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Abstract Background The determination of left ventricular diastolic dysfunction (LVDD) and filling pressure in patients with significant (>moderate) mitral regurgitation (MR) poses a complex challenge. We recently validated an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm to detect LVDD and estimate LV filling pressures. Methods This retrospective study sought to examine the risk of all-cause mortality across AI-ECG LVDD grades. Patients from the AI-ECG LVDD study test cohort who underwent transthoracic echocardiography confirming significant MR and an ECG within fourteen days of each other at Mayo Clinic between 09/2001 and 06/2022 were included. LVDD status was determined based on the index ECG, and patients were categorized into groups representing normal diastolic function (NDF) or LVDD grades 1 (G1), 2 (G2), or 3 (G3). Results Of 4,019 patients with significant MR (mean age 69.8, 49.0% women), 1,175 (29.2%), 1,881 (46.8%), and 963 (24.0%) were classified by AI-ECG as NDF/G1-LVDD, G2-LVDD, and G3-LVDD, respectively. The median mitral effective regurgitant orifice area was 26 mm² (interquartile range 20-36 mm²). Over a median follow-up of 3.5 years, 1,636 (40.7%) patients died. In multivariable survival analysis adjusted for multiple risk factors, a worse AI-ECG LVDD grade was independently associated with an increased death risk [G2DD: adjusted hazard ratio (aHR) 1.98 (95% confidence interval (95% CI) 1.63-2.40), G3DD: aHR 2.59 (95% CI 2.09-3.20)]. These findings were consistent when accounting for mitral valve intervention and among patients with >moderate MR or after mitral valve intervention. Conclusion In patients with significant MR, the grading of LVDD by AI-ECG is independently associated with all-cause mortality.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

AbstractINTRODUCTIONWe investigated longitudinal associations between self‐reported exercise and Alzheimer's disease (AD)‐related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.METHODSParticipants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aβ) measured by positron emission tomography were investigated.RESULTSGreater volume of weekly exercise at baseline was associated with slower accumulation of brain Aβ at preclinical disease stages β = –0.16 [–0.23 to –0.08], and a slower decline in multiple brain regions including hippocampal volume β = 0.06 [0.03 to 0.08].DISCUSSIONExercise is associated with more favorable profiles of AD‐related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented.Highlights Greater self‐reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self‐reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.

Abstract Background In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. Methods The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or >6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). Results A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG > 6 vs. CGD > 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. Conclusion Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

AbstractIntroductionRelapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644).MethodsIn a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination.ResultsAmong the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).ConclusionThe combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

Abstract The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Abstract Background: For resectable gastric cancer, postoperative adjuvant chemotherapy remains the standard modality for preventing recurrence and improving survival. Although a previous study proposed a model for stratifying risk and determining the likelihood of chemotherapeutic benefit following surgery, this model requires molecular genomic analysis of tumour tissues and only uses unidimensional data. However, a recent study revealed that a multiomics approach reflects more compressive cancer characteristics, providing more precise prediction of treatment response. Recent advancements indicate that radiomics features are predictive biomarkers of treatment response. The present study investigated whether computed tomography (CT) image-based quantitative radiomics combined with genomics data can provide clinically actionable information for a more detailed stratification of cancer patients. Methods: This retrospective multicohort study included patients with advanced gastric cancer treated with surgery plus adjuvant chemotherapy or surgery alone. Two filters were used to extract 1,106 radiomics features from preoperative venous-phase CT images. Dimensional reduction was performed via Cox regression with the LASSO method, following which the coefficients were used to determine the Rad-score. The optimal cutoff point was determined via the Kaplan-Meier method and used to divide the cohort into high- and low-risk groups. The primary endpoints were the predictive and prognostic performance of the Rad-score and nomogram in terms of overall survival and the value of adding the Rad-score to genetic information. Findings: The optimal Rad-score (11·978379207) successfully stratified patients into low- and high risk groups. Improved survival was noted among patients defined to have a ‘poor prognosis’ with GZMB–, WARS–, and SFRP+ genetic test results and among high-risk patients based on the Rad-score when no adjuvant chemotherapy was provided. Interpretation: Our findings suggest that the Rad-score can be used to further stratify patients in the response group, preventing potentially ineffective treatment and unnecessary adverse events in those with advanced gastric cancer

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

3588 Background: The brain-gut axis, a bidirectional network between the central and enteric nervous systems, plays a critical role in modulating the gastrointestinal tract function. Increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers; however, the mechanisms remain unclear. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and dysregulated GABA signaling has been found in CRC, affecting both tumor and tumor microenvironment. Here, we investigated the association between tumor GABA pathway gene expression and first-line treatment outcomes in mCRC. Methods: We evaluated the impact of the expression of 25 genes in the GABA pathway ( GABBR1, GABBR2, GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRD, GABRE, GABRG1, GABRG2, GABRG3, GABRQ, GABRR1, GABRR2, ABAT, ALDH5A1, GAD1, GAD2, SLC6A1, SLC6A13, SLC6A11, SLC6A12) on treatment outcomes (overall survival: OS; progression free survival: PFS) of 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). The associations between gene expression (continuous, per standard deviation increase) and outcomes were assessed via the multivariable Cox proportional framework, with hazard ratios (HR) and 95% confidence intervals (CI) computed. The likelihood ratio test was used for interaction tests. False discovery rate (FDR) was controlled at 5% with the Benjamini-Hochberg method. Results: Overall, low GAD1 (encoding for glutamate decarboxylase 1, the enzyme responsible for catalyzing the production of GABA from L-glutamic acid) was associated with longer PFS (HR: 1.26, 95% CI [1.13, 1.41], P = 3.2E-05) and OS (HR 1.27 [1.13, 1.43], P = 5.9E-05) across all treatment arms. High ABAT (encoding for the aminotransferase responsible for GABA catabolism) was also associated with longer OS (HR 0.81 [0.72, 0.91], P = 6E-04). To evaluate the predictive value, interactions with targeted therapies bevacizumab (n = 226) vs cetuximab (n = 207) were tested. We found significant interactions for PFS with ABAT ( P= 0.0017) and OS with SLC6A13 ( P= 0.0014 ).In pts treated with cetuximab, high ABAT expression was significantly associated with longer PFS (HR 0.73 [0.61, 0.87], P = 2.8E-04), and high SLC6A13 was marginally associated with worse OS (HR 1.18 [1.00, 1.39], P = 0.052). We did not observe similar associations in pts treated with bevacizumab. Conclusions: Our results highlight a potential role for GABA signaling in affecting mCRC treatment outcomes, suggesting that GABA pathway genes may be promising novel predictive and prognostic biomarkers and supporting the rationale to investigate GABA as a target for drug development. ClinicalTrials.gov Identifier: NCT00265850