination to use in a randomized study of ival + cape vs cape as maintenance therapy. Methods: Key eligibility criteria for phase 1b included unresectable or metastatic PDAC; ≥18 years old; ≥1 prior therapy; ECOG PS 0-1; and no known germline BRCA1/2 mutation. Three cohorts were enrolled, receiving ivaltinostat at 60, 125, or 250mg/m 2 iv (weekly on days 1 and 8) in combination with cape (1000mg/m 2 po BID on days 1-14) of a 21-day cycle. 1o objectives: safety, tolerability and RP2D; 2o objectives: pharmacokinetics (PK) of ival + cape. Results: A total of 28 patients were enrolled at the 60 (n=6), 125 (n=10) and 250 (n=12) mg/m 2 ival dose levels. Median prior lines of therapy: 2 (range 1-7). Median age: 67 years (range 50-83). Only one DLT (G4 thrombocytopenia) was observed at 250mg/m 2 dose level. Treatment-emergent AE profile was similar across dose levels, with common TEAEs including fatigue (n=15, 53.6%), nausea (n=14, 50.0%), palmar-plantar erythrodysesthesia syndrome (n=12, 42.9%), diarrhea (n=10, 35.7%), and constipation (n=9, 32.1%). G3 AEs included neutropenia (n=6, 21.4%), anemia (n=4, 14.3%), abdominal pain (n=3, 10.7%) and diarrhea (n=3, 10.7%). G4 AEs included 1 (3.6%) event of neutropenia and 1 (3.6%) of thrombocytopenia. No SAEs related to study drugs occurred in any of the 3 dose cohorts. PK analyses indicated dose proportional increases in exposure with increasing doses of ival. Histone H3K27 acetylation for ival showed the similar trend in optical density evaluation. Across all dose levels and prior treatments, median OS and PFS were 9.6 and 3.3 months, respectively. Conclusions: The combination of ival and cape was generally well tolerated in this heavily pretreated patient population. Ival 250 mg/m 2 is the dose selected for the ongoing randomized study of ival + cape vs cape in the maintenance setting for mPDAC pts post-FOLFIRINOX, which is expected to finish accrual in 2025. Clinical trial information: NCT05249101 .

A retrospective study of the prognostic value of early induction of S-1 postoperative adjuvant therapy for pancreatic cancer.

689 Background: The usefulness of oral S-1 administration as adjuvant therapy (AC) after pancreatic cancer surgery has been demonstrated (1). Our study also suggested the importance of maintaining relative dose intensity or postoperative early induction (2). In a large Japanese data set, a comparison of induction before and after the postoperative 10 weeks showed a worse prognosis in the group which started 10 weeks after surgery (3). However, the number of patients of which early induction is possible are gradually increasing with recent improvements of surgical outcomes. In the present study, we retrospectively evaluated the survival benefit of AC which was started within 2 weeks after surgery. Methods: 129 patients with invasive pancreatic cancer who underwent radical surgery from January 2018 to May 2023 were enrolled in this retrospective study. The patients were divided into the following groups: 46 (36%) underwent induction within 2 weeks, 56 (43%) within 3-6 weeks, 13 (10%) after 7 weeks, and 14 (10%) without AC (4 with low renal function, 4 with deteriorating physical condition after surgery, 4 with not desired, and 2 with comorbid disease treatment). The background of each group was as follows (Described in the following order; induction within 2 weeks after surgery: 3-6 weeks: after 7 weeks: without AC), age 71: 71: 71: 78 (n.s.), pancreatic head cases 52: 68: 69: 50% (n.s.), BR cases 35: 23: 8: 21% (n.s.), NAC performed 86: 38: 15: 29% (p < 0.001), preoperative CEA ≥ 5.0ng/ml 24: 23: 8: 21% (n.s.), preoperative CA19-9 ≥ 37U/ml 48: 52: 54: 64% (n.s.), PV/SMV reconstruction 20: 16: 31: 14% (n.s.), postoperative complications (Clavien Dindo ≤3) 0: 16: 31: 43% (p < 0.001), Pathological stage 2 or higher 83: 65: 77: 79% (n.s.). Results: The need for reduction of S-1 dosage was 87: 89: 92% of the patients (n.s.), and the 6-month completion rate was 70: 71: 61% (n.s.). Median overall survival duration in each group was as follows: not reached: 49.5: 35.5: 48.6 months, and 1-year postoperative recurrence-free survival was 73: 66: 45: 71%, median recurrence free survival time was 34.0: 20.8: 10.3: 12.1 months, and induction within 2 weeks after surgery group significantly improved the recurrence-free survival in comparison with the group of after 7 weeks (p < 0.05). No significant factors were detected in multivariate analysis. Conclusions: These results suggest that early induction of AC as a result of improvement of surgical outcomes would contribute to postoperative recurrence-free survivals. 1. Uesaka et al, Lancet, 2016. 2. Matsushima et al. Anticancer Res, 2022. 3. Tomimaru et al, J Gastroenterol, 2023.

Prognostic factors for thermo-ablation of liver metastases in colon cancer: A Maltese perspective.

267 Background: Malta is a small Mediterranean archipelago with an annual colon cancer incidence of 300 patients per year and a cumulative 5-year overall survival of 58%. Despite major improvements in therapeutic strategies, colon cancer remains the third leading cause of cancer deaths locally with an annual mortality rate of circa 110 patients per year. Percutaneous thermal ablation of colorectal liver metastases involves exposure of metastatic deposits to temperature extremes using radiofrequency, microwave or cryotherapy. The role of this case series was to examine the prognostic value of clinico-pathological variables to provide insight into patient selection for ablative therapy. Methods: This retrospective analysis of 66 adult patients with colorectal liver oligometastatic disease who underwent thermal ablation between January 2014 and January 2022, reviews demographic and pathological criteria including tumour grade, presence of vascular invasion, mismatch repair and k-RAS & BRAF mutational status, CEA & Ca19.9 assay at time of treatment. Other parameters include metachronous versus synchronous disease, hepatic burden and concurrent chemotherapy. All these co-variables were analysed using the Cox Regression Hazard model to assess their impact on progression free- (PFS) and overall survival (OS). Results: For this patient cohort, the mean PFS and OS were 13.1 and 33.8 months. Our data indicates that most individuals experience progression within the first 10 months, with a gradual decline in PFS for the remaining individuals. A Ca19.9 level within normal limits (p=0.004, HR 0.157-0.700 95% CI) was related to an improved PFS but not OS. The presence of synchronous metastases (p=0.004, HR 0.168-0.715 95% CI) and ablation of one lesion (p=0.013 HR 0.191 (0.052-0.702 95 CI) were favourable prognostic markers for improved OS. k-RAS wt status was a prognostic adverse biomarker for PFS (p=0.002, HR 1.529, 6.686 95% CI). There was a paucity of data for BRAF and MMR status so these were excluded from the final analysis. No statistical survival benefit was noted for patients treated with chemotherapy, and other variables including gender, age, primary tumour sidedness, LVSI or CEA value. Conclusions: There are two surprising trends here- the paucity of survival benefit for the use of chemotherapy in conjunction with ablation and the worse outcome for k-ras wt tumours. We postulate that the absence of BRAF sub-stratification at the time of patient accrual, impacted statistical hazard. This case series suggests that the prognosis and survival of colorectal liver oligometastatic disease is multifactorial and complex, highlighting the need for further genomic and molecular insights.

Patterns of metastatic spread and survival outcomes for stage IV left-sided colon vs. rectal cancers: A real-world analysis.

75 Background: A growing body of literature has reported differences in biology, metastatic potential, and outcomes among patients with colorectal cancer based on the sidedness of their primary tumor (right vs. left). Left-sided primary tumors have comprised both colon and rectal tumors, despite differences in venous and lymphatic drainage patterns and treatment paradigms. The present work sought to investigate patterns of metastases and survival outcomes among patients with left sided colon primary tumors and rectal primary tumors. We hypothesized that these two disease sites metastasize differently and exhibit different survival patterns based on metastatic site. Methods: The National Cancer Database (NCDB) was queried for all patients with a diagnosis of metastatic left-sided colon (splenic flexure, descending colon, rectosigmoid) or rectal adenocarcinoma with known primary site and known metastatic site(s) between 2010 and 2021 using parameters outlined in the NCDB Data Dictionary. Patients with left-sided colon primaries (LP) were compared to patients with rectal primaries (RP) along clinicodemographic parameters. Incidence of metastases to the liver, lungs, bone, brain, and non-regional lymph nodes were also compared. Multivariable survival analyses were performed to analyze differences in overall survival (OS). Results: Among 84,958 patients, 51,931 (61.1%) had LP while 33,027 (38.9%) had RP. Patients with RP were less likely to have liver metastases than those with LP (79.4% vs. 90.3%), but more likely to have lung (40.7% vs. 29.2%), bone (8.3% vs. 6.0%), and distant lymph node metastases (11.3% vs. 8.6%) (all p<0.001). Compared to patients with LPs, patients with RP were less likely to undergo surgery to the primary tumor (25.1% vs. 46.3%) or any metastatic site (15.3% vs. 18.8%), more likely to receive chemotherapy for metastatic disease (80.8% vs. 75.2%), and more likely to receive radiation to the primary site (17.7% vs. 4.3%) (all p<0.001). Additionally, patients with RP had longer median OS than those with LP (27.3 months vs. 26.4 months, p<0.001). On multivariable analysis controlling for age, gender, tumor grade, RAS mutation status, MSI status, CEA level, clinical T and N category, and treatment details, patients with RP with liver metastases (HR 0.91, 95% CI 0.89-0.92), lung metastases (HR 0.85, 95% CI 0.82-0.87), and bone metastases (HR 0.89, 95% CI 0.84-0.95) (all p<0.001) demonstrated improved OS compared to those with LP. Conclusions: Patterns of metastases, treatment regimens, and, in certain instances, survival outcomes, differ among patients with stage IV left-sided colon cancer and rectal cancer. Future work evaluating the implications of sidedness in colorectal cancer as well as future staging efforts should consider assessing left-sided colon cancer separately from rectal cancer, as these demonstrate distinct clinical behavior and outcomes.

Serum mucin 5AC (MUC5AC) as a predictor of outcomes and microscopic distant metastasis in pancreatic ductal adenocarcinoma (PDA).

767 Background: Our prior studies demonstrated that tissue extracellular MUC5AC (EM) detection (EM-D) is associated with early recurrence, and serum MUC5AC (sM) levels have prognostic value in resected PDA following neoadjuvant therapy. This study evaluates the predictive value of post-operative sM before adjuvant therapy (AT). Methods: Serum samples, collected from January 2010 to June 2021 and sourced from the Ohio State University biorepository, were analyzed using enzyme-linked immunoassays with a human MUC5AC kit (NBP2-76703). Multivariate (MV) Cox regression models quantified progression-free survival (PFS) and overall survival (OS), while Wilcoxon tests compared group differences. Results: Nineteen patients had serum samples available post-operative and pre-AT. The cohort's median age was 65 years (range: 48-83), predominantly Caucasian (n=18), and 58% female. Serum was collected a median of 2 weeks (range: 1-16) after surgery, with a mean sM level of 1.1 ng/mL (range: 0.42 to 3.3). Most patients (17/19) received Gemcitabine-based therapy, one received chemoradiation, and another FOLFIRINOX. Among patients, 3 had no recurrence (Nr), 10 experienced distant metastases only (mets), 3 had local recurrence only (Lr-o), and 3 had both Lr and liver recurrence (Liv/Lr). In the MV model, incorporating sM, EM-D, and AT, higher sM levels (HR=2.83, p=0.04) and negative EM-D (HR=6.85, p=0.02) were associated with increased recurrence risk, whereas AT type did not influence recurrence. Regarding OS, sM was significant (HR=2.95, p=0.04) while other factors were not. Elevated sM levels correlated with metastasis risk (mets vs. Liv/Lr vs. Lr-o vs. Nr = 1.54 vs. 0.61 vs. 0.62 vs. 0.92, p=0.01). Patients with locoregional recurrence had significantly lower sM than those with distant metastasis and no recurrence (mets vs. Liv/Lr+Lr-o vs. Nr = 1.54 vs. 0.62 vs. 0.92, p=0.005). In a separate cohort of 10 metastatic patients (mean sM of 1.8 ng/mL, range: 0.43 to 11.2), liver metastases were linked to significantly lower sM than non-liver metastases (0.54 vs. 3, p=0.02), while peritoneal metastases were associated with higher sM levels (3 vs. 0.6, p=0.04). Conclusions: This small study suggests that sM can serve as a biomarker for assessing outcomes and recurrence sites post resection before the initial dose of AT. Elevated sM should prompt suspicion of microscopic metastases, particularly non-liver metastases.

Real-world evidence on genomic profiles and survival outcomes in patients with HER2-positive metastatic colorectal cancer.

58 Background: Patients (pts) with HER2-positive (HER2+) metastatic colorectal cancer (mCRC) represent a small, but increasingly important subgroup due to emerging HER2-targeted therapies. Although HER2 positivity is associated with resistance to anti-EGFR therapy (EGFRi), it is unclear if EGFRi or bevacizumab (BEV) is preferable as first-line (1L) therapy. Here, we offer novel evidence on the genomic profiles of pts with HER2+ mCRC and examine differences in survival between key treatment groups. Methods: This study used the US-based deidentified Flatiron Health-Foundation Medicine mCRC clinico-genomic database. The deidentified data originated from approximately 280 US cancer clinics (~800 sites of care). Included pts were 18 years or older, had evidence of stage IV or recurrent mCRC diagnosed between 01 Jan 2012 and 31 Mar 2022, and underwent tissue-based Comprehensive Genomic Profiling testing. HER2+ was defined as an ERBB2 copy number of ≥5 for diploid tumors. A doublet regimen was defined as fluoropyrimidines plus oxaliplatin or irinotecan. Data cut-off was 31 Mar 2024. Kaplan-Meier methods were used to examine real-world overall survival (rwOS) and progression-free survival (rwPFS) overall, by 1L treatment class and across key subgroups defined by tumor sidedness and genomic profile, indexed to the start of 1L with pts censored at their last EHR-recorded activity. Results: Among a cohort of 5545 pts, HER2+ was detected in 171 (3.1%) pts. Median age (years) was 57 for HER2+ vs 61 for HER2-; 69.3% of HER2+ pts were White, compared to 72.1% in HER2-. Among pts with HER2+, 31 (18.1%) had RAS mutation (mt), BRAF V600E mt, or microsatellite instability-high. ERBB2 copy number was significantly lower in pts with RAS mt or BRAF V600E mt compared to those without these mutations (p < 0.01, p = 0.045, respectively). Among pts who received 1L treatment (n=4748), rwPFS significantly differed between HER2+ (n=144) and HER2-negative (HER2-; n=4604) groups (7.6 vs 8.7 months, unadjusted HR (uHR) 1.20, p=0.04). This difference was consistent in pts with left-sided RAS/BRAF V600E wild-type microsatellite stable (MSS) mCRC and treated with 1L doublet plus EGFRi (8.7 vs 12.5 months, uHR 2.18, p=0.02; n=10 HER2+,n=117 HER2-) or 1L doublet plus BEV (8.9 vs 10.5 months, uHR 1.65, p=0.04; n=20 HER2+, n=387 HER2-). No significant rwPFS difference was observed between EGFRi and BEV in the HER2+ subgroup. rwOS showed no significant difference between HER2+ and HER2- groups (overall: 26.1 vs 24.5 months, uHR 0.94, p=0.52; n=144 HER2+, n=4604 HER2-). Conclusions: Although about 80% of pts with HER2-positive mCRC are RAS/BRAF V600E wild-type and eligible for EGFRi, no survival benefit was observed in EGFRi relative to BEV as first-line combination. While the impact of potential confounders needs to be examined in further analyses, these findings highlight the need for specific treatments for pts with HER2+ mCRC.

Molecular mechanisms of mitochondrial dynamics

κ/β‐Ga ₂ O ₃ Type‐II Phase Heterojunction

Abstract Ultrawide‐bandgap gallium oxide (Ga 2 O 3 ) holds immense potential for crucial applications such as solar‐blind photonics and high‐power electronics. Although several Ga 2 O 3 polymorphs, i.e., α, β, γ, δ, ε, and κ phases, have been identified, the band alignments between these phases have been largely overlooked due to epitaxy challenges and inadvertent neglect. Despite having similar stoichiometry, heterojunctions involving different phases may exhibit band offsets. Here, β‐Ga 2 O 3 /κ‐Ga 2 O 3 ‐stacked “phase heterojunction” is demonstrated experimentally. This phase heterojunction has a sharp and well‐defined interface, and subsequent measurements reveal an unbeknown type‐II band alignment with significant valence/conduction band offsets of ≈0.65 eV/0.71 eV. This alignment is promising for self‐powered deep ultraviolet (DUV) signal detection, necessitating an internal electric field near the junction and matching the absorption properties for effective electron–hole separation. The fabricated phase heterojunction photodetector displays a responsivity of three orders of magnitude higher at 17.8 mA W −1 , with improved response times (rise time ≈0.21 s, decay time ≈0.53 s) under DUV illumination and without external bias in comparison to the bare β‐Ga 2 O 3 and κ‐Ga 2 O 3 photodetectors, confirming the strong interfacial electrical field. This study provides profound insight into Ga 2 O 3 /Ga 2 O 3 heterojunction interfaces with different polymorphs, allowing the use of phase heterojunctions to advance electronic device applications.

Evaluating novel therapies and circulating tumor DNA (ctDNA) as a marker of response in curatively treated gastrointestinal cancers with microscopic residual disease.

TPS850 Background: ctDNA can identify the earliest sign of relapse (MRD) after curative therapies with specificities of 93-100%, positive predictive values over 95%, and median lead times of 8-9 months before radiographic relapse. ctDNA has identified a "new stage" of high-risk patients (pts) with no evidence of disease radiographically (rNED) and MRD who lack treatment (tx) strategies as, traditionally, they wait for radiographic progression of disease (POD) before starting therapies. Treating MRD is a promising strategy supported by observational studies where ctDNA clearance is linked with improved survival and on-tx kinetics predict drug efficacy . We designed a pilot investigator-initiated trial to 1) determine the feasibility of using ctDNA as a rapid signal for positive therapeutic activity and 2) obtain pilot data on the efficacy of a novel combination therapy (atezolizumab [A] + bevacizumab [B]) in eradicating MRD in previously curatively treated pts with GI cancers. Methods: We will enroll 20 pts with any-stage cancers divided over 4 cohorts (n=5 colorectal [CRC], n=5 hepatocellular/biliary tract carcinoma, n=5 upper GI, n=5 pancreatic adenocarcinoma) who have a positive Signatera ctDNA test and rNED any time after completing standard curative therapies. Pts are treated with A 1200 mg IV + B 15 mg/kg IV on day 1 of a 21-day cycle for up to 1 year with imaging every 12 weeks and serial ctDNA testing every 3 weeks. Co-primary endpoints are rates of pt enrollment in 12 months and rates of ctDNA responses at a 12-week landmark after tx initiation. Pts with ctDNA POD (ctDNA doubling on each of 2 sequential tests, any rate of rise in 3 sequential tests, or radiographic relapse) will stop while those with ctDNA complete response (CR; clearance on 2 sequential tests + ongoing rNED) or ctDNA partial/stable response (PR; not ctDNA CR or POD + ongoing rNED) will continue tx. Each cohort's Bayesian predictive probability of positive therapeutic activity will be calculated. If at least 60% of a cohort experiences ctDNA CR, it will be expanded by 5 pts. This scenario is equivalent to Simon's 2-stage Minimax design testing a null hypothesis of 20% CR vs. an alternative hypothesis of at least 60% CR at 5% alpha with 80% power. If at least 5/10 pts in an expanded cohort experience ctDNA CR, this will generate interest in developing a larger confirmatory trial to evaluate pt survival outcomes with A+B and ctDNA as a surrogate for survival. Secondary endpoints are toxicity and enrollment barriers. Exploratory endpoints are associations between ctDNA conversion and disease-free survival, tumor whole exome sequencing data, and peripheral blood immune profiles collected at baseline and on tx. Enrollment began in Q1 2023, paused in 7/2023 due to funding changes, and re-opened 8/2024 with 5 patients enrolled currently (n=4 CRC, n=1 biliary). Clinical trial information: NCT05482516 .

Tislelizumab (Tisle) combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): OS analysis results of the SYLT-023.

450 Background: Tisle is an anti-PD-1 antibody. The combination of Tisle + XELOX/FP is a first-line treatment of AGC in China. Both irinotecan and paclitaxel have also shown antitumor activity in AGC. In this phase I/II study, we explore the safety, tolerability, and efficacy of Tisle + POFI as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m 2 ): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tisle 200 mg plus oxaliplatin 85 mg/m 2 , levoleucovorin 200 mg/m 2 , and 5-FU 2400 mg/m 2 for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and RP2D. Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with GE junction cancer, 11 (73.3%) had undifferentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for DLT. One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. As of 18th Sep 2024, confirmed objective response rate in 13 subjects with measurable disease was 100% (1 CR, 12 PR) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. The median PFS was 10.51 (95% CI: 7.44, 13.58) months (versus 6.9 [5.7-7.2] months for ITT population for RATIONALE 305, ESMO 2023), the median DOR was 7.39 (95% CI: 5.34, 9.44) months, and the median OS was 14.75 (95% CI: 5.48, 24.02) months. The OS showed no significant differences between CPS ≥ 1 and CPS < 1. All subjects (100%) had AEs. Seven (n=7, 46.67%) of the 15 subjects reported grade ≥3 AEs, including neutropenia (n=7; 46.67%), leukopenia (n=3; 20%), anemia (n=2; 13.33%). Conclusions: Tisle+POFI was well tolerated and showed preliminary antitumor activity in AGC. A phase II study is ongoing. Clinical trial information: NCT05319639 .

Multi-site blinded validation of a deep learning approach for clinical-grade MSI/dMMR detection in colorectal cancer from H&E-stained pathology images.

44 Background: Testing for microsatellite instability (MSI) or mismatch repair deficiency (dMMR) is part of the diagnosis and clinical management of patients with colorectal cancer (CRC). Healthcare services recommend MSI or dMMR testing for all CRC patients to guide therapeutic choices and assist in identifying Lynch Syndrome. However, in clinical practice, high costs and the demand for timely test results, combined with the rising prevalence of CRC and a shrinking pathology workforce, present a barrier to universal adoption. This highlights the need for rapid and affordable alternatives. PANProfiler CRC (PPC) is a deep learning-based solution for detecting MSI/dMMR in CRC tumors that only requires whole slide images (WSIs) of haematoxylin and eosin (H&E)-stained tissue to provide test results. Using only WSIs, PPC offers an efficient alternative to standard testing. This study evaluates PPC's performance in a multi-site blinded setting. Methods: Blinded validation was performed using 3246 WSIs of H&E-stained CRC specimens. PPC provided outputs as "Stable", "Unstable", or "Indeterminate", with "Unstable" indicating dMMR or MSI-High, and "Stable" indicating proficient mismatch repair or non-MSI-High. "Indeterminate" was returned when PPC did not have a definitive result. PPC was evaluated by comparison to standard MSI/dMMR tests. Validation data spanned three cohorts from two sites (Table). St James’s University Hospital (SJUH), Leeds, UK, supplied Cohorts 1 and 2; Cohort 3 was sourced from Wales Cancer Biobank (WCB), UK. Blinded analysis was performed at SJUH. Results: Results are given (Table). PPC demonstrated an overall percent agreement of 93.91%, a positive percent agreement of 92.17%, and a negative percent agreement of 94.15%, returning a definitive result for 88.05% of WSIs. Conclusions: This real-world, multi-site, blinded validation study demonstrates PPC’s remarkable performance, comparable to standard tests for detecting MSI/dMMR in CRC, with high test replacement rates. In the clinical setting, PPC could significantly accelerate testing and enable timely delivery of stratified treatment plans. This accurate and cost-effective diagnostic solution promises to revolutionize MSI/dMMR testing in CRC. Blinded validation results of PPC with confidence intervals (CI) at 95%. Site Cohort Sample Size (Unstable; Stable) Overall Percent Agreement % (CI) Positive Percent Agreement % (CI) Negative Percent Agreement %(CI) Test Replacement Rate % SJUH 1 488 (78; 410) 92.79 (89.86-95.08) 90.16 (79.81-96.30) 93.24(90.11-95.62) 85.25 SJUH 2 2704 (318; 2386) 94.31(93.31-95.21) 92.31(88.48-95.18) 94.57(93.52-95.50) 88.42 WCB 3 54 (11; 43) 84.31 (71.41-92.98) 100.00(71.51-100.00) 80.00(64.35-90.95) 94.44 All 3246 (407; 2839) 93.91 (92.97-94.76) 92.17(88.82-94.78) 94.15(93.16-95.04) 88.05

Mechanism and regulation of kinesin motors

Zero‐Waste Polyanion and Prussian Blue Composites toward Practical Sodium‐Ion Batteries

AbstractClosed‐loop transformation of raw materials into high‐value‐added products is highly desired for the sustainable development of the society but is seldom achieved. Here, a low‐cost, solvent‐free and “zero‐waste” mechanochemical protocol is reported for the large‐scale preparation of cathode materials for sodium‐ion batteries (SIBs). This process ensures full utilization of raw materials, effectively reduces water consumption, and simplifies the operating process. Benefiting from the synergistic effect between the cubic Prussian blue analogs (c‐NFFHCF) and dehydrated polyanionic sulfates (m‐NFS), the generated composite exhibits promising wide‐temperature electrochemical performance and excellent practical application potential. The synergistic effect between m‐NFS and c‐NFFHCF in the composite is revealed through multiple in situ characterizations and density functional theory calculations. The proposed mechanochemical strategy can be scaled to a kilogram‐grade level, providing a sustainable method for the value‐added utilization of the by‐products during Prussian blue analogs synthesis, advancing the design of “zero‐waste” cathode materials for low‐cost practical SIBs.

Patient-reported outcomes in GI cancer: Leading change to meet the needs of the gastrointestinal cancer community.

813 Background: According to the World Health Organization International Agency for Research on Cancer, globally gastrointestinal (GI) cancers account for 1 in 4 cancer cases and 1 in 3 cancer deaths, with an estimated 4.8 million new cases and 3.4 million GI cancer deaths reported annually. Understanding the global burden of GI cancers and the importance of understanding the real-world impact of a GI cancer diagnosis, the GI Cancers Alliance (GICA) conducted a 12-month patient-reported outcomes (PRO) research initiative that included a workshop at the 2023 American Society of Clinical Oncology (ASCO) annual meeting. In addition, our PRO research was published in the Journal of Clinical Oncology (J Clin Oncol 42, 2024 suppl 3; abstr 731) with a poster presented at the 2024 ASCO Gastrointestinal Cancers Symposium. Methods: Based on our 2022-2023 PRO research of 1,122 patients highlighting the unmet needs and critical gaps in services of the GI cancers community, we developed a series of follow-up initiatives. Nutrition education 17%, biomarker/precision medicine education 19%, patient-centered care education 11% and caregiver support 16% were four of the highest levels of unmet need based on our global research. Subsequently, in 2023 we created the ‘GI Cancers Patient & Caregiver Advisory Board’ representing all GI cancers. The board hosts educational forums supporting patients and caregivers throughout the care continuum. Our pilot nutrition program launched at the 2024 ASCO annual meeting, consisting of in-person and online video components, and an extensive nutrition guide with recipes tailored for GI cancer patients. In 2024, we partnered with our gastric cancer advocates to develop ‘Test Your Biomarkers’ enhancing education and awareness of biomarker testing and precision medicine. Results: Implementing direct patient feedback from our published research, we are creating actionable solutions to unmet needs and gaps in services. Our ‘Patient & Caregiver Advisory Board’ continues to amplify the patient and caregiver voice participating in global engagement opportunities. GICA provided 10,000 nutrition guides to community oncology centers, and our online messaging reached 250,000 individuals across digital platforms and partner websites in the first three months from launch. In the first six months of the ‘Test Your Biomarkers’ campaign our messaging reached 1.7 million individuals across all digital platforms, campaign, and partner websites. Conclusions: Our PRO research provides the roadmap for new initiatives and programming to meet the needs of our GI cancer community. The GI Cancers Alliance will proceed to collaborate with our 100+ partner organizations to activate change by targeting the needs of our patient community while eliminating critical gaps in services. By doing so, we will continue to provide greater patient impact through the amplification of the patient voice.

Mortality and other outcomes of hospitalizations due to pancreatic cancer.

780 Background: Pancreatic cancer continues to be a highly fatal malignancy of the digestive system and imposes a significant financial strain on healthcare systems. Although it is often diagnosed incidentally, several risk factors have been identified, including smoking, family history, age, race, gender, and alcohol use. In this study, we aimed to examine inpatient outcomes and the healthcare burden of patients hospitalized with pancreatic cancer. Methods: Patients admitted to the hospital in 2019 and 2020 were identified using the Nationwide Inpatient Sample database and categorized into two groups based on the presence of a pancreatic cancer diagnosis (with relevant ICD-10 codes). To account for confounding factors, multivariate regression analysis was applied when calculating mortality. Statistical analyses were conducted to assess mortality rates, length of stay and hospital charges. Results: : A total of 74,584 patients met the inclusion criteria, with a mean age of 68.5 years. The majority were white (69%), while black patients made up 13% of the study population, and 49% were female (36,570 patients). Thrombosis (OR: 2.08, p < 0.001), age over 60 (OR: 1.22, p = 0.042), and being of black race (compared to white race, OR: 1.45, p = 0.001) were linked to higher mortality rates. Thrombosis was also associated with longer hospital stays (+1.9 days, p<0.001) and increased costs (+$16,003, p= 0.001). However, age over 60 (+0.26 days, p = 0.088; +$589, p = 0.833) and black race (+1.01 days, p< 0.001; +$1,493.7, p = 0.649) showed trends toward longer stays and higher costs, these were not statistically significant. On the other hand, pancreatic conditions such as chronic pancreatitis, pancreatic cysts, pseudocysts, or exocrine pancreatic insufficiency (OR: 0.589, p < 0.001), female gender (OR: 0.78, p = 0.002), and care at urban teaching facilities (OR: 0.37, p < 0.001) were associated with lower mortality. While female gender (+0.06 days, p=0.603; -$1699, p=0.448) did not significantly impact hospital length of stay or costs, pancreatic disease (+0.33 days, p = 0.031; +$10,826, p < 0.001) and being treated at urban teaching facilities (+1.8 days, p < 0.001; +$57,106, p < 0.001) were linked to longer stays and higher costs. Conclusions: Although some unmodifiable risk factors significantly increase mortality, thrombosis contributes not only to higher mortality but also to increased healthcare costs and longer hospital stays. However, it may be preventable with anticoagulation therapy. The inverse relationship between pancreatic disease and mortality could potentially be explained by more frequent imaging and earlier detection of malignancies in these patients. Analysis of factors influencing in-hospital mortality, length of hospital stay, and total charges in hospitalized patients. Data Mortality Length of hospital stay Total Charge Age>60 1.22(p=0.042) +0.26 days, p=0.088 $589, p=0.833 Race (black compared to white race) 1.45 (p=0.001) +1.01 days, p< 0.001 $1493.7, p=0.649 Female gender 0.78 (p=0.002) +0.06 days, p=0.603 -$1699, p=0.448 Treatment at urban teaching facility 0.37(p<0.001) +1.8 days, p<0.001 $57,106, p<0.001 Thrombosis 2.08(p<0.001) +1.9 days, p< 0.001 $16,003, p= 0.001 Pancreatic conditions 0.589(p<0.001) +0.33 days, p= 0.031 $10,826, p<0.001

Preclinical analysis and clinical validation to identify biomarkers for trifluridine/tipiracil (FTD/TPI) efficacy with or without bevacizumab in patients with metastatic colorectal cancer.

230 Background: We previously identified candidate biomarkers for FTD/TPI efficacy through preclinical and translational studies in patients with metastatic colorectal cancer (mCRC). Recent studies reported that FTD/TPI plus bevacizumab (BEV) improved survival compared to FTD/TPI alone. This study evaluated the clinical significance of these biomarkers in patients with refractory mCRC receiving either FTD/TPI plus BEV or FTD/TPI alone. Methods: Candidate biomarkers were selected based on our transcriptomic and cell biological analyses. We validated these biomarkers in mCRC patients treated with FTD/TPI plus BEV (cohort A) or FTD/TPI alone (cohort B). Blood samples were collected at baseline (BL), before the second cycle (2nd), and progressive disease (PD), with serum biomarker levels measured using ELISA. Change patterns were classified as ‘increased’ or ‘decreased’ from BL. To address the unbalanced distribution of baseline characteristics between cohorts, propensity score matching (PSM) was performed. Results: A total of 112 patients were included, with 34 in each cohort after PSM. Cohort A showed significantly longer overall survival (OS) (14.4 vs 6.2 months, HR 0.53, 95%CI: 0.30-0.93) and higher disease control (DC) (58.8 vs 34.4%, P=0.047) compared to cohort B. In univariate analysis, increased IL-8 or AREG at 2nd and increased IFI16 at PD were associated with poorer clinical outcomes. Grade ≥3 neutropenia (NEU) was linked to better survival in both cohorts. Multivariable analysis identified decreased AREG and Grade ≥3 NEU as better markers for progression-free survival and OS. OS was significantly longer in cohort A compared to B (12.8 vs 5.8 months, HR 0.43, 95%CI: 0.21-0.89) when IL-8 increased at 2nd. Cohort A also had longer OS compared to cohort B when EREG (12.8 vs 6.2 months, HR0.27, 95%CI: 0.11-0,65) or AREG (14.2 vs 9.7 months, HR 0.40, 95%CI: 0.17-0.95) decreased at 2nd. There was no significant interaction between the regimen and biomarkers (IL-8, EREG, and AREG) for OS. Conclusions: Our data suggest that AREG may serve as a prognostic marker for FTD/TPI efficacy. Changes in IL-8, EREG and AREG potentially contribute to the extended survival benefit of combining BEV with FTD/TPI.

Mechanisms and regulation of substrate degradation by the 26S proteasome

Relationship in gene amplification between <i>ERBB2</i> and other oncogenes: Implications for the therapeutic efficacy of trastuzumab (Tmab)-based chemotherapy (CTx) in HER2 positive gastric cancer.

468 Background: This study aimed to elucidate the molecular characteristics, focusing on the co-amplification of ERBB2 and other oncogenes, and to investigate their impact on treatment efficacy in HER2 positive GC. Methods: We conducted a phase 2 clinical trial (UMIN 00017602) evaluating the efficacy of S-1, oxaliplatin, and Tmab. Next-generation sequencing was performed using the TS-170 (Illumina). Results: 32 patients were enrolled, of whom 6 (19%) were IHC2+/FISH+. The median progression-free survival (PFS) and overall survival (OS) were 11.8 and 28.8 months. ERBB2 amplification with a cut-off value of 2.84 was present in 84.4% with a median copy number (CN) of 9.3 (range 2.4-76.6). Amplification of oncogenes other than ERBB2 , such as KRAS, FGFR2, MET, and CCNE1, was observed in 87.5%, and the median CN of the highest CNs among oncogenes other than ERBB2 was 7.8 (range 2.4-22.9). Eventually co-amplification was observed in 75%, and CNs of ERBB2 and other oncogenes showed an inverse correlation (r=0.345, p=0.058). In all tumors having ERBB2 CN ≥ 7.25 obtained by the ROC analysis, CN of ERBB2 was the highest among oncogenes ( ERBB2 dominant). Conversely, in 92% of the tumors having ERBB2 CNs &lt; 7.25, CNs of oncogenes other than ERBB2 was higher than ERBB2 ( ERBB2 non-dominant) (p&lt;0.001). Moreover, the highest CN of the oncogenes other than ERBB2 was higher in tumors with ERBB2 CNs &lt; 7.25 than that with ERBB2 CNs ≥ 7.25 (median 12.6 vs 6.4 p=0.018). Patients with ERBB2 non-dominant tumors showed significantly shorter PFS (median 6.9 vs 17.0 months, HR 6.40, p=0.001) and OS (median 14.8 vs 35.5 months, HR 2.72, p=0.016) and numerically lower response rate (63.6 vs 90.0%, p=0.151) compared with those with ERBB2 dominant tumors. Conclusions: Most patients had co-amplification of ERBB2 and other oncogenes, and the dominance of oncogene amplification in the tumor was associated with treatment efficacy of Tmab-based CTs in HER2 positive GC. These results suggest that the dominance of oncogene CNs within the tumor may determine tumor drivenness and influence treatment efficacy.

A comprehensive molecular and clinical study of patients with young-onset CRC.

235 Background: Young-onset colorectal cancer (YO-CRC), defined as colorectal cancer diagnosed in individuals under 50 years of age, has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We retrospectively reviewed 110 patients diagnosed with YO-CRCfrom our institution’s molecular database. All patients underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo Stage 4. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of &lt;0.05. Results: Among 110 patients, N=44 (40%) presented with local disease (stage 1-3), while N=66 (60%) patients presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4% respectively. Tumor mutation burden (TMB) was &lt;10 in 57% of patients, with 14% having TMB &gt;20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among the 66 Stage 4 patients, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7 - not reached). KRAS mutation was found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, P = 0.002 &lt; 0.05), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic need to improve outcomes in this high-risk group.