Citations

SUMMARY Bloodstream infections (BSIs) are a significant cause of mortality and morbidity. Rapid identification of pathogens and detection of a few resistance markers from positive blood cultures are now possible through the increased availability of commercial rapid diagnostic tests, including nucleic acid amplification tests and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. This document describes the clinical utility of rapid diagnostics performed on positive blood cultures and provides evidence-based laboratory medicine guidelines for using rapid tests to diagnose BSIs in hospitalized adult and pediatric patients. This guideline was developed for use by medical (a.k.a. clinical) microbiologists, medical laboratory professionals, infectious disease clinicians, pharmacists, hospital administrators, healthcare providers, and other stakeholders associated with BSIs. A panel of experts, including medical microbiologists and experts in systematic literature review, was assembled to formulate the Population–Intervention–Comparison–Outcome (PICO) question, review the literature, and provide recommendations for using rapid tests to diagnose BSI and improve patient outcomes. A comprehensive literature search of four electronic bibliographic databases (MEDLINE, Embase, CINAHL, and Cochrane) was conducted to identify studies with measurable outcomes. The panel followed a systematic process, which included a standardized methodology for rating the certainty of the evidence and strength of recommendations using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. The panel evaluated the literature to answer the question: Does using rapid diagnostic tests improve clinical outcomes in adult and pediatric patients hospitalized with a BSI? Peer-reviewed literature was available to address three outcomes, including time to targeted therapy, mortality, and length of hospital stay. In general, the quality of the evidence was low to moderate due to the paucity of controlled, randomized clinical trial studies. However, eight recommendations were made based on evidence derived from the systematic review of the published literature. To answer the PICO question, the expert committee recommended using rapid diagnostic tests combined with active communication to decrease the time to targeted therapy and length of stay (strong recommendation). While the strength of the evidence for the impact on mortality is low, the panel supports using rapid tests to impact these outcomes. A summary of the recommendations is listed in the Executive Summary, which includes a detailed description of the background, methods, evidence summary, and rationale that supports each recommendation in the full text.

e17159 Background: Socioeconomic inequality (SI) is a recognized risk factor for negative outcomes in prostate cancer (PCa), influenced by biology, healthcare access, and lifestyle. This study aims to explore the molecular impact of SI on PCa, focusing on targetable and prognostic biomarkers. Methods: We conducted a retrospective analysis of 100 metastatic hormone-sensitive PCa patients (2016-2023), with 97 undergoing next-generation sequencing (NGS). We examined only pathogenic variants alongside clinical variables. The Area Deprivation Index (ADI) assessed neighborhood SI, with higher scores indicating greater disadvantage. Patients were divided into tertiles. Chi-square and Fisher’s exact tests evaluated the relationships between tertiles and genomic alterations, while ordinal logistic regression analyzed outcomes by various stratifications. Results: Of the 97 patients, 29 were in tertile 1, 34 in tertile 2, and 35 in tertile 3. Tertile 1 had a significantly higher percentage of non-Hispanic patients (90%) compared to tertile 2 (62%) and tertile 3 (37%), p=0.0001. Other demographic factors, such as age, comorbidities, and cancer history, showed no significant differences by tertile. Median PSA levels increased from tertile 1 (22 ng/mL) to tertile 3 (95 ng/mL), although this was not statistically significant (p=0.14). Tumor volume and visceral metastasis were notably higher in tertile 3 (p=0.029 and p=0.02). BRCA1/2 mutations were more prevalent in tertile 3 (11%, p=0.03) via liquid biopsy compared to tertiles 1 and 2 (0%). TMPRSS2-ERG fusion mutations were significantly more common in tertile 3 (66.6%) compared to tertile 2 (19.1%) and tertile 1 (14.2%), p=0.009. The association between ADI tertile and TMPRSS2 approached significance when controlled for ethnicity (p=0.061), with Hispanic ethnicity having 3.5 times the odds of the fusion compared to non-Hispanics (p=0.02). Tertile 1 patients were more associated with receiving progressive therapy lines (2L p=0.01, 3L p=0.03, 4L p=0.04), but median time to subsequent treatment at 5 years was similar across tertiles (p=0.84). Conclusions: Higher SI was linked to increased PSA, tumor volume, visceral metastasis risk, and higher prevalence of BRCA1/2 and TMPRSS2-ERG mutations. This study highlights the need for further research on the molecular impacts of SI on adverse PCa outcomes, particularly among Hispanic populations.

7507 Background: CARTITUDE-1 evaluated cilta-cel in pts with heavily pretreated RRMM who historically have an expected median progression-free survival (PFS) of <6 months (mo) and median overall survival (OS) of ~1 year (y). At 33.4 mo median follow-up, median PFS was 34.9 mo, and median OS was not reached (36-mo OS rate, 62.9%; Lin et al, ASCO 2023). We report OS, ≥5 y progression-free outcomes, and safety with a median study follow-up of 60.3 mo. Methods: Pts in CARTITUDE-1 received a single cilta-cel infusion. Correlative analyses were performed utilizing drug product, baseline, and postinfusion samples. Pts are followed for progression, survival, and safety in a 15-y follow-up study, CARTinue (NCT05201781), with pt evaluations per local standard of care (reported annually at a minimum). Results: Of 97 pts treated, 32 (33.0%) remain alive and progression free for ≥5 y after cilta-cel, without further MM treatment. For these 32 pts, prior to enrollment in CARTITUDE-1, median time from start of last line of therapy (LOT) to progression was 4.0 mo (range, 0.7–48.6). Among the 32, median age was 60 y (range, 43–78), median number of prior LOT was 6.5 (range, 3–14), 23.3% had high risk cytogenetics, 12.5% had extramedullary disease (EMD), 90.6% were triple-class refractory, and 46.9% were penta-drug refractory. Baseline characteristics of pts who were progression free for ≥5 y, including those with high-risk cytogenetics and EMD, were comparable to pts with progressive disease (PD) within 5 y. Compared with pts who had PD within 5 y, biomarkers significantly associated with ≥5 y progression free status included a higher fraction of naïve T cells in the drug product, lower neutrophil to T cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio (Cmax to sBCMA at baseline). At Cmax, these pts also had significantly higher CD4 central memory CAR+ T cell subsets and CAR+ T cells that were positive for the activation markers CD38, CD25, and PD-1. Data were collected on a subset of pts from a single center where local serial MRD assessments were performed. All 12 pts at this center who were progression free for ≥5 y were MRD negative at 10 –6 and imaging negative by PET/CT yearly for 5 y. Overall, at 60.3 mo median follow-up in CARTITUDE-1 (N=97), median OS was 60.6 mo (95% CI, 41.9–NE). With continued follow-up, 3 additional pts reported a second primary malignancy (1 of which was acute myeloid leukemia; onset, 2.8 y after infusion). No new cases of movement and neurocognitive disorders were reported. Conclusions: The median OS for pts enrolled in CARTITUDE-1 was 5 y, and 33% of pts remain progression free for ≥5 y following a single cilta-cel infusion. These data provide the first evidence that cilta-cel is potentially curative in pts with RRMM. Clinical trial information: NCT03548207 , NCT05201781 .

TPS8113 Background: There are currently three approved approaches for patients with resectable NSCLC including neoadjuvant chemoimmunotherapy, adjuvant chemoimmunotherapy and perioperative treatment with neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy. All regimens were approved after showing event-free survival (EFS) or disease-free survival (DFS) benefit with the addition of immunotherapy to chemotherapy compared to chemotherapy alone. Each approach has its benefits and risks. Starting immunotherapy prior to surgery may improve treatment compliance and efficacy of immunotherapy. Nevertheless, neoadjuvant chemoimmunotherapy may result in missing an opportunity for curative surgery and increase the complexity of tumor resection. PROSPECT-LUNG (NCT06632327) is a randomized study evaluating whether starting chemoimmunotherapy before or after surgery leads to better outcomes. Methods: This is a randomized phase 3 trial in which patients will be randomized 1:1 to surgery followed by chemoimmunotherapy (adjuvant arm) or neoadjuvant chemoimmunotherapy followed by surgery and adjuvant therapy (perioperative arm). Patients with histologic or cytologic confirmation of surgically resectable stage IIA-IIIB NSCLC (per AJCC 9th edition) or stage IIA to IIIB per AJCC 8 th edition up to single ipsilateral mediastinal station (N2a), ECOG PS ≤ 2 (or Karnofsky ≥ 60%), no prior treatment for NSCLC and no previous malignancy within 3 years are eligible. The dual primary endpoints are real-world event free survival (rwEFS) defined as date from randomization to date of the first of the following events: failure to undergo resection for any reason, progression prior to surgery that precludes resection, recurrence or progression at any time after surgery or death from any cause, and overall survival (OS) defined as time from randomization to death from any cause. The target accrual is 1,100 patients assuming one-sided type I error of 0.03 for OS endpoint and 0.02 for rwEFS endpoint. This sample size will enable the detection of a 3-year rwEFS improvement from 55% in the adjuvant therapy arm to 64% in the perioperative arm with an 84% power. This sample size would detect an HR of 0.73 (improvement in median OS from 8.1 to 11 years in favor of the perioperative arm, 5-year OS from 65% in the adjuvant arm to 73% in the perioperative arm, assuming exponential survival) with 83.6% power. The study has a pragmatic design with minimal data collection, reporting of adverse events that lead to discontinuation of therapy, hospitalization or death only. It allows providers to choose therapy per standard of care (FDA approved or on NCCN), includes patients with ECOG performance status 2, permits use of local laboratory testing and imaging studies and determination of recurrence/progression will be done by local treating physicians with no use of RECIST. Clinical trial information: NCT06632327 .

Abstract Background: Given the dramatic rise in incidence of colorectal cancer in young adults, there remain limited treatment options effective in metastatic disease. Although T cell-based therapies have been successful in treating highly antigenic cancers, like melanoma and lung, they have not yet been shown to induce consistent and durable tumor regression in common epithelial malignancies, including metastatic colorectal cancer (mCRC). CISH (Cytokine inducible SH2 containing protein) is a novel intracellular checkpoint target demonstrating PD-L1 ligand independent mechanisms of enhanced anti-cancer activity. Given that CISH is not currently tractable via antibody or small molecule drug modalities, we employed CRISPR for precise inhibition of CISH in tumor infiltrating lymphocytes (TILs). Here, we provide the first clinical report of safety and anti-tumor activity of CISH edited TILs in 12 patients with metastatic gastrointestinal cancers (NCT04426669), including a clinical complete response (CR) in a young-adult patient with immunotherapy-refractory mCRC. Methods: Tumors were surgically resected for TIL harvest, followed by a rapid expansion protocol and CRISPR/Cas9 knockout (KO) CISH. CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. To establish mechanistic attribution of the CR, we used iR-RepSeq+ for serial analysis of the TCR immune repertoire. Results: Our CRISPR engineering led to KO of CISH in T cells with high-efficiency (&gt;90%) without detectable off-target editing. We safely dosed patients at all five dose levels (range: 1.91e8 to 9.93e10 cells). No dose-limiting toxicities attributable to the CISH-KO TIL product were observed. Adverse events were consistent with established risks of LD chemotherapy, IL-2, or disease progression. A durable ongoing complete response (&gt;21 months) was achieved in a patient with microsatellite instability-high (MSI-H) mCRC refractory to anti-PD1/CTLA-4 combination therapy. Conclusions: We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway. Citation Format: Emil Lou, Modassir S. Choudhry, Timothy K. Starr, Timothy Folsom, Jason Bell, Blaine Rathmann, Anthony P. DeFeo, Ji Hyun Kim, Nicholas Slipek, Zhaohui Jin, Darin Sumstad, Christopher A. Klebanoff, Katherine Ladner, Akshat Sarkari, R Scott McIvor, Thomas A. Murray, Jeffrey Miller, Madhuri Rao, Eric Jensen, Jacob Ankeny, Mahmoud A. Khalifa, Anil Chauhan, Benjamin Spilseth, Ajay Dixit, Paolo P. Provenzano, Wenjing Pan, Daniel Weber, Miranda Byrne-Steele, Tom Henley, David H. McKenna, Matthew J. Johnson, Beau R. Webber, Branden S. Moriarity. First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT269.

Abstract Firework injuries remain a significant public health concern, with an estimated 9700 injuries reported in 2023. This study examines trends in pediatric facial injuries from fireworks over the past decade using the National Electronic Injury Surveillance System. Pediatric cases from 2014 to 2023 were identified using the fireworks consumer code (1313) and filtered for facial injuries (body part code 76). Data was analyzed using chi-square tests to assess significance and logistic regression to evaluate trends. An estimated 4625 pediatric facial injuries from fireworks presented to emergency departments nationwide from 2014 to 2023. Among cases (n = 177), 68.4% were male and 31.6% were female. Thermal burns (60.5%), lacerations (15.3%), and contusions/abrasions (11.9%) were the most common injuries. Males were more likely to be injured than females (P-value: &lt; .001). Overall, 17.5% of injuries required hospitalization or transfer. Older children were significantly more likely to sustain injuries requiring hospitalization (Odds Ratio [OR]: 1.13, 95% CI, 1.04-1.23, P = .005). Younger children had higher odds of sparkler-related injuries, although the risk rapidly decreased with age (OR: 0.76, 95% CI, 0.68-0.86, P &lt; .001). Our results show fireworks continue to cause significant pediatric facial injuries, with thermal burns being the most common diagnosis, and nearly one in 5 facial injuries from fireworks requiring hospitalization. Efforts to reduce facial injuries from fireworks should focus on minimizing the risk of injury in younger children while ensuring safety protocols are in place to address more significant injuries in older children.

Abstract Background: Bladder cancer patients with lower socioeconomic status (SES) often present with more aggressive disease and face poor outcomes, likely due to complex interactions with risk factors linked to lower SES. However, little is known about the effect of low SES on bladder tumor biology at the molecular level. This study sought to characterize better the impact of low SES on the bladder tumor microenvironment. Methods: This is a retrospective analysis of 93 patients (63 male and 30 female) ranging from age 33 to 92 presenting to the University of Arizona Cancer Center with bladder cancer from 2016-2023. Each patient's neighborhood level of SES was scored using the Area Deprivation Index on a scale of 1-100, with 1 representing the highest SES and 100 the least. These patients were then split into tertile 1: 1-33 (T1: N=16), tertile 2: 34-67 (T2: N=43), and tertile 3: 68-100 (T3: N=34), and each patient’s tumor microenvironment and mutational landscape was characterized and compared utilizing NGS (592, NextSeq; WES, NovaSeq) and WTS Sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Statistical significance was determined using chi-square and Mann-Whitney U (p&lt;0.05). Results: Our study had no significant difference between age, sex, and race between the three tertiles. Hispanic ethnicity was significantly higher in T3 (26.5%) when compared to T2 (7%) and T1 (0%), p=0.013. The frequency of TMB-H (&gt;10 mutations/megabase) was significantly lower in T3 (15.6%) when compared to T2 (51.2%, p=0.02) and T1 (50%, p=0.01). There was significantly less T cell CD8+ infiltration in tertile 3 (0.02%) when compared to T2 (0.43%, p=0.04) and T1 (0.37%, p=0.08), and less dendritic cell infiltration in T3 (0%) when compared to T2 (0.1%, p=0.13) and T1 (0.64%, p=0.008). T regulatory cells were lower in T3 (1.37%) compared to T2 (2.13%, p=0.09) and T3 (2.02%, p=0.24). IHC-PD-L1 and gene expression for immune checkpoint genes, MHC-Class I, and MHC-Class II did not vary significantly between tertiles. KMT2C-mt was highest in T2 (21.1%) compared to T1 (3.12%, p=0.03) and T3 (6.67%). There was no other significant differences in mutation prevalence between the three tertiles. Discussion: In our study, lower SES bladder cancer patients had a lower amount of CD8+ cells, dendritic cell infiltration, and a low frequency of TMB-H, indicating a lower level of adaptive immune response present in the tumor microenvironment. Lower levels of adaptive immune activity have been associated with more aggressive tumor behavior and worse outcomes in bladder cancer patients. These findings provide a partial explanation of the molecular mechanisms underlying the poor prognosis observed in low SES patients with bladder cancer. Larger-scale studies exploring the impact of SES on tumor biology are essential as they hold significant therapeutic and preventive implications. Citation Format: Tom Marco, Kenneth Barker, Jesse Ritter, Numaan Mahmood, Rishab Srivastava, Amith Rao, Isaac Zarif, Ricardo Estrada Mendizabal, Sachin Deshmukh, Edgar Tapia, Jose Guillen-Rodriguez, Juan Chipollini, Alejandro Recio-Boiles. The effects of socioeconomic deprivation on the tumor microenvironment of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7392.

Introduction: Deep neural networks are increasingly used to generate diagnostic algorithms in cardiovascular medicine. A biomarker of cardiovascular aging, derived from a deep-learning algorithm applied to digitized 12-lead electrocardiograms (ECGs), has recently been introduced. This biomarker, delta age (δ-age), is defined as the difference between predicted ECG age and chronological age. Hypthesis: We hypothesized that δ-age will improve the prediction of incident fatal and non-fatal myocardial infarction (MI) and stroke on top of what contemporary CVD prediction tools would do. Methods: In this cohort study, we included 7,111 men and women from the Norwegian Tromsø Study conducted in 2015-16, with follow-up through 2021 for incident fatal and non-fatal myocardial infarction (MI) and hemorrhagic or cerebral stroke. We used Cox proportional hazards regression models to assess the independent effect of δ-age on MI and stroke. Discrimination was evaluated using Harrell’s concordance statistic (C-index) and the net reclassification improvement (NRI). Results: During a median follow-up of 5.9 years, we observed 155 incident cases of MI, 141 cases stroke and 290 cases with either MI or stroke. δ-age was observed with a mean of 0 and standard deviation of 6.2 years. In men and women combined, hazard ratios (HRs) per standard deviation increase in δ-age, after adjustment for traditional risk factors, were 1.24 (95% confidence interval (CI) 1.09, 1.41) for the combined outcome, 1.26 (1.06, 1.49) for MI and 1.25 (1.03, 1.50) for stroke. In men, the corresponding HRs were 1.27 (1.09, 1.49), 1.46 (1.18, 1.79) and 1.02 (0.80, 1.31), respectively, and in women, 1.20 (0.97, 1.49), 0.87 (0.64, 1.20) and 1.58 (1.19, 2.11), respectively. The C-index increased modestly when δ-age was added to a model with traditional risk factors. The 95% CI for the C-index increase excluded zero for the combined outcome overall, and for MI in men and for stroke in women. The NRI was 26.0% (13.3%, 38.1%) for the combined outcome, 17.5% (0.6%, 33.5%) for MI and 37.2% (20.1%, 53.0%) for stroke. Conclusions: Incorporating δ-age into primary prevention risk prediction models significantly improved performance beyond traditional cardiovascular risk factors for the combined outcome and separately for MI and stroke.