Citations

4574 Background: Mutations of COMPASS-related proteins KMT2D, KMT2C, and KDM6A are observed in 66% of advanced urothelial carcinomas (UC). In vivo, the administration of tazemetostat, an enzymatic EZH2 inhibitor (EZH2i), reduced tumor burden and enhanced the immune response in animal models of UC. We hypothesized that tazemetostat might improve response to immunotherapy in advanced UC. Methods: ETCTN 10183 (NCT03854474) is a multicenter pilot study evaluating the safety and efficacy of tazemetostat 800 mg BID+ pembrolizumab 200 mg given every three weeks for up to two years in patients (pts) with platinum-refractory (Arm A) or cisplatin/chemo-ineligible advanced UC (Arm B). The primary objective was to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives included safety, response rate, and progression-free survival. Translational objectives included determining tumor mutational burden in COMPASS-related genes, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: There were no dose-limiting toxicities in the safety lead-in phase (n=6 pts), and the RP2D for tazemetostat was established at 800 mg BID. Baseline characteristics for Arm A N=12, Arm B N=13: 72% males; 96% white, 4% Black; 88% ECOG PS 0-1; 88% had bladder primary, 20% Stage III, 72% stage IV; 80% had visceral or bone metastases. The median number of cycles was 5 in Arm A (range 1-35) and 4 in Arm B (range 2-12). Treatment related G3/4 adverse events (AEs) were observed in 8 patients, most common were anemia and lymphopenia (n=2 each). Treatment related G1/2 AEs included nausea (n=6); skin and subcutaneous tissue disorders (n=3); anemia, lymphopenia, and thrombocytopenia (n=2 each). Among evaluable patients (n=10 in each arm), partial response rate was: Arm A 30%, Arm B 20%; stable disease: Arm A 30%, Arm B 30%; and progressive disease: Arm A 30%, Arm B 20%. 8 pts were on study treatment for ≥ 9 cycles (5 in Arm A, 3 in Arm B). All pts are off protocol treatment. Median progression-free survival was 3.06 (95% CI: 1.38-7.75) months for Arm A and 3.02 (95%CI: 2.4-5.65) for Arm B. Conclusions: Tazemetostat 800 mg BID and pembrolizumab combination is feasible and well-tolerated in patients with advanced UC. In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated. Clinical trial information: NCT03854474 .

Abstract Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objectives By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate genome-wide association study and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n = 1,278) and adults from the UKBiobank (n = 369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP (hedgehog interacting protein), DSP, and NPNT as potential molecular targets based on colocalization of their expression. A higher dysanapsis genetic risk score was associated with obstructive spirometry among 5-year-old children and among adults in the fifth, sixth, and seventh decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development, and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endophenotype link between the genetic variations associated with lung function and COPD.

AbstractBackgroundIntensity Modulated Proton Therapy (IMPT) is a sophisticated radiation treatment allowing for precise dose distributions. However, conventional spot selection strategies in IMPT face challenges, particularly with minimum monitor unit (MU) constraints, affecting planning quality and efficiency.PurposeThis study introduces an innovative Two‐Stage Mixed Integer Linear Programming (MILP) method to optimize spot intensity in IMPT with Lower Bound (LB) constraints. This method seeks to improve treatment planning efficiency and precision, overcoming limitations of existing strategies.MethodsOur approach evaluates prevalent IMPT spot selection strategies, identifying their limitations, especially concerning MU constraints. We integrated LB constraints into a MILP framework, using a novel three‐phase strategy for spot pool selection, to enhance performance over traditional heuristic methods and L1 + L∞ strategies. The method's efficacy was tested in eight study cases, using Dose‐Volume Histograms (DVHs), spot selection efficiency, and computation time analysis for benchmarking against established methods.ResultsThe proposed method showed superior performance in DVH quality, adhering to LB constraints while maintaining high‐quality treatment plans. It outperformed existing techniques in spot selection, reducing unnecessary spots and balancing precision with efficiency. Cases studies confirmed the method's effectiveness in producing clinically feasible plans with enhanced dose distributions and reduced hotspots, especially in cases with elevated LB constraints.ConclusionsOur Two‐Stage MILP strategy signifies a significant advancement in IMPT treatment planning. By incorporating LB constraints directly into the optimization process, it achieves superior plan quality and deliverability compared to current methods. This approach is particularly advantageous in clinical settings requiring minimum spot number and high MU LB constraints, offering the potential for improved patient outcomes through more precise and efficient radiation therapy plans.

Abstract Objective Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)‐based metabolomics could differentiate AE from drug‐resistant epilepsy (DRE), and stratify AE subtypes. Methods This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin‐associated protein‐like 2 (CASPR2), 29 with leucine‐rich glioma inactivated 1 (LGI1) and 20 with N‐methyl‐ d ‐aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS‐DA). Results The OPLS‐DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS‐DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high‐density lipoprotein (HDL, −(C H 2 ) n −, –C H 3 ), phosphatidylcholine and albumin (lysyl moiety). AE subtype‐specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, –C H 2 CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR‐antibody patients. Interpretation This study presents the first non‐antibody‐based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Importance Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS ( P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases ( P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045 ) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant ( Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

AbstractBackgroundThe impact of atrial fibrillation (AF) among patients with amyloidosis on in‐hospital outcomes is not well‐established. We aimed to examine in‐hospital outcomes among patients admitted with a primary diagnosis of AF with and without amyloidosis.Methods and ResultsWe queried the Nationwide Readmissions Database to compare the in‐hospital outcomes among AF patients with and without amyloidosis. Our study demonstrated that in‐hospital all‐cause mortality, adverse events, and 30‐day readmission were comparable between the two groups.ConclusionsPatients with AF and concurrent amyloidosis did not have worse in‐hospital outcomes than those with AF alone.

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.

AbstractBackgroundThis systematic review and meta‐analysis quantitatively examines the efficacy of angle‐based minimally invasive glaucoma surgery (MIGS) in normal tension glaucoma (NTG).MethodsA literature search was performed on Medline, Embase, PubMed, CINAHL and Cochrane Library from inception until 20 December 2022. Pilot, cohort, observational studies and randomised controlled trials including at least 5 subjects undergoing angle‐based MIGS (trabecular‐bypass devices, excisional trabeculotomy, goniotomy and ab‐interno canaloplasty) for NTG, with or without cataract surgery, were included. Meta‐analysis of continuous outcome using the meta routine in R version 2022.12.0+353 was performed to determine mean intraocular pressure (IOP) and anti‐glaucoma medication (AGM) reduction post‐operatively.ResultsOf the 846 studies initially identified, 15 studies with a pooled total of 367 eyes which underwent combined phacoemulsification and angle‐based MIGS were included for final meta‐analysis. Outcomes of the iStent were reported in 5 studies, iStent inject in 7 studies, Hydrus Microstent in 1 study, Kahook Dual Blade in 3 studies, and Trabectome in 2 studies. There was significant reduction in both IOP and AGM post‐operatively at 6 months (2.44 mmHg, 95%CI: 1.83–3.06; 1.21 AGM, 95%CI: 0.99–1.44), 12 months (2.28 mmHg, 95%CI: 1.71–2.84; 1.18 AGM, 95%CI: 0.90–1.47), 24 months (2.10 mmHg, 95%CI: 1.51–2.68; 1.26 AGM, 95%CI: 0.85–1.68) and 36 months (2.43 mmHg, 95%CI: 1.71–3.15, 0.87 AGM, 95%CI: 0.21–1.53) (all p < 0.05). Subgroup analysis on combined phacoemulsification‐iStent inject surgery demonstrated a reduction in both IOP (2.31 mmHg, 95%CI: 1.07–3.56, p < 0.001) and AGM (1.07 AGM, 95%CI: 0.86–1.29, p < 0.001) at 12 months post‐operatively.ConclusionsAngle‐based MIGS combined with phacoemulsification effectively reduces IOP and AGM in NTG eyes for up to 36 months after surgery.

TPS5108 Background: Penile cancer is a devastating malignancy that affects just over 2000 patients per year in the United States and approximately 40,000 worldwide. Metastatic or unresectable penile cancer is rapidly fatal in most cases and there are few effective systemic therapy options.1 There is an urgent need for alternatives to chemotherapy such as immunotherapy or targeted therapy. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 protein on the tumor cell surface and having efficacy in treatment of metastatic urothelial carcinoma.2 Recent studies have demonstrated frequent and strong expression of nectin-4 in penile squamous cell carcinoma (PSCC).3,4 In this setting, Mayo Clinic is leading a phase II trial of EV for advanced PSCC, currently in progress. Methods: This single arm, open-label, two-stage, phase II trial evaluates best overall response rate (BRR) to EV in patients with PSCC regional lymph node involvement or distant metastatic (M1) disease. Participants may have had any prior systemic therapy or be treatment naïve. Previously untreated patients must be ineligible for or have refused surgery or radiotherapy, have N2-N3 disease and are ineligible for or have refused neoadjuvant chemotherapy, or have clinical evidence of M1 disease. Participants will receive treatment with EV until disease progression, withdrawal, death, or limiting toxicity. Participants will receive EV 1.25 mg/kg intravenous on days 1, 8, and 15 of a 28-day cycle, with tumor assessment performed at 8-week intervals. The primary endpoint is the combined BRR of partial and complete responses (whether confirmed or unconfirmed) according to RECIST 1.1. Secondary endpoints are confirmed response rate, duration of response, progression-free survival, overall survival, adverse events, and BRR in HPV related and unrelated subgroups. Stage 1 will consist of 15 participants, and if there are 2 or more responses will proceed to Stage 2 with an additional 10 participants. The trial opened to enrollment in December 2023, and is active at Mayo Clinic sites in Minnesota, Arizona, and Florida. Clinical trial information: Funding and drug supplied by Astellas Pharma Global Development, Inc./Seagen Inc. NCT06104618. 1. Chahoud J, et al., Curr Opin Urol. 2022 Jan 1;32(1):8-16. 2. Powles T, et al. N Engl J Med. 2021 Mar 25;384(12):1125-1135. 3. Tekin B, et al. Hum Pathol. 2023 Dec;142:42-50. 4. Grass GD, et al. Eur Urol Open Sci. 2023 Jan 10;49:1-5. Clinical trial information: NCT06104618 .