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Investigating survival outcomes in patients with early- vs late-onset colorectal cancer with liver metastases.

282 Background: Approximately 50% of patients with colorectal cancer develop liver metastases (CRLM). The incidence of early onset colorectal cancer (EOCRC), defined as <50 years of age at time of diagnosis, is increasing. In this study, we aim to explore the prognosis of early vs late onset colorectal cancer patients with CRLM who receive curative-intent treatment. Methods: A retrospective study was conducted to assess clinical outcomes in patients with CRLM presenting with EOCRC compared to those with late onset colorectal cancer (LOCRC). All patients underwent surgical resection and/or ablation between 2009 and 2024 at a tertiary care center. Groups were defined by patient age at the time of diagnosis of the primary tumor < 50 years versus ≥ 50 years. Demographics, tumor characteristics, and treatment modalities were compared between groups using Chi-square, independent samples t-test, and median test. Survival outcomes were assessed using Kaplan-Meier. Results: 342 patients met inclusion criteria. There were 85 (24.9%) EOCRC patients, with a median age at diagnosis of 44 years versus 63 years in the LOCRC group. EOCRC patients had fewer major medical comorbidities. EOCRC patients had a smaller proportion of right-sided (15.9% vs 29.6%, P=0.049) tumors. Rates of synchronous metastases (74.1% in EOCRC vs 72.4%, P=0.781), median size (28cm in EOCRC vs 25cm, P=0.421) median number of metastases (2 in EOCRC vs 2, P=0.385), and initial CEA levels (339.18 + 1276.48 ng/ml vs 328.87 + 2520.59 ng/ml, P=0.482) were similar between groups. However, EOCRC patients had higher rates of node-positive disease (75.6% vs 58.8%, P=0.010) and Fong Clinical Risk Scores 3-5 (57.0% vs 39.7%, P=0.009). Both groups underwent similar operative management with no differences in morbidity, but more EOCRC patients received neoadjuvant therapy (82.4% vs 66.1%, P=0.017). There were no significant differences in RAS/RAF (37.6% in EOCRC vs 34.2%, P=0.669) or TP53 (25.9% vs 34.6%, P=0.98) mutational status or microsatellite instability (stable in 74.1% in EOCRC vs 69.3%, P=0.523). Both intra- (46.5% in EOCRC vs 50.6%, P=0.535) and extra-hepatic (47.7% in EOCRC vs 38.1%, P=0.129) recurrences occurred at similar rates, with no significant differences in post-recurrence treatments received. Patients with CRLM and EOCRC had significantly worse overall survival, with a median time of 80 months versus 116 months (P=0.042). Conclusions: Despite similar clinical, pathologic, and genetic features, fewer medical comorbidities, and receiving similar medical and surgical treatments, EOCRC patients had worse median overall survival than LOCRC patients. High risk Fong Clinical Risk Scores were more common in the EOCRC group, who also received neoadjuvant therapy at higher rates. Additional research is needed to understand the differences in survival.

Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM).

23 Background: BOT is an Fc-enhanced, multifunctional anti-CTLA−4 antibody designed to improve Fc gamma receptor-mediated effector functions and extend the reach of I-O to tumor types such as MSS mCRC. Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT05608044). The study aimed to inform dose and contribution of components based on the primary endpoint of objective response rate (ORR) by RECIST 1.1 per investigator, and safety, and was not powered for statistical comparisons between arms. Methods: A total of 234 pts (intent-to-treat [ITT]) were randomized to BOT (up to 4 doses) 75 or 150 mg every 6 wks (Q6W), BOT 75 or 150 mg Q6W plus BAL 240 mg Q2W (up to 2 years), or standard of care (SOC; regorafenib or trifluridine/tipiracil). Results: Median age was 58 yrs (range 23—90), 50% male, 39% rectal, 44% 3L+, 43% ECOG 1, 58% KRAS mutant, 4% NRAS mutant, 83% prior bev, all MSS and/or pMMR by local testing. Key characteristics were well balanced with some exceptions including median time from diagnosis of metastatic disease to study entry (30 mos across arms; 45 mos SOC) and presence of peritoneal metastases (34% across arms; 42% 75 mg BOT / 240 mg BAL; 27% SOC). As of July 29, 2024, median follow-up was 9.8 mos. Key efficacy and safety data are shown (Table). Image based endpoints by blinded independent review, as well as overall survival will be reported in the future. Grade ≥3 treatment-related adverse events (TRAEs) were highest with SOC followed by BOT + BAL combination, and then BOT monotherapy, with dose dependency. Treatment-related immune-mediated diarrhea/colitis (imDC) was manageable and highest with 150 mg BOT / 240 mg BAL. No new safety signals and no treatment-related deaths occurred. Conclusions: The study met the objectives of informing dose and contribution of components. Overall ORR was higher with BOT + BAL vs BOT monotherapy. ORR was highest with 75 mg BOT / 240 mg BAL with less toxicity as compared to 150 mg BOT / 240 mg BAL. Consistent with published data, there were no objective responses in SOC whereas most responses seen with BOT + BAL were ongoing, similar to the durable responses observed in the ph1 study. These responses are differentiated from previous I-O-only combinations and SOC, supporting further investigation of 75 mg BOT / 240 mg BAL vs SOC in a planned global ph3 trial. Clinical trial information: NCT05608044 . 75 mg BOT/240 mg BAL 150 mg BOT/240 mg BAL 75 mg BOT 150 mg BOT SOC ITT (Randomized) n=62 n=61 38 n=40 n=33 ORR, % (95% CI) 19%(10—31) 8%(3—18) 0%(0—10) 8%(2—20) 0%(0—11) Safety (Treated) n=62 n=60 n=37 n=39 n=21 Any Grade TRAEs, n (%) 54 (87) 59 (98) 28 (76) 31 (79) 19 (90) Grade ≥3 TRAEs, n (%) 22 (35) 25 (42) 8 (22) 9 (23) 12 (57) Any Grade Treatment-related IMDC, n (%) 19 (31) 28 (47) 13 (35) 12 (31) 0 (0)

Clinical outcomes and molecular characteristics of patients with locoregional ampullary carcinoma.

732 Background: Ampullary carcinoma (AC) is a rare malignancy arising from the ampulla of Vater which has a more favorable prognosis compared to other pancreatic malignancies. Current guidelines favor surgical resection followed by adjuvant therapy for average risk patients (pts), however the type of regimen as well as other perioperative treatment modalities are still being explored. The objective of this retrospective study aims to provide insight into the management of locoregional disease. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) denoting AC between 2010 to 2024 were searched using Mayo Data Explorer and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) data were collected. Statistical analysis was conducted using SAS version 9.04. Results: A total of 137 pts (62% male, n = 85) were identified with median age 66 years old. Histologic subtypes were 54% pancreatobiliary (44/81), 40% intestinal (32/81), 6% mixed (5/81), with 56 pts unknown. Stages at diagnosis were 81% resectable (111/137), 11% locally advanced (15/137), and 8% metastatic (11/137). Nearly all (93%, n = 103/111) pts with localized disease had resection with a 97% R0 resection rate (100/103). Majority (68%, n = 75/111) of resectable pts had perioperative chemotherapy with 5-FU or gemcitabine-based regimens (24%, n = 18/75 neoadjuvant vs. 76%, n = 57/75 adjuvant). Perioperative chemoradiation was given in 17% (19/111) of pts. At median follow up of 30.5 months, recurrence rates were 40% (41/103), primarily to the liver (18/41). Median recurrence free survival (RFS) was 29.3 months (95% CI 24.7 – NE). Median overall survival (OS) has not been reached. The 5-year RFS and OS rates were 0.37 (95% CI 0.25 - 0.55) and 0.69 (95% CI 0.58 - 0.82), respectively. Univariate analysis showed no difference in OS with the addition of neoadjuvant or adjuvant chemotherapy or chemoradiation. Somatic NGS testing showed pathogenic mutations in 90% of pts (63/70): 57% KRAS (36/63; 44% G12D, 19% G12V, 8% G12C, 8% G12D, 19% others); 13% homologous recombination (HR) (8/63); 6% ERRB2 /Her2 amplification (4/63), and 5% mismatch repair (MMR) (3/63). Conclusions: AC has a favorable prognosis in resectable pts. However, high recurrence rates indicate the need for better systemic therapies and improved selection of pts who would benefit from these treatments. Future research should focus on refining perioperative strategies to enhance outcomes and reduce recurrence.

Impact of prior nivolumab use on the efficacy of second-line taxane-based chemotherapy in advanced gastric or esophagogastric junction adenocarcinoma.

352 Background: Taxane-based chemotherapy remains the standard second-line treatment after first-line treatment including anti-PD-1 antibody therapy for patients with advanced gastric or esophagogastric junction adenocarcinoma (GA/EGA). The CheckMate 649 trial suggested that prior use of nivolumab in the first-line setting was associated with longer progression-free survival (PFS) with subsequent treatment. However, there have been few reports on the difference in efficacy of taxane-based chemotherapy as second-line treatment with or without prior nivolumab use in the real-world setting. Methods: We retrospectively reviewed the medical records of patients with advanced GA/EGA who received solvent-based paclitaxel or nanoparticle albumin–bound (nab)-paclitaxel chemotherapy regimens as second-line treatment after first-line platinum-based chemotherapy between January 2018 and August 2024. We divided the patients into two groups: those who received nivolumab with the first-line chemotherapy (Nivo group) and those who did not (non-Nivo group). PFS and overall survival (OS) were estimated using the Kaplan–Meier method and compared between the two groups using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 115 patients were included: 27 patients in the Nivo group and 88 in the non-Nivo group. Patient backgrounds did not differ significantly in terms of age (median 67/67 years), sex (male 59%/57%), performance status (PS; ≥2 11%/15%), site of primary tumor (EGA 11%/9%), number of metastatic sites (≥3 33%/18%), and ramucirumab use (yes 82%/82%). For the taxane regimens, nab-paclitaxel-based treatment was significantly more common in the non-Nivo group (11.1% /55.7%, p<0.001). There was a tendency toward longer PFS in the Nivo group compared with the non-Nivo group (median 4.2 months [95%CI 2.8-6.0] vs. 2.3 months [95%CI 2.0-3.0], HR 0.65 [95%CI 0.40-1.03]; p=0.067.) The objective response rate was numerically higher in the Nivo group compared with the non-Nivo group (29.4% vs. 17.6%, p=0.315). OS was not significantly different between the Nivo and non-Nivo groups (median 9.6 months [95%CI 4.9-NA] vs. 6.6 months [95%CI 5.5-10.8], HR 0.92 [95%CI 0.52-1.64]; p=0.785). In the non-Nivo group, 64 patients (73%) received subsequent chemotherapy, and 63 patients (72%) received nivolumab. Multivariate analysis identified prior use of nivolumab was a favorable prognostic factor for PFS (HR 0.55 [95%CI 0.31-0.97]; p=0.039). However, prior use of nivolumab did not show a significant benefit for OS (HR 1.09 [95% CI: 0.56-2.13]; p = 0.802). Conclusions: Prior use of nivolumab in first-line platinum-based chemotherapy had a positive impact on PFS with taxane-based second-line chemotherapy in advanced GA/EGA.

The impact of locus of control on somatic and psychological profiles of patients with irritable bowel syndrome engaging in aerobic exercise

Magnesium-dependent-protein phosphatase 1B regulates the protein arginine methyltransferase 5 through the modulation of myosin phosphatase

Real-world analysis of the impact of timing of biomarker testing on first-line treatment choice in patients with metastatic colorectal cancer in British Columbia.

253 Background: The treatment landscape for metastatic colorectal cancer (mCRC) has evolved significantly, shifting from chemotherapy alone to more personalized approaches that include immune checkpoint inhibitors and targeted therapies. Treatment decisions in mCRC are driven by molecular characteristics, and current guidelines recommend a minimum standard of biomarker testing, such as mismatch repair (MMR) status, and RAS and BRAF mutations, at the time of metastatic disease diagnosis to guide treatment selection. This study aimed to assess the real-world implementation of biomarker testing in a contemporary cohort of mCRC patients in British Columbia (BC) and its impact on treatment decisions by medical oncologists. Methods: We conducted a retrospective chart review of patients who received first-line systemic therapy for mCRC in BC between January 2022 and December 2023. Patient demographics, tumour characteristics, and treatment details were obtained from the BC Cancer provincial pharmacy database. Medical oncology documentation and pathology reports were reviewed to determine the availability of biomarkers, including MMR status, and RAS and BRAF mutations (OncoPanel), at the time of initial medical oncology consultation, and to assess how these results influenced treatment plan. Results: To date, 71 eligible patients have been identified, with data collection ongoing. Of these, 82% had proficient MMR status, 17% had deficient MMR status, and 1% had incomplete data. RAS mutations were present in 55% of cases, while BRAF mutations were found in 21% (Table). At the time of the initial medical oncology consultation, MMR status was unavailable in 14 patients (20%), two of whom were later found to have deficient MMR status. OncoPanel results were unavailable for 63 patients (88%) at the time of the initial consultation, and in 16 of these cases (25%), the systemic therapy plan was modified once the results were received. Conclusions: Even in contemporary practice with publicly funded biomarker testing, the results for RAS and BRAF mutations were not available at the time of initial medical oncology consultation for most patients. Biomarker testing is an essential tool for guiding therapeutic decisions in mCRC. This subsequently led to treatment plan changes in one-quarter of cases after results were received. These findings highlight the importance of timely biomarker testing to ensure optimal and efficient treatment decision-making for all mCRC patients. Metastatic colorectal cancer biomarker testing. Proficient/WT Deficient/Mutated Incomplete MMR 58 12 1 RAS 29 39 3 BRAF 53 15 3

Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC): NEST clinical trial update.

207 Background: Checkpoint inhibitors (CPI) have been transformative for localized dMMR CRC (microsatellite instability-high [MSI-H]), but not for localized pMMR CRC (microsatellite stable [MSS]). The combination of BOT, a novel Fc-enhanced multifunctional CTLA-4 antibody, and BAL, an anti-PD-1 antibody, has demonstrated significant activity in metastatic CRC. We examined this novel dual CPI therapy in patients with MSI-H and MSS localized CRC. Methods: This is a single arm trial of neoadjuvant BOT 75 mg/m 2 (day 1) and BAL 240 mg/m 2 every 2 weeks x2 (NEST1) or x4 (NEST2) in patients with localized CRC who were candidates for surgery. The primary endpoint was major pathologic response (MPR), defined as ≥90% pathologic tumor regression. The 95% confidence interval (CI) was computed based on exact method for binomial distribution. Results: NEST1 (n=12: 9 MSS / 3 MSI-H) accrued from 3/21/23 to 9/25/23 and NEST2 (n=14: 13 MSS / 1 MSI-H; 2 MSS patients had synchronous CRC) accrued from 2/15/24 to 5/6/24; 2 patients in NEST1 were not evaluable (1 with rectal cancer not resected [ypT0N0 on local excision] and 1 patient with occult lung metastasis). In total, 7 MSS CRC tumors were evaluable from NEST1 and 15 from NEST2; and 3 MSI-H tumors were evaluable from NEST1 and 1 from NEST2, leaving a final evaluable study population of 24 patients (20 MSS / 4 MSI-H) and 26 tumors (22 MSS / 4 MSI-H). The Table provides pathologic response rates across NEST1, NEST2, and MSI-H. With a median follow-up of 13.1 months (NEST1) and 4.8 months (NEST2), no patients have recurred and ctDNA testing remains negative. No grade 4 toxicities were observed and the only treatment-related grade 3 toxicity was diarrhea/colitis in 15% and fever in 4%. Treatment-related grade 2 diarrhea/colitis occurred in 8%, grade 2 fever in 15%, and grade 2 fatigue in 4% of patients. Diarrhea/colitis resolved in all cases with steroids ± anti-TNFα therapy. All patients underwent laparoscopic resection, with 1 conversion to open. No surgeries were delayed due to treatment-related adverse events. Median length of stay was 2 days (range 1-14). Translational data including pathologic evaluation of tumor infiltrate and response will be presented. Conclusions: Neoadjuvant BOT/BAL is safe, with no delays to surgery, and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date. The MPR and pCR rate improved with extended time to surgery. Clinical trial information: NCT05571293 . Pathologic response to neoadjuvant BOT/BAL in localized CRC. Pathologic Response NEST 1n=7 MSS tumors NEST 2n=15 MSS tumors MSI-H (3 NEST1, 1 NEST2) 100% (CR%, 95%CI) 1 (14%, 0.4-58%) 6* (40%, 16-68%) 3** (75%, 19-99%) ≥ 90% (MPR%, 95%CI) 2 (29%, 4-71%) 7 (47%, 21-73%) 4^ (100%, 40-100%) ≥ 50% 4 (57%) 9 (60%) 4 (100%) Median days to Surgery (range) 29 (21-37) 57 (45-104) 46 (34-78) *2 with carcinoma in situ , no tumor bed. ^MPR was in NEST1. **1 was rectal.

Nimotuzumab combined with chemotherapy plus immunotherapy as first-line treatment for advanced esophageal squamous cell carcinoma.

344 Background: Esophageal squamous cell carcinoma (ESCC) is the primary type of esophageal cancer with poor prognosis in China. Chemotherapy plus immunotherapy as first-line standard treatment has limited benefit in advanced ESCC patients. Nimotuzumab, a humanized anti-EGFR antibody, exhibited favorable efficacy in advanced ESCC with good safety profile. We explored the efficacy and safety of nimotuzumab as first-line therapy for patients with advanced ESCC. Methods: In this retrospective study, patients were aged ≥ 18 years with histologically diagnosed advanced ESCC, ECOG of 0-3, given nimotuzumab (400 mg, Q3W) combined with chemotherapy (paclitaxel: 300-400mg and platinum: 400-500mg or tegafur: 60mg/bid, Q3W) plus immunotherapy (PD-(L)1: 200-240 mg, Q3W). They assigned into two groups: metastasis group and locally advanced group. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR) and safety. Results: As of July 2024, 58 patients were enrolled (metastasis group: n=20, locally advanced group: n=38). The median age was 59.5 years (range: 44-80). The median follow-up was 32.59 months (95% CI: 23.0, 36.7). The ORR was 74.1% (95% CI: 0.6, 0.8). Survival analysis showed that the 1-year OS was 79.16% (95% CI: 64.5, 88.3) and 2-year OS was 57.38% (95% CI: 41.3, 70.5), 1-year PFS and 2-year PFS was 64.41% (95% CI: 49.4, 76.0) and 32.80% (95% CI: 19.7, 46.5), respectively. The median OS (mOS) was 31.01months, the median PFS (mPFS) was 17.84 months. Nimotuzumab plus chemotherapy and immunotherapy displayed a favorable survival outcomes both in metastasis group and locally advanced group with OS (1-year OS: 77.76% and 80.37%; 2-year OS: 62.21% and 55.91%) and PFS (1-year PFS: 53.46% and 69.99%; 2-year PFS: 25.06% and 36.66%), the mOS was not reached and 31.01 months, mPFS was 18.27 months and 16.69 months, respectively. There were 74.1% patients occurred grade 1-2 adverse events (AEs), and 13.8% occurred grade 3-5 AEs. The most common AEs included nausea (60.3%), myelosuppression (51.7%), leukopenia (41.4%), thrombocytopenia (29.3%), and neutropenia (24.1%). No serious treatment-related AEs or death recorded. Conclusions: This study demonstrated a favorable survival profile and acceptable toxicity in first-line treatment of advanced ESCC patients with nimotuzumab regimen. Further prospective study needed to certify in order to benefit more patients.

Effect of homologous recombination deficiency on survival in patients with metastatic colorectal cancer with KRAS mutations.

252 Background: Metastatic colorectal cancer (mCRC) patients exhibit intertumoral genetic heterogeneity, making it difficult to apply precision medicine. In the molecular genetic profile of mCRC, there are relatively few other gene alterations that significantly impact treatment decisions beyond KRAS and MSI status. We aim to investigate the prognostic impact of Homologous recombination deficiency (HRD)-related genetic alterations in mCRC patients, focusing on how mutation status influences on patient outcomes. Methods: The analysis included 364 mCRC patients who underwent comprehensive genomic profiling at Korea University Anam Hospital from Sep. 2016 to Dec. 2020. HRD was defined by the presence of pathogenic variants in genes including ATM, ATR, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, MRE11A, PALB2, RAD50/51. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Multivariate Cox proportional hazards regression analyses were performed to assess the independent impact of HRD status. Results: Of the total cohort, 181 of patients (49.78%) harbored KRAS mutations. HRD gene mutations were identified in 38 of patients (10.4%) of patients, predominantly in ATM, BRCA 1/2, ARID1A genes. KRAS-HRD co-mutations were present in 18 of patients (4.7%). There is no significant difference in HRD status between the KRAS mutant and wild-type groups (p=0.73). While first-line treatment PFS was independent of KRAS mutational status (wt 10.8 vs. mut 9.6 months, p=0.31), it was significantly associated with HRD gene mutation status (16.2 vs. 10.6 months, p=0.001). OS was similar with KRAS mutations (34.7 vs. 32.9 months, p=0.72) and HRD mutations (34.7 vs. 39.1 months, p=0.73). However, patients with both KRAS and HRD mutations had significantly worse OS compared to those with either KRAS and HRD mutation (21.3 vs. 36.7 vs. 65.3 months, p=0.034, <0.001). A multivariate analysis was performed to evaluate factors affecting OS in mCRC patients. Among the variables, metastasectomy, which 44% of patients underwent, had a significantly low HR (=0.28) and would contributed to more favorable outcomes when evaluating OS. Neither KRAS nor HRD mutation alone was a significant prognostic factor, but their co-mutation was significantly associated with poor survival (HR=2.39, p=0.048). Conclusions: Poor OS in patients with KRAS-HRD co-mutations, despite metastasectomy, highlights the need for additional treatment strategies beyond surgery. Future studies with larger sample sizes and analyses stratified by metastasectomy status are necessary to strengthen these findings. Variables HR (95% CI) p-value Metastasis site Liver 2.16 (1.60 – 2.92) < 0.001 Peritoneum 1.52 (1.01 – 2.11) 0.013 Bone 1.69 (0.96 – 2.97) 0.067 Metastasectomy 0.28 (0.47 – 0.74) < 0.001 KRAS 1.03 (0.77 – 1.37) 0.826 HRD 0.75 (0.40 – 1.41) 0.367 Co-mutation 2.39 (1.01 – 5.66) 0.048

Changes in optic nerve head microvasculature following disc hemorrhage absorption in glaucomatous eyes

Abstract This study investigated the changes in optic nerve head (ONH) microvasculature, circumpapillary retinal nerve fiber layer (cpRNFL) thickness, and visual field (VF) sensitivity following the absorption of optic disc hemorrhage (DH). Intradisc vessel density (dVD) was calculated using a 3 × 3 mm optic disc scan in 60 eyes of 60 patients with primary open angle glaucoma and DH who had undergone two or more swept-source optical coherence tomography angiography exams. Clinical parameters at the time of DH occurrence and after absorption, as well as those between the subgroups based on DH recurrence and location, were compared. Linear regression analysis was performed to identify factors associated with changes in cpRNFL thickness in the DH-affected quadrant. Mean dVD, cpRNFL thickness, and VF sensitivity significantly decreased after DH absorption (all P < 0.05). The reduction in dVD was more pronounced in eyes with recurrent DH compared to those with a single episode (P = 0.032). Eyes with DH occurring within or at the margin of the disc cup showed a greater dVD reduction than those with DH occurring outside the disc cup (P = 0.049). The reduction in cpRNFL thickness in the DH-affected quadrant correlated with dVD reduction in the same quadrant (β = 0.370, P = 0.013) and DH recurrence (β = -2.617, P = 0.033). This finding suggests that DH pathogenesis may be associated with changes in optic disc vasculature, contributing to glaucomatous progression.

Familial Alzheimer’s disease mutations in amyloid precursor protein impair calcineurin signaling to NMDA receptors

Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal, and non-small cell lung cancers with KRAS G12V mutations.

TPS792 Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking. FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A*11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A*11+ adult based on a strong pre-clinical dataset. Methods: This is an ongoing, investigator-initiated, phase 1, first-in-human, single-center, dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A*11-restricted KRAS G12V mutation. Dose modification is guided by the Bayesian Optimal Interval design (BOIN). Patients are initially treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 10 9 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 10 9 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least one line of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, and -4 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. The study is actively recruiting. Clinical trial information: NCT06043713 .

Preliminary safety and efficacy of upfront FOLFOXIRI and bevacizumab with cadonilimab in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer: A multicenter phase II study (SYLT-026).

198 Background: The AtezoTRIBE phase II trial reported that adding Atezolizumab to upfront FOLFOXIRI plus Bevacizumab significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, the improvement in OS was modest within the pMMR/MSS subgroup (HR, 0.80 [80% CI, 0.63–1.02]; P = 0.117) [1]. Cadonilimab, a humanized bispecific antibody targeting both PD-1 and CTLA-4, may offer enhanced therapeutic benefits. Therefore, this study aims to investigate whether the addition of Cadonilimab to upfront FOLFOXIRI plus Bevacizumab improves efficacy while maintaining safety in patients with pMMR/MSS mCRC. Methods: This multicenter, single-arm phase II study enrolled treatment-naive patients with pMMR/MSS mCRC, aged 18–75, who had at least one measurable lesion according to RECIST 1.1, an ECOG performance status (PS) of 0–2, and adequate organ function. Patients with dMMR/MSI-H tumors or prior immunotherapy were excluded. Eligible participants received FOLFOXIRI (irinotecan 165 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2400 mg/m² as a 48-hour infusion), along with Bevacizumab (5 mg/kg), and Cadonilimab (6 mg/kg). Treatment was administered for up to twelve 14-day cycles, followed by maintenance therapy with fluoropyrimidine and Bevacizumab plus Cadonilimab for up to 52 weeks, or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were equally enrolled, with 10 having liver metastases and 10 without. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of August 30, 2024, 20 patients were enrolled, with a median age of 65.5 years (range: 33–74). Of these, 40% had an ECOG PS of 1 or 2, 55% had three or more metastatic organs, and 7 patients (35%) had RAS or BRAF mutations. The median follow-up was 5.0 months. Fifteen patients underwent at least two imaging assessments, revealing a confirmed ORR of 100% (15/15) and a disease control rate (DCR) of 100%. The median progression-free survival (PFS) and OS data were not yet mature. All 20 patients experienced treatment-emergent adverse events, most of which were grade 1 or 2. One patient (5%) discontinued treatment due to immune-mediated colitis. The most common grade 3/4 adverse events included neutropenia (55%), leukopenia (15%), infusion reactions (5%), dermatitis (5%), colitis (5%), anemia (5%), elevated ALT (5%), and diarrhea (5%). No new safety signals were identified. Conclusions: In conclusion, Cadonilimab in combination with FOLFOXIRI and Bevacizumab demonstrated promising efficacy and a manageable safety profile as a first-line treatment for patients with pMMR/MSS mCRC. Further investigation in larger trials is warranted. 1. Antoniotti, et al, J Clin Oncol, 2024. Clinical trial information: NCT05839470 .

Serial monitoring of circulating tumor DNA as a marker of response to immune checkpoint blockade in MSI-H gastrointestinal tumors.

273 Background: Microsatellite instability- high (MSI-H) tumors have high rates of response to immune checkpoint blockade (ICB) with prolonged durability of response. However, predicting who will have a response is difficult and there are limitations to radiographic evaluation of response. As circulating tumor DNA (ctDNA) offers a noninvasive approach to monitoring response and therapeutic efficacy, we sought to correlate ctDNA change with response to ICB in MSI-H gastrointestinal (GI) tumors. Methods: We conducted a retrospective study of MSI-H GI patients receiving ICB who underwent serial ctDNA sequencing. Tissue-informed ctDNA monitoring utilized comprehensive genomic profiling results of pre-treatment tumor tissue from a clinical trial assay based on FoundationOne CDx, a variant selection algorithm to exclude non-tumor variants, and multiplex PCR of up to 16 patient-specific variants to detect and quantify ctDNA. ctDNA changes were correlated with radiographic response. Results: A total of 20 patients with MSI-H tumors were evaluated including 17 colon, 2 small bowel, and 1 pancreatic. For 12 patients, it was the first exposure to ICB whereas 8 had previously progressed and were being rechallenged with ICB. Response was seen in 9 patients with a best overall response (BOR) of complete response (CR) in 4 and partial response (PR) in 5 while 5 showed stable disease (SD) and progression (PD) in 6. All patients had baseline ctDNA samples and at least 1 serial ctDNA after ICB initiation (median number of samples was 3). The mean time from baseline to first on-treatment sample was 30 days (range 13-64 days). 4 patients had undetectable ctDNA levels at baseline and remained undetectable on treatment. Of the 16 that had detectable ctDNA at baseline, 11 had a decrease in ctDNA levels at 1st on-treatment sample and 5 had an increase. The mean percent change of ctDNA at 1st on-treatment for those who had a response (CR + PR) was a 76% decrease while the mean percent change for those with SD was a 7% increase and for those with PD a 72% increase (p=0.05). Of the 6 patients with BOR of PD, 5 had an increase in ctDNA and 1 had undetectable levels at baseline. Of the 5 patients with BOR of SD, 2 had a decrease, 1 had an increase, and 2 were undetectable at baseline. Duration of SD did not correlate with initial ctDNA response. Conclusions: Early ctDNA change correlated with response in MSI-H GI tumors suggesting that serial ctDNA monitoring may provide early indication of response even prior to radiographic evaluation.

Adequate racial and ethnic representation in cancer clinical trial enrollment: Real-world evidence from an NCI-designated cancer center in a minority-majority county.

803 Background: Despite strides to increase diversity in clinical trial enrollment, significant racial and ethnic disparities persist. This limits the generalizability of clinical trial data and consequently the application of novel therapeutics for diverse populations. We hypothesized that enrollment of underrepresented minorities (URM) is feasible, with improved access to clinical care and a tailored clinical trial portfolio addressing the unmet needs in URM. Methods: A retrospective cohort study was conducted at the University of California Irvine Chao Comprehensive Cancer Center (CFCCC), an NCI-Designated cancer center located in Orange County (OC), CA (a minority-majority county). Clinical trial enrollment data from 2015-2023 through the CFCCC clinical research database was included. Collected data on patient demographics, tumor types, and trial enrollment was compared to data provided by the NIH SEER reports in both OC and United States. Results: Between 2015-2023, 2317 subjects were enrolled in clinical trials at CFCC. Demographics were as follows: White, Asian, Black, American Indian/Alaska Native, mixed/unknown race (66.4%/20.1%/2.4%/0.7%/0.7%/9.3%). Non-Hispanic vs Hispanic ethnicity (77.8%/20.5%). Female vs Male sex (47.6%/52.3%). Age <70 vs >70 years (73.3%/26.7%). Study Phase: Phase I/II (35.6%), Phase II (25.4%), Phase II/III (2.8%), Phase III (26.6%), and Phase IV (0.3%). Study sponsor: Industry (61.1%), Institutional (23.6%), National (14.8%), and Externally Peer Reviewed (0.3%). Most notably, the Asian enrollment (20.1%) and Hispanic enrollment (20.6%) exceeded demographic representation of Asians (17%, RR 1.18) and Hispanics (19%, RR 1.07) at CFCCC. Lastly, Asian patients enrolled at significantly higher rates in lung and liver cancer trials, while Hispanic patients and Black patients enrolled at higher rates in breast cancer and prostate cancer trials respectively. Conclusions: Our results demonstrate that robust URM clinical trial enrollment, particularly among Asian and Hispanic populations, is feasible at an NCI-designated cancer center despite minority-specific barriers. These findings suggest that minority populations can be optimally enrolled in clinical trials when these trials are accessible and tailored to the population at hand. Further research is necessary to investigate factors that influence clinical trial participation in the pursuit of equitable cancer care.

Effect of thermal stress on the life of DC link capacitors for smart grid

Acute heat stress upregulates Akr1b3 through Nrf-2 to increase endogenous fructose leading to kidney injury

Performance of a blood-based test for colorectal cancer screening adjusted to the US census age and sex distribution.

18 Background: Despite availability of various screening options, nearly 40% of eligible U.S. adults were not up to date with the colorectal cancer (CRC) screening. Blood-based testing offers a promising complementary approach and may enhance patient adherence among unscreened individuals. In the PREEMPT CRC study, we evaluated clinical performance of an investigational blood-based screening test for detecting molecular signals of advanced colorectal neoplasia (ACN) in an average-risk population. Freenome blood-based CRC screening test met all primary endpoints demonstrating 79.2% sensitivity for CRC, 91.5% specificity for ACN, 90.8% negative predictive value (NPV) for ACN and 15.5% positive predictive value (PPV) for ACN. Sensitivity for advanced precancerous lesions (APLs) was 12.5%. To evaluate how the test would perform in the standard U.S. population, an analysis of test performance weighted to the U.S. census sex and age distribution was prespecified and performed. Methods: Between May 2020 and April 2022, the study enrolled participants aged 45-85 at average risk for CRC. Enrolled participants had a blood drawn before the bowel preparation for the standard of care screening colonoscopy (CS). CS and applicable histopathology reports underwent central pathologist review. Blood samples were processed blind to clinical findings. Primary endpoints included sensitivity for CRC, specificity for ACN, NPV for ACN and PPV for ACN. A secondary endpoint was sensitivity for APLs. Results: A subset of 32,731 sequentially enrolled participants were included in the clinical validation cohort. Out of those, 27,010 (82.5%) had evaluable blood samples and CS. The median age of the evaluable participants was 57.0 years, and 55.8% were women versus 50.5% in the U.S. Census. Age distribution included 11.0% participants in the 45-49 age group versus 15.3% in the U.S. Census, 33.0% in the 50-54 age group versus 15.6%, and 32.3% in the 55-64 age group versus 32.3%, 20.8% in the 65-74 age group versus 24.3%, 3.0% participants aged 75 or older versus 12.5%. After performance was weighted to match U.S. Census sex and age distributions, sensitivity for CRC was 81.1% (95% CI 71.3%-88.1%), specificity for those without ACN was 90.4% (95% CI 90.0%-90.7%), NPV for those without ACN was 90.5% (95% CI 90.5%-90.7%), and PPV for ACN was 15.5% (95% CI 13.8%-16.2%). Sensitivity for APL was 13.7% (95% CI 12.4%-15.0%). Conclusions: PREEMPT CRC is the largest study evaluating a CRC screening blood-based test to date. The study successfully met all primary endpoints, demonstrating acceptable clinical performance of the investigational blood-based test. The U.S. census sex-age adjusted clinical performance estimates showed improvement in CRC and APL sensitivity. This blood-based test may provide a convenient and effective option for CRC screening in the average-risk U.S. population. Clinical trial information: NCT04369053 .

Clinical outcomes of malignant portal vein thrombosis in patients with pancreatic cancer: A retrospective analysis.

784 Background: Portal vein thrombosis (PVT) includes portal vein blockage with a blood clot. Recently, there has been an increase in the incidence of PVT with solid malignancy. Portal vein thrombosis (PVT) is a potentially high-risk complication associated with pancreatic cancer. A hypercoagulable state is frequently observed in pancreatic cancer, with the incidence of thromboembolic events reported to range between 17% and 57%. We wanted to analyze the prevalence of PVT in patients with pancreatic cancer and its impact on hospital outcomes. Methods: We performed a retrospective analysis using the National Inpatient Sample Database (NIS) from 2018 to 2020. Patients with the primary diagnosis of pancreatic cancer and age >18 were diagnosed using ICD-10 codes. They were then stratified based on the presence of portal vein thrombosis. The Chi-square test was used to analyze categorical variables, and the T-test was used to analyze continuous variables. The confounders were adjusted using multivariate regression analysis. We observed the outcomes on mortality, length of stay, and total hospital charges. Results: A total of 336894 patients were diagnosed with a primary diagnosis of pancreatic cancer. Of them, 0.04% (n=13475 patients) were diagnosed with metastatic portal vein thrombosis. The mean age of the patients was 64 years (p <0.001). Out of them, 47% of patients were female. In comparison, the remaining 53% were male (p-value: 0.5). Almost 71% f the patients were White, 13% were African American and 0.09% were Hispanics (p-value <0.001). The presence of PVT was found to be associated with increased mortality in pancreatic patients (aOR 1.6, p-value <0.001) as compared to those without PVT. It was also associated with an increase in mean length of stay (LOS)(7.1 vs 6 days, p-value 0.009) and total hospital charges ($86,000 vs $73794, p-value <0.001). It was also observed that the presence of PVT was associated with increased odds of secondary outcomes, including venous thromboembolism (p-value <0.001), stroke (p-value 0.5), and acute kidney injury (p-value <0.001). Conclusions: The presence of portal vein thrombosis (PVT) in pancreatic cancer patients is associated with significantly worse hospital outcomes. These findings emphasize the importance of early detection and aggressive management of PVT in this patient population. Comparison of hospital outcomes between pancreatic cancer patients with and without portal vein thrombosis. Hospital Outcomes Pancreatic cancer patients with PVT Pancreatic cancer patients without PVT Adjusted Odds Ratio (aOR) 95% CI P-value Mortality 9.4% (n=1310) 7.2% (n=23300) 1.3 0.3-1.5 <0.001 LOS (Days) 7.1 6.0 1.6 1.1-2.3 0.009 Venous thromboembolism (VTE) 11% (n=1645) 4.2% (n=13734) 2.9 2.5-3.3 <0.001 Stroke 0.03% (n=5) 0.02 (n=79) 1.8 0.2-14 0.5 Acute Kidney Injury 21% (n=2970) 20% (n=68499) 1.2 1.09-1.3 <0.001