Citations

158 Background: PIK3CA mutations are common in CRC and may be a negative prognostic factor. INAVO is a potent and selective PI3Kα inhibitor that also promotes mut p110α degradation. BEV and CETUX are standard treatment (tx) components for RAS mut and RAS -wildtype (wt) mCRC, respectively. The Phase I/Ib INTRINSIC open-label umbrella study (NCT04929223) evaluates targeted therapies in biomarker-selected mCRC subpopulations. We report INAVO + BEV and INAVO + CETUX results. Methods: Patients (pts) with PIK3CA mut, RAS mut mCRC received INAVO (9 mg oral once daily) + BEV (intravenous [IV] 15 mg/kg every 3 weeks). Pts with PIK3CA mut, RAS wt mCRC received INAVO + CETUX (IV 400 mg/m 2 then 250 mg/m 2 weekly thereafter). Primary endpoint: confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), and safety. Progression-free survival (PFS) and overall survival (OS) were exploratory. Results: At the clinical cut-off dates, 16 pts were enrolled in the BEV arm; 35, in the CETUX arm. Most had ≥2 metastatic sites at enrollment (n = 16 [100%] and 30 [85.8%], respectively) and ≥2 prior lines of metastatic therapy (16 [100%] and 28 [80.0%]). In the BEV arm, 3 pts (18.8%) had no prior BEV. In the CETUX arm, 25 pts (71.4%) had no prior CETUX; 17 (48.6%) had prior anti-EGFR therapy. All pts in the BEV arm and 34 in the CETUX arm were evaluated for efficacy and safety. Median follow-up was 9.4 months (mo; interquartile range: 5.5–14.4) and 12.6 mo (8.9–16.6), respectively. Efficacy is shown in the Table. All pts had adverse events (AEs); 15 (93.8%) and 34 (100%), respectively, had tx-related AEs (TRAEs); 5 (31.2%) and 12 (35.3%), grade 3–4 TRAEs; 2 (12.5%) and 11 (32.4%), serious AEs. One grade 5 AE (infusion-related reaction) occurred (CETUX arm). Dose reduction/interruption due to AEs occurred in 12 (75.0%) and 27 (79.4%) pts; tx withdrawal due to AEs, in 0 and 4 (11.8%) pts, respectively. Hyperglycemia was the most common AE, TRAE, and AE leading to dose reduction/interruption in both cohorts. Hypertension was observed more frequently with BEV; dermatitis acneiform and dry skin, with CETUX. Conclusions: INAVO + BEV and INAVO + CETUX showed encouraging efficacy in pts with PIK3CA mut mCRC, with no new or unexpected safety signals. Clinical trial information: NCT04929223 . INAVO + BEV(n = 16) INAVO + CETUX(n = 34) cORR, all PR, n (%) 1 (6.3) 7 (20.6)* SD, n (%) 10 (62.5) 17 (50.0) Progressive disease, n (%) 3 (18.8) 9 (26.5) Missing/NE, n (%) 2 (12.5) 1 (2.9) mDoR, mo (90% CI) 7.7 (NE) 4.4 (4.2–5.3) DCR, n (%) 11 (68.8) 15 (44.1) mPFS, mo (90% CI) 4.2 (2.8–6.8) 3.5 (2.8–4.4) mOS, mo (90% CI) 11.0 (8.5–14.5) 12.8 (10.7–13.8) CI, confidence interval; m, median; NE, not evaluable; PR, partial response; SD, stable disease. *3 pts with PRs received prior anti-EGFR therapy; 1 had a best prior response of SD (last dose 233 days before study tx) and 2 had best prior responses of PRs (last doses 134 and 171 days before study tx).

126 Background: NNT/NNH analyses can estimate the magnitude of benefit vs harm of therapeutic agents and can inform clinical decision making. We quantified the benefit/risk profile of fruquintinib (F; a highly selective, oral inhibitor of all 3 VEGFRs) vs other later-line mCRC monotherapies. Methods: Six phase 3 randomized (2:1), placebo (P)-controlled trials (F: FRESCO, FRESCO-2; regorafenib [rego]: CONCUR, CORRECT; TAS-102: TERRA, RECOURSE) were identified. NNT (average number of pts needing treatment to prevent 1 additional death/progression event) for overall survival (OS) and progression-free survival (PFS) was calculated as the inverse of difference in survival function between treatment and P. NNH (average number of pts needing treatment for 1 additional pt to have an adverse event; AE) for treatment-emergent AEs (TEAEs) was calculated as the inverse of absolute risk increase relative to P. Low NNTs and high NNHs suggest a more favorable treatment profile. Results: F had the lowest NNT (most favorable) for 6-month OS (FRESCO-2) and PFS (FRESCO) vs rego and TAS-102 (Table). F had the highest NNH (most favorable) for grade ≥3 TEAEs, palmar-plantar erythrodysesthesia (PPE; FRESCO-2), and fatigue (FRESCO). TAS-102 (TERRA) had the highest NNH for diarrhea, followed by F (FRESCO-2). Consistent with mechanism of action of anti-VEGFRs, F and rego had lower NNHs for hypertension (HTN) vs TAS-102 (TERRA). F (FRESCO) had the lowest NNH for discontinuation due to TEAEs. Conclusions: In this cross-trial comparison, F had the lowest NNT for OS (FRESCO-2) and PFS (FRESCO/FRESCO-2), indicating survival benefit. F had the highest NNHs for grade ≥3 TEAEs, PPE (FRESCO-2), and fatigue (FRESCO), indicating a low risk profile. The analysis highlights fruquintinib as a favorable treatment for pts with mCRC. Clinical trial information: NCT02314819 , NCT04322539 , NCT01584830 , NCT01103323 , NCT01955837 , NCT01607957 . NNT/NNH (95% CI) for mCRC treatments.* F Rego TAS-102 FRESCO NCT02314819 N=416 FRESCO-2 NCT04322539 N=691 CONCUR NCT01584830 N=204 CORRECT NCT01103323 N=760 TERRA NCT01955837 N=406 RECOURSE NCT01607957 N=800 6-month OS 6.5(5.5–8.1) 5.3(4.8–5.9) 5.9(NA) 9.8(NA) 14.1(NA) 7.2(NA) 6-month PFS 4.2(3.7–4.8) 4.4(3.9–5.1) 5.0(NA) 9.1(NA) 7.1(NA) 7.2(NA) Grade ≥3 TEAEs 2.4 (2.0–3.1) 8.1 (5.0–22.5) 2.6 (2.0–3.7) 2.5 (2.2–3.0) 2.8 (2.3–3.6) 5.9 (4.1–10.2) TEAE leading to discontinuation 10.8 (6.7–28.5) NA † (18.0–NA) 12.5 (6.2–NA) 17.5(11.3–39.2) 250.0 (15.3–NA) 50.0 (22.9–NA) PPE 2.2 (1.9–2.5) 6.0 (4.8–8.0) 1.4 (1.3–1.7) 2.6 (2.2–3.0) NA (NA) NA (46.0–NA) HTN 2.4 (2.0–3.0) 3.6 (3.0–4.5) 5.3 (3.6–9.5) 4.5 (3.7–5.8) 14.3 (10.0–25.2) NA (NA) Diarrhea 5.1 (3.8–7.4) 7.3 (5.2–12.3) 6.2 (4.3–11.4) 3.8 (3.2–4.8) 7.9 (5.7–13.0) 5.0 (3.9–6.9) Fatigue 32.5 (10.3–NA) 25.8 (10.1–NA) 10 (5.3–80.3) 5.3 (3.8–8.4) 7.4 (5.0–13.9) 8.3 (5.4–18.1) *All trials except TERRA included best supportive care in both arms. † Lower rate of pts discontinued F vs P due to TEAEs, thus NNH was not applicable (NA).

117 Background: Oxaliplatin remains a cornerstone of colorectal cancer (CRC) chemotherapy but is frequently complicated by chemotherapy-associated liver injury (CALI). This manifests as sinusoidal obstruction syndrome (SOS), nodular regenerative hyperplasia (NRH), or porto-sinusoidal vascular disorder (PSVD). These microvascular changes lead to portal hypertension (PH), splenomegaly, and thrombocytopenia, interrupting chemotherapy delivery and compromising survivorship. Despite increasing recognition, the incidence, spectrum, and management of oxaliplatin-induced portal hypertension (OIPH) remain undefined. Methods: We systematically reviewed PubMed, Embase, and Cochrane through August 2025 for prospective and retrospective cohorts of oxaliplatin-treated CRC patients reporting OIPH incidence, pathology, radiology, or interventional management. Case reports were excluded. Outcomes included incidence, latency, complications, misdiagnosis, and interventions such as bevacizumab and partial splenic embolization (PSE). Results: Eight studies including 730 patients were analyzed. OIPH developed in ~20–30% of patients, with 2–5% progressing to clinically overt disease requiring variceal banding, Transjugular Intrahepatic Portosystemic Shunt (TIPS), PSE, or management of liver failure. Latency to presentation was typically 4–10 years after oxaliplatin exposure. Common features included splenomegaly, thrombocytopenia, varices, and ascites. Histopathology consistently showed sinusoidal dilatation, congestion, perisinusoidal fibrosis, NRH, and microthrombi, confirming endothelial-mediated injury. Up to half of chronic cases were misclassified as metabolic dysfunction–associated steatotic liver disease (MASLD/NAFLD) or cryptogenic cirrhosis. Bevacizumab demonstrated consistent hepatoprotection, delaying splenic enlargement and reducing thrombocytopenia, likely via preservation of sinusoidal endothelial integrity and reduction of von Willebrand factor–mediated platelet microthrombi. Interventional radiology provided therapeutic options: in a prospective phase II study, PSE restored platelet counts >130×10⁹/L in 94% and enabled chemotherapy resumption within a median of 14 days, with no grade ≥3 adverse events. Conclusions: OIPH is an under-recognized complication of CRC chemotherapy, with latency spanning years after treatment. Splenomegaly and thrombocytopenia serve as early clinical signals, while misdiagnosis as MASLD or cirrhosis is common. Bevacizumab provides hepatoprotection, and PSE offers a safe and effective option for chemotherapy-limiting thrombocytopenia. Routine monitoring of spleen volume and platelet trends should be integrated into follow-up, and prospective validation of prophylactic and interventional strategies is urgently needed.

103 Background: Clinicians spend significant time extracting and synthesizing information to risk-stratify and make adjuvant chemotherapy (AC) recommendations for CRC. By automating parts of this process, LLMs could help reduce documentation burden and variability in decision-making. Methods: We selected 144 stage III, pMMR CRC patients treated at Mayo Clinic (2017–2021). HIPAA-compliant Gemini-2.0-Flash-001 and GPT-4o extracted clinical variables (age, neuropathy grade, pathological stage) from EHRs and generated AC recommendations. Two approaches were compared: (1) a rule-based algorithm with nested if/else statements translating variables into NCCN-based recommendations, and (2) a dynamic LLM agent generating recommendations using a structured prompt informed by NCCN guidelines. Concordance with treating physicians was assessed, with disagreements reviewed by a blinded GI oncologist. Results: The dataset included 144 patients with median age 67 (IQR 66–68), 48.6% female. The LLM pipeline extracted neuropathy grade with 100% accuracy and pathological T/N stages with 99.3% accuracy. Concordance with physician recommendations was 93.1% for the rule-based algorithm and 62.5% for the LLM agent. In discordant cases, blinded adjudication by a GI oncologist favored the algorithm and LLM agent over physicians in most cases (Table 1). Conclusions: This exploratory work shows LLM agents can reliably extract variables and generate evidence-based treatment recommendations for stage III CRC. The high rate of expert preference for LLM recommendations in discordant cases is intriguing but limited by small sample size and possible adjudicator bias. Discordant physician recommendations reflect the complexity of decision-making, including patient preferences, performance status, comorbidities, and subtle findings not fully captured in EHRs. Rather than replacing judgment, we envision LLMs as decision support tools—analogous to an advanced trainee reviewing charts and presenting evidence-based recommendations to the attending physician with ultimate authority. Larger multi-institutional studies with multiple adjudicators are needed to validate these findings and clarify AI’s role in oncology. Patient characteristics, LLM extraction accuracy, and concordance with physician recommendations. Metric Result Total patients 144 Median age (IQR) 67 (66-68) Female (%) 48.6% LLM extraction accuracy – Neuropathy grade 100% LLM extraction accuracy – Pathological T and N stages 99.3% Primary Concordance – Rule-based algorithm vs. physician 93.1% Adjudicator preference of rule-based algorithm over treating physician for discordant cases 100% Concordance – LLM agent vs. physician 62.5% Adjudicator preference of LLM agent over treating physician for discordant cases 82.0%

Abstract Aims Cardiogenic shock (CS) is often treated with catecholamines titrated to an adequate target mean arterial pressure (MAP) while minimizing adverse effects. We aim to assess the optimal catecholamine dose/MAP balance in heart failure-associated CS (HF-CS). Methods Patients with HF-CS were retrospectively enrolled from 16 tertiary centres in 5 European countries (2016–2021; NCT03313687). Dosage was quantified by inotropic scores (epinephrine, norepinephrine, and dobutamine). Associations of baseline and seven-day summarized dosage with intensive care unit (ICU) discharge (mixed-effects logistic regression) and 30-day mortality (Cox regression) were analysed. Potential catecholamine/MAP target ratios for optimized outcomes were assessed in models adjusted for age, sex, pH, lactate and prior resuscitation, stratified by centre. Results N = 704 patients: median age 63 years, 74% male, 34% post-resuscitation, median lactate 5.2 mmol/l. Of these, 53% were discharged from ICU, 48% died within 30 days. Higher inotropic scores independently predicted a lower probability of ICU discharge (baseline score: OR 0.78 [95%-CI 0.69–0.88]; summarized score: OR 0.46 [0.38–0.56]; both P < .001) and higher risk of 30-day mortality (baseline score: HR 1.27 [1.15–1.40], summarized score HR 1.83 [1.60–2.09]; both P < .001). A score/MAP ratio <0.403 µg/kg/min/mmHg was associated with higher ICU discharge odds (ceiling effect); a < 0.426 µg/kg/min/mmHg with lower 30-day mortality hazards (no ceiling effect). Lowering catecholamine doses by accepting reduced MAP targets was linked to better outcomes. Conclusion In HF-CS, higher catecholamine support independently associates with worse outcomes. Accepting lower blood pressure targets to reduce catecholamine dosage may improve outcomes. Validation in randomized controlled trials is urgently needed.

Abstract Graves’ disease (GD) is an autoimmune entity that had an unchanged treatment paradigm for more than half a century with radioactive iodine, antithyroid drugs (ATDs), and surgery representing the mainstay of therapy, with variation in their use over time and geographic location. Hypothyroidism has been an accepted tradeoff in many cases, though recently there are increased concerns about altered quality of life in these patients. Fortunately, the last decade has seen an intense pursuit of GD's immunological mechanisms and a recalibration of classic treatment modalities focusing on thyroid preservation, as reflected in the preference for ATD as primary therapy, including its use in long-term protocols. The immune targets currently explored aim to address this gap by intervening in the TRAb lifecycle: minimizing production (eg, B-cell targeting), enhancing clearance (eg, neonatal Fc receptor inhibitors), or neutralizing its target—the TSH receptor (eg, receptor blockade). While these approaches are going through the necessary clinical trials evaluation, we are starting to see the potential for technology and artificial intelligence to make an impact on how we identify, treat, and monitor patients with GD. The combination of these approaches will likely lead to a significant individualization of GD management that will take us from the goal of normalization of thyroid levels to that of inducing long-term remission and prevention of the associated autoimmune phenomena that GD is associated with. While time is needed for these aspects to mature, the future looks bright for our GD patients and maybe soon these lessons will open new doors for our patients with Hashimoto's thyroiditis as well.

Purpose of review Indoor water parks, with over 1100 facilities in the United States, are popular recreational venues with an estimated 1.5 million visitors per year in North America. While generally well tolerated, they can be associated with significant respiratory and nonrespiratory health risks. This review focuses exclusively on the infectious and noninfectious respiratory health issues associated with indoor water park usage and is timely due to increasing popularity, evolving water-treatment practices, and the unique vulnerability of specific populations. Recent findings This review synthesizes peer-reviewed studies and institutional data from 2014 to 2024, detailing exposure mechanisms, health effects, mitigation strategies, and impacts on vulnerable populations such as children, asthmatic individuals, cystic fibrosis patients, immunocompromised individuals, and workers. Topics covered include disinfection by-products (DBPs), chloramine inhalation effects, asthma risks, hypersensitivity pneumonitis from nontuberculous mycobacteria, and occupational exposures. Emerging technologies in air and water quality management, alongside recent policy and facility-design developments, are also examined. Summary While indoor water parks remain a valued recreational resource, they pose significant and often under-recognized respiratory risks. Through better facility ventilation, hygiene education, disinfection innovation, and regulatory reform, these risks can be mitigated to protect both patrons and staff, particularly in vulnerable subpopulations.

Background: Arthroscopic treatment of excessive acetabular coverage with pincer morphology or coxa profunda can be challenging. In patients with excessive acetabular coverage with nondistractible hips, an outside-in capsuolotomy can be considered to gain safe and efficient intra-articular access to the hip. Indications: The indications for an outside-in capsulotomy include patients with acetabular retroversion, a lateral center-edge angle >40°, coxa profunda or protrusio, or stiff, older male patients who remain hip preservation candidates. Technique Description: The outside-in capsulotomy is performed once it is recognized that traction on the operative extremity will not provide adequate working space for safe intra-articular access. Traction is taken off the operative extremity, and an anterolateral portal is localized to the 12:00 position on the hip joint with the use of fluoroscopy. The camera is then placed in a juxta-capsular location, and a modified anterior portal is created under direct arthroscopic visualization. We then proceed with extracapsular dissection to identify the indirect head of the rectus. An outside-in capsulotomy is then performed parallel to the indirect head of the rectus, approximately 5 mm distal to its insertion on the acetabular rim. Prior to deep completion of the capsulotomy, the hip joint is flexed to 30° to protect the articular cartilage of the femoral head. Once intra-articular access is obtained, traction can be reapplied, and one can proceed with hip arthroscopy in a standard fashion. Results: This technique decreases the traction time needed, given that the capsulotomy is performed without traction applied. Additionally, the amount of force required for hip distraction is decreased once the capsuolotomy has been completed, through usual sectioning of the iliofemoral ligament. The presented technique is both safe and efficacious, with no published difference in complications as compared to standard inside-out access. A published series of patients with severe pincer morphology and lateral overcoverage who undergo hip arthroscopy with outside-in access demonstrates satisfactory postoperative improvements in patient-reported outcome measures. Discussion/Conclusion: The outside-in capsulotomy provides a means for safe access to the hip joint in otherwise limited or nondistractible hips.

Abstract Background Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear. Methods We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models. Results Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Conclusions These findings suggest that Aβ40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular Aβ exposure contributes directly to the early development of brain insulin resistance in AD.

Background: The effect of intrauterine exposure to SARS-CoV-2 infection during pregnancy on neurodevelopment and growth trajectories during the first year of life remains under investigation. Methods: We retrospectively reviewed the electronic medical records of all pregnant women who received care at Mayo Health System and tested positive for SARS-CoV-2 (RT-PCR) from March 2020 through October 2021 and examined the effects of fetal sex and trimester of maternal SARS-CoV-2 infection on the risk of neurodevelopmental disorder diagnosis and growth trajectories of head circumference (HC) and body weight (BW) percentiles over the first year of life using linear mixed models. Results: We observed that a higher percentage of male infants (n = 357), compared to females (n = 344), have neurodevelopmental disorders (10.9% vs. 5.2%, p = 0.008), and infants exposed to maternal SARS-CoV-2 infection in the second (n = 183) or third trimester (n = 358) have a higher prevalence of neurological diagnoses compared to those exposed in the first trimester (n = 160) (1st vs. 2nd vs. 3rd trimester: 0% vs. 0.9% vs. 0.7%, respectively, p = 0.037). In addition, female infants, compared to males, had significantly lower BW (B = −0.04, p < 0.0001) and HC (B = −0.06, p < 0.0001) percentile growth trajectories over the first year of life. Moreover, infants exposed to maternal SARS-CoV-2 infection in the second trimester had a significantly lower BW percentile growth trajectory (B = −0.01, p = 0.006), while infants exposed to maternal SARS-CoV-2 infection in the third trimester had a significantly lower HC percentile growth trajectory (B = −0.02, p = 0.02). Conclusions: In utero exposure to maternal SARS-CoV-2 infection could have long-term effects on growth trajectories, depending on the infant’s sex and timing of exposure.