OBJECTIVE:To leverage the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (an Australian cancer database) to explore the ideal timing and sequence of therapies and the factors influencing these decisions in colorectal cancer (CRC) patients with liver-only metastases to inform contemporary decision-making and future trials. STUDY TYPE:Retrospective registry-based cohort study using the TRACC registry. SETTING AND PARTICIPANTS:Consecutive patients with liver-only metastatic CRC enrolled in the TRACC registry. MAIN OUTCOME MEASURES:To explore cancer biology, intended treatment at presentation, actual treatment received and the resultant outcomes for early-onset CRC (EOCRC) (≤ 50 years) and late-onset CRC (LOCRC) (> 50 years) patients with liver-only metastases from a real-world perspective. RESULTS:Between 14 January 2009 and 2 September 2024, 1691 patients with liver-only metastatic CRC were enrolled in TRACC. These included 276 EOCRC patients (16.3%) and 1415 LOCRC patients (83.7%). In the EOCRC subset, there were more females (48.2% vs. 34.5%, p < 0.001), less comorbidity (Charlson comorbidity index score 0, 90% vs. 59%, p < 0.001), more left-sided primaries (76.1% vs. 65.7%, p < 0.001), more synchronous disease (53.3% vs. 42.1%, p < 0.001) and BRAF V600E mutations (13.9% vs. 8.1%; p = 0.010). Overall, EOCRC patients had a longer median survival compared with LOCRC patients (3.20 vs. 2.38 years, p < 0.001). For the 662 patients (39.1%) undergoing liver resection, median survival was 5.99 years in EOCRC patients and 5.88 years in LOCRC patients. For all patients and for those undergoing resection, respectively, B-Raf proto-oncogene, serine/threonine kinase (BRAF) (hazard ratio, 1.97 [p < 0.001] and hazard ratio, 2.25 [p < 0.001]) and Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations were associated with worse outcomes (hazard ratio, 1.29 [p < 0.001] and hazard ratio, 1.34 [p = 0.003]). CONCLUSION:Differences in sex distribution, BRAF mutation rates, primary tumour site and overall survival suggest biological differences between EOCRC and LOCRC. Liver resection was associated with improved survival in LOCRC, with the benefits of all therapies varying depending on age, primary tumour site and whether patients presented with synchronous or metachronous liver-only metastases.

Feature selection is a critical step in electronic health record (EHR)-based predictive modeling, where input variables are often high-dimensional, sparse, noisy, and redundant. Large feature sets not only increase computational burden and overfitting risk, but also make model interpretation difficult, leading to limited usefulness in clinical settings. In this study, we focus on diagnosis-related features and compare five feature selection paradigms for opioid use disorder (OUD) prediction: recurrence enrichment, NTK-motivated early gradient sensitivity, LightGBM-SHAP, Elastic Net, and large language model (LLM)-guided semantic selection. We use a unified preprocessing and evaluation framework and assess each method by downstream predictive performance, resampling stability, and representation of infrequent diagnosis codes. Our results demonstrate that performance improves with larger feature budgets with diminishing returns beyond a moderate size. NTK sensitivity provides the best overall balance of accuracy and stability, and LLM-guided selection contributes complementary clinically meaningful signals despite lower standalone performance.

IntroductionThe 5-year follow-up results of KEYNOTE-177 [1] established pembrolizumab as a standard first-line (1L) treatment for deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC), demonstrating improved response rates, progression-free survival (PFS) and tolerability over chemotherapy. Pembrolizumab became available as a 1L option in Australia following government reimbursement in August 2021. Real-world treatment patterns and outcomes since then have not previously been reported. Patients and methodsPatients with dMMR mCRC diagnosed 1/8/2021-30/5/2025 were analysed using data from TRACC and TRACC-SELECT, Australian multi-site prospective registries. Clinicopathologic characteristics, treatment patterns, and outcomes were examined. Survival outcomes for 1L pembrolizumab-treated patients were analysed using Kaplan-Meier. ResultsFrom 36 sites, 120 dMMR mCRC patients were identified; 109 (91%) received any systemic treatment. 1L treatment included pembrolizumab (n=103, 94%), clinical trial enrolment (n=4,4%), and chemotherapy (n=2,2%). Among pembrolizumab-treated patients, the median age was 76 years, 49% had a BRAFV600E mutation, and 17% had an ECOG performance status ≥ 2. Median follow-up was 25.8 months. The clinician-assessed response rate was 58%, while 17% had progressive disease as best response. Median duration of therapy was 15.2 months. Of 74 patients who discontinued pembrolizumab, 21 (28%) completed the 2-year course, 28 (38%) had progressive disease, 11 (15%) discontinued due to toxicity, 6 (8%) had a complete response before 2 years, and 8 (11%) had other reasons. Median PFS was 37.9 months. Median overall survival (OS) was not reached; 12- and 24-month OS rates were 88% and 77%, respectively. ConclusionIn this real-world cohort, patients were older and had higher rates of BRAFV600E mutation and poorer ECOG performance status than those in KEYNOTE-177. There has been rapid and wide uptake of pembrolizumab as a new standard of care, with promising outcomes. Ongoing data collection and analyses will evaluate predictors of immunotherapy response and real-world second-line treatment patterns and outcomes.

Background:Interleukin-6 (IL-6) is a cytokine that plays a key role in systemic hyperinflammation and may mediate the relationship between acute COVID-19 and severe long-term outcomes such as Long COVID or death. IL-6 modulating drugs may reduce patients' risk of severe post-COVID-19 outcomes. Methods:We conducted an emulated target trial in a retrospective cohort of patients with moderate-to-severe rheumatoid arthritis who were prescribed IL-6 receptor antagonists (sarilumab or tocilizumab, pooled treatment) or other biologic agents (anakinra or baricitinib, pooled comparator) in 2022. We compared the 12-month cumulative incidence of mortality and Long COVID (diagnosed and probable) between groups using Super Learner and targeted maximum likelihood estimation, adjusting for covariates of interest. Results:In our cohort of 3,553 patients, we found that prescription of IL-6 receptor antagonists was associated with a lower 12-month cumulative mortality (adjusted relative risk (aRR) 0.40, 95% CI 0.27, 0.59), diagnosed Long COVID aRR 0.42, 95% CI 0.23, 0.78), and probable Long COVID (aRR 0.71, 95% CI 0.61, 0.83), compared to prescription of other biologic agents, among rheumatoid arthritis patients. Conclusions:IL-6 receptor antagonists may prevent the incidence of severe post-COVID-19 outcomes, such as Long COVID or mortality. This supports the hypothesis that IL-6 may be a mechanistic biomarker of COVID-19 sequelae and that acute COVID-19 severity may mediate this relationship.

Introduction:The prognosis in pancreatic ductal adenocarcinoma (PDAC) remains poor with 2-year recurrence rates around 80% despite curative-intent surgery. This study evaluated factors associated with early recurrence in a contemporary, multi-center, Australasian population. A better understanding of patients at risk of early recurrence (ER) could improve selection of operative candidates. Methods:De-identified data were extracted from 23 hospitals participating in the PURPLE pancreatic cancer registry between 2016 and 2024. Clinicopathological features, treatment, recurrence patterns, and survival were examined. ER was defined as cancer recurrence within 12 months of surgery. Results:Of 3041 patients identified, 539 completed curative intent surgery. At a median follow-up of 21.8 months, 74% of resected cases had recurred. The median recurrence free survival was 14.3 months. ER occurred in 41% of patients and was associated with advanced age (P = 0.04), worse performance status (P < 0.01), T3-T4 stage (P = 0.01), CA19-9 > 300 U/ml (P < 0.01), involvement of more than two lymph nodes (P < 0.01), lymphovascular invasion (P = 0.01), and no neoadjuvant and/or adjuvant treatment (P < 0.01). There was a significant association between the primary tumor location and recurrence site (P = 0.046). The median OS of those with isolated lung (31.4 months) and locoregional (29.2 months) recurrences was longer than those with liver (21.3 months) or peritoneal (20.7 months) recurrences (P = 0.01). The use of neoadjuvant and adjuvant therapy was associated with lower ER rates (P < 0.01). Conclusion:A high proportion of resected PDAC patients experienced ER. Multiple pathological factors can predict ER. Primary tumor location was associated with site of recurrence. Neoadjuvant and adjuvant therapy significantly reduced ER and increased OS.

e15550 Background: The 5-year follow up results of KEYNOTE-177 established pembrolizumab as a standard first-line treatment for dMMR mCRC, demonstrating improved response rates, progression-free survival (PFS) and tolerability over chemotherapy. Pembrolizumab became widely available as a first-line option in Australia following government reimbursement in August 2021. Real world treatment patterns and outcomes have not been reported. Methods: Consecutive patients with mCRC diagnosed between 1/8/2021 and 30/5/2025, and had dMMR as determined by immunohistochemistry test, were analysed, using data from TRACC, an Australian multi-site prospective registry. Clinicopathologic characteristics, treatment patterns and outcomes were examined. Results: From 32 sites, we identified 120 dMMR mCRC patients, of whom 109 (91%) received any systemic treatment. First-line treatment included pembrolizumab (n = 103, 94%), a clinical trial (n = 4, 4%), and chemotherapy (n = 2, 2%). Pembrolizumab treated patients had a median age of 75 years; 50% were also BRAF mutant. Further baseline characteristics are shown in the table. Median follow up was 25.8 months. The clinician-assessed response rate (partial or complete response) was 57%, with 17% of patients having progressive disease noted as best response. Median duration of therapy was 15.2 months. Discontinuation of pembrolizumab in 73 patients was due to progressive disease (37%), completion of 2 years of treatment (29%) and toxicity (15%). Median PFS was 37.9 months. Median overall survival (OS) was not reached, with a 12-month OS of 89% and 24-month OS of 73%. Conclusions: In this real-world population of dMMR mCRC patients, we noted older age, a greater proportion of BRAFV600E mutant, and poorer ECOG functional status compared with KEYNOTE-177. There has been rapid uptake of pembrolizumab as a new standard of care, with promising response rates, PFS and landmark OS achieved. Ongoing data collection are planned to explore predictors of immunotherapy response, and treatment and outcomes in the second line setting. Baseline characteristics. TRACC (n=103) KEYNOTE-177 pembrolizumab cohort (n=153) Age ≥ 65 years 76 (74%) 73 (48%) Male 44 (43%) 71 (46%) ECOG 0 40 (39%) 75 (49%) Charlson Comorbidity Index ≥4 56 (54%) - Primary tumor locationRight sideLeft sideOther / Unknown site 65 (63%)23 (22%)15 (15%) 102 (67%)46 (30%)5 (3%) Stage IV at diagnosis 53 (51%) 80 (52%) BRAF V600E mutant 51 (50%) 34 (22%) KRAS or NRAS mutant 15 (15%) 33 (22%) Site of metastasesLiverLungLymph nodesPeritoneum 40 (39%)15 (15%)44 (43%)27 (26%) -

The incidence of early-onset colorectal cancer (CRC), commonly defined as diagnosis prior to age 50, is increasing. Studies of patients diagnosed prior to age 35 as a distinct subset of all early-onset patients have yielded inconsistent results. We extracted prospectively collected data from consecutive patients with metastatic colorectal cancer (mCRC) entered in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australasian registry. We focused on comparing demographic and clinicopathologic characteristics of those diagnosed < 35Y with remaining early-onset patients (35-49Y) whilst including a comparison to older patients (≥ 50Y) as a reference point. Molecular data were examined from 2015 when testing became reflexive. From July 2009 to December 2023, we identified 4399 patients with mCRC, including 133 (3.0%) < 35Y, and 537 (12%) 35-49Y. The proportion of < 35Y among newly diagnosed mCRC increased per calendar year (odds ratio 1.07, 95% CI 1.02-1.11). Gender, ECOG performance status and primary tumour location were similar for < 35Y and 35-49Y. Compared to 35-49Y, < 35Y had more de novo metastatic disease (79% vs. 70%; p = 0.04), BRAF V600E mutations (32% vs. 10%, p < 0.001) and deficient mismatch repair (dMMR) tumours (9.8% vs. 2.8%, p = 0.008). Rates of chemotherapy, rates of liver resection and overall survival (OS) were similar between < 35Y and 35-49Y. Multiple differences were observed between < fand 35-49Y, most notably a higher rate of BRAF V600E mutations and dMMR cancers. Collectively, these findings may inform the interpretation of clinical outcomes, refine screening approaches and advance understanding of CRC tumorigenesis in younger patients.

BACKGROUND & AIMS:Accurate risk stratification in Stage II colorectal cancer is essential for treatment decision-making, as current guidelines recommend adjuvant chemotherapy only for patients with a high risk of relapse. We aimed to develop and validate an artificial intelligence-based approach for automated invasive front assessment to improve prognostic stratification in this population. METHODS:We developed Semantically-Enhanced Multiple Instance Learning (SÉMIL), integrating vision-language foundation models with attention-based multiple instance learning for automated invasiveness assessment from H&E-stained whole slide images. We trained and validated SÉMIL on 1608 H&E-stained whole slide images from 3 cohorts (Austin n = 697, MCO n = 478, DYNAMIC n = 433). We compared SÉMIL performance against manual pathologist assessment and nonsemantic MIL approaches. RESULTS:For binary classification, SÉMIL outperformed nonsemantic MIL across all cohorts (external validation: AUC 0.713-0.821 vs 0.686-0.803). For survival prediction, SÉMIL demonstrated validated prognostic stratification in both the internal (Austin: hazard ratio [HR] = 4.73; P = .0012) and the 2 external (MCO: HR = 2.84; P = .0032; DYNAMIC: HR = 2.10; P = .0396) Stage II validation cohorts. Critically, among National Comprehensive Cancer Network guideline-defined high-risk Stage II patients, SÉMIL successfully stratified outcomes across all 3 cohorts (HRs, 2.96-3.50; all P < .05), demonstrating consistent reproducible performance. In multivariate analysis of the combined Stage II cohort (n = 1220), SÉMIL retained independent prognostic significance (HR = 1.98; P = .005) after adjusting for conventional clinicopathologic features including T stage, MMR status, and lymph node examination adequacy. Concordance analysis between SÉMIL and manual assessment showed concordant infiltrative classification identified the highest-risk group (HR = 3.96; P < .0001), with discordant cases showing intermediate risk. CONCLUSIONS:SÉMIL demonstrates validated prognostic stratification in Stage II colorectal cancer, with potential utility for refining risk assessment within National Comprehensive Cancer Network guideline-defined high-risk categories where treatment decisions are most challenging.

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .

Background and aims The current lack of quality indicators for patients with metastatic colorectal cancer compromises our ability to examine the quality of care delivered, and to ensure optimal patient outcomes. We sought to define a novel set of quality indicators that could be assessed using available data from a prospective comprehensive clinical colorectal cancer registry, ultimately enabling us to explore local practice and benchmark performance between institutions. Methods We performed a systematic review of the literature to review existing quality indicators for metastatic colorectal cancer. We engaged an expert panel of medical oncologists in a two-step modified Delphi analysis, using online questionnaires to rate and refine our initial list of candidate indicators, and to generate potential new ones. Results Thirty-five unique quality indicators for metastatic colorectal cancer were identified from the literature. Nine of these 35 were able to be captured in TRACC, and an additional 3 novel indicators, also captured in TRACC, were added to the list to reflect current practice. After 2 online surveys of eight medical oncologists, a final list of 14 quality indicators were recommended for inclusion. Conclusion A modified Delphi method was used to propose a set of 14 novel quality indicators to be extracted from an existing comprehensive metastatic colorectal cancer clinical registry. The quality indicators intentionally encompassed critical components of modern, multi-disciplinary care, spanning the treatment continuum across diagnosis to end of life. These will be used in work underway utilising TRACC data to identify potential gaps in care and avenues for quality improvement.

3503 Background: Despite adjuvant chemotherapy (ACT) a proportion of patients (pts) with stage III colon cancer (CC) will recur. Most at risk are those with detectable ctDNA, whereas those with undetectable ctDNA have a reduced recurrence risk. The DYNAMIC-III study explored the impact of ACT de-escalation or escalation as informed by post-surgery ctDNA results. Here, we report the primary analysis on the impact of treatment escalation in ctDNA-positive pts. Outcome data for treatment de-escalation in ctDNA-negative pts is immature. Methods: DYNAMIC-III is a multi-center, randomized, phase II/III trial. Eligible pts had resected stage III CC and were fit for ACT. Pts were randomly assigned 1:1 to ctDNA-informed or standard of care (SOC) management. Clinicians nominated the selected SOC ACT regimen prior to randomization. For ctDNA-informed management, a ctDNA-positive result at 5-6 weeks after surgery with a tumor-informed assay prompted an escalation ACT strategy (from single agent fluoropyrimidine [FP] to oxaliplatin-based doublet, from 3 months doublet to 6 months doublet or FOLFOXIRI [clinician choice], or from 6 months doublet to FOLFOXIRI). The primary efficacy endpoint for the ctDNA-positive cohort was 2-year RFS. The target sample size of 250 provided 80% power with 90% confidence to confirm superiority of ctDNA-informed treatment escalation compared to SOC with a HR of 0.746. Results: Of 961 eligible pts randomized between Oct 2017 and Apr 2023, 259 (27%) were ctDNA-positive. Of these, 113 (44%) had clinical low risk disease (non-N2 + non-T4). Median follow-up was 42.2 months (range 0.78 – 63.0). 115 (89%) of 129 ctDNA-informed pts received ACT escalation, with 65 (56%) receiving FOLFOXIRI. Of 130 SOC pts, 14 (11%) and 112 (86%) received single agent FP and oxaliplatin doublet, respectively. 2-year RFS for ctDNA-informed treatment escalation was 52% (90% CI: 44 - 59%) vs 61% (90% CI: 54 - 68%) for SOC (HR 1.11, 90% CI: 0.83 - 1.48; P = 0.6). The 3-year RFS for ctDNA-positive pts receiving FOLFOXIRI and FOLFOX/CAPOX was similar (47% vs 51%, HR 1.09, 90% CI 0.78 to 1.53; P = 0.7). In a pre-specified correlative analysis of all ctDNA positive pts, recurrence risk increased with ctDNA burden, with 3-year RFS of 78%, 63%, 36% and 22% for tumor-derived mutant molecules/mL quartiles < 0.06, 0.06 – 0.17, 0.18 – 1.31, and > 1.31, respectively (P < 0.01). Treatment-related hospitalisation was similar for escalated and SOC pts (OR 1.21, P = 0.58). Analysis of post-ACT ctDNA is underway. Conclusions: In this first randomised study of ctDNA-informed management in stage III CC, we confirm the prognostic significance of detectable ctDNA, with the novel finding of recurrence risk increasing markedly with ctDNA burden. Treatment escalation, including to FOLFOXIRI, did not improve RFS. Future studies in ctDNA positive pts should explore other escalation strategies. Clinical trial information: ACTRN12617001566325 .

Parallel processing is a fundamental organizing principle in the nervous system and understanding how parallel neural circuits generate distinct outputs from common inputs is a key goal of neuroscience. In the mammalian retina, divergence of cone signals into multiple feedforward bipolar cell pathways forms the initial basis for parallel retinal circuits dedicated to specific visual functions. Here, we used patch-clamp electrophysiology, electron microscopy, and two-photon imaging of a fluorescent glutamate sensor to examine how kinetically distinct responses arise in transient versus sustained ON alpha retinal ganglion cells (ON-T and ON-S RGCs) of the mouse retina. We directly compared the visual response properties of these RGCs with their presynaptic bipolar cell partners, which we identified using 3D electron microscopy reconstruction. Different ON bipolar cell subtypes (types 5i, 6, and 7) had indistinguishable light-driven responses whereas extracellular glutamate signals around RGC dendrites and postsynaptic excitatory currents measured in ON-T and ON-S RGCs in response to the identical stimuli used to probe bipolar cells were kinetically distinct. Anatomical examination of the bipolar cell axon terminals presynaptic to ON-T and ON-S RGCs suggests that bipolar subtype-specific differences in the size of synaptic ribbon-associated vesicle pools may contribute to transient versus sustained kinetics. Our findings indicate that feedforward bipolar cell synapses are a primary point of divergence in kinetically distinct visual pathways.

11125 Background: ctDNA detection following curative intent treatment is highly prognostic, with potential to impact patient fear of cancer recurrence (FCR). In 3 separate randomized trials (DYNAMIC II, III, rectal), pts with early-stage CRC were randomly assigned to treatment decision guided by ctDNA results (adjuvant chemotherapy escalation if ctDNA positive, de-escalation or no treatment if ctDNA negative), or according to standard clinicopathological features. The relationship between being informed of a high recurrence risk, or treatment de-escalation, and FCR is unclear. This study aims to explore the relationship between biomarker-informed adjuvant chemotherapy (ACT) decision making and FCR, including changes over time. Methods: A subset of pts from the 3 DYNAMIC studies completed validated self-report questionnaires measuring FCR, anxiety, depression and quality of life. Data were collected at three time points: after surgery (T1), at the time of the ACT decision (T2), and 9-12 months later (T3). Pts randomized to the ctDNA-guided group received a ctDNA test result (positive or negative) at T2, while those in the standard of care (SOC) group did not. The primary endpoint was the FCR Inventory Short Form score (FCRI-SF). FCR patterns over time were analyzed using a mixed model 2 (Randomization) x 3 (Time) ANCOVA. A 2 (Randomization) x 2 (Chemotherapy Status) ANCOVA was used to assess ACT’s impact on FCR at follow-up. Gender, age, and cancer stage were included as covariates. Results: 317 pts from 35 Australian sites participated in the FCR substudy (74% response rate for all timepoints). Two-thirds were male, and the mean age was 60 years. Of the ctDNA-guided group (n=176), 73% had a negative ctDNA result. At baseline, 63% of patients exhibited clinically significant levels of FCR (FCRI-SF >13). Younger age, female gender, anxiety, and higher cancer stage all predicted higher baseline FCR. FCR significantly decreased over time for all pts ( F (2,176) = 3.64, p = .03). This reduction was more pronounced in the ctDNA-guided group compared to the SOC group ( F (2, 176) = 3.83; p = .02), although the effect size was small (Cohen’s d =0.24). In the ctDNA-guided group, no differences in FCR were found between pts based on ctDNA result (positive vs. negative). High baseline anxiety was the only independent predictor of FCR at 12 months. Chemotherapy receipt, cancer stage, depression, and quality of life scores were not predictive of FCR over time. Conclusions: In pts with early-stage CRC, neither a positive nor negative ctDNA result impacted FCR. ctDNA-guided approach to determining ACT was associated with a greater reduction in FCR over time compared to SOC. This biomarker-guided treatment approach has potential to improve ACT selection as well as psychosocial outcomes. Temporal reduction in FCR is likely driven by increased prognostic certainty over time. Clinical trial information: 12615000381583 .

Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval -5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; P = 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; P = 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (P < 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583 .

Background Epidermal growth factor receptor inhibitors (EGFRi), most commonly cetuximab and panitumumab, are first-line options for patients with left-sided, RAS wildtype (RASwt) metastatic colorectal cancer. Limited data is available comparing EGFRi outcomes. Methods Data for patients diagnosed January 2015 to October 2024 was reviewed from TRACC, a prospective, multi-site Australasian colorectal cancer registry. Patients with left-sided, RASwt disease treated with an EGFRi as first-line (1 L) therapy were identified. Survival outcomes were calculated using Kaplan-Meir methods. Results We identified 747 patients with RASwt, left-sided, metastatic colorectal cancer. Of these, 287 (38%) received 1 L therapy that included cetuximab (n = 210, 73%) or panitumumab (n = 77, 27%). A switch from one to the other agent occurred in seven patients, all due to skin toxicity, including six patients (7.8%) initially treated with panitumumab and 1 (0.5%) initially treated with cetuximab. After switching, median time on the second EGFRi agent was 212 days. For 242 patients treated with an EGFRi in combination with doublet chemotherapy, toxicity contributed to treatment cessation more often in patients treated with panitumumab (32% vs. 13%, P = .003). For the subset of patients treated with palliative intent (n = 156), median progression-free (P = .43) and overall survival (P = .98) were similar for both EGFRi. Conclusion In this real-world analysis, a switch from one EGFRi agent to the other in the presence of skin toxicity led to durable treatment benefit with the alternate EGFRi. For patients receiving first-line cetuximab or panitumumab in combination with doublet chemotherapy, toxicity-related treatment cessation rates differed between EGFRi agents. No differences were seen in survival outcomes.

Introduction Elevated glycosylated hemoglobin (HbA1c) in individuals with type 2 diabetes is associated with increased risk of hospitalization and death after acute COVID-19, however the effect of HbA1c on Long COVID is unclear.Objective Evaluate the association of glycemic control with the development of Long COVID in patients with type 2 diabetes (T2D).Research design and methods We conducted a retrospective cohort study using electronic health record data from the National COVID Cohort Collaborative. Our cohort included individuals with T2D from eight sites with longitudinal natural language processing (NLP) data. The primary outcome was death or new-onset recurrent Long COVID symptoms within 30–180 days after COVID-19. Symptoms were identified as keywords from clinical notes using NLP in respiratory, brain fog, fatigue, loss of smell/taste, cough, cardiovascular and musculoskeletal symptom categories. Logistic regression was used to evaluate the risk of Long COVID by HbA1c range, adjusting for demographics, body mass index, comorbidities, and diabetes medication. A COVID-negative group was used as a control.Results Among 7430 COVID-positive patients, 1491 (20.1%) developed symptomatic Long COVID, and 380 (5.1%) died. The primary outcome of death or Long COVID was increased in patients with HbA1c 8% to <10% (OR 1.20, 95% CI 1.02 to 1.41) and ≥10% (OR 1.40, 95% CI 1.14 to 1.72) compared with those with HbA1c 6.5% to <8%. This association was not seen in the COVID-negative group. Higher HbA1c levels were associated with increased risk of Long COVID symptoms, especially respiratory and brain fog. There was no association between HbA1c levels and risk of death within 30–180 days following COVID-19. NLP identified more patients with Long COVID symptoms compared with diagnosis codes.Conclusion Poor glycemic control (HbA1c≥8%) in people with T2D was associated with higher risk of Long COVID symptoms 30–180 days following COVID-19. Notably, this risk increased as HbA1c levels rose. However, this association was not observed in patients with T2D without a history of COVID-19. An NLP-based definition of Long COVID identified more patients than diagnosis codes and should be considered in future studies.