Citations

PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes—both pathologic and time-to-event survival end points—particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor–positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

OBJECTIVES To describe the quality of pediatric resuscitative care in general emergency departments (GEDs) and to determine hospital-level factors associated with higher quality. METHODS Prospective observational study of resuscitative care provided to 3 in situ simulated patients (infant seizure, infant sepsis, and child cardiac arrest) by interprofessional GED teams. A composite quality score (CQS) was measured and the association of this score with modifiable and nonmodifiable hospital-level factors was explored. RESULTS A median CQS of 62.8 of 100 (interquartile range 50.5–71.1) was noted for 287 resuscitation teams from 175 emergency departments. In the unadjusted analyses, a higher score was associated with the modifiable factor of an affiliation with a pediatric academic medical center (PAMC) and the nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. In the adjusted analyses, a higher CQS was associated with modifiable factors of an affiliation with a PAMC and the designation of both a nurse and physician pediatric emergency care coordinator, and nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. A weak correlation was noted between quality and pediatric readiness scores. CONCLUSIONS A low quality of pediatric resuscitative care, measured using simulation, was noted across a cohort of GEDs. Hospital factors associated with higher quality included: an affiliation with a PAMC, designation of a pediatric emergency care coordinator, higher pediatric volume, and geographic location. A weak correlation was noted between quality and pediatric readiness scores.

Background: RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis. Methods: Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke. Results: Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l -1 [-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l -1 [-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]). Conclusions: In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.

Abstract Background and Aims The use of multiple markers may improve the accuracy in glomerular filtration rate (GFR) estimation especially when the interpretation of creatinine and cystatin C is limited. We sought to externally validate a recently developed multi-marker nuclear magnetic resonance (NMR)-based estimated GFR equation (eGFR-NMR) using the biracial Genetic Epidemiology Network of Arteriopathy cohort. Method We included 224 sex, race/ethnicity, and mGFR-category-matched participants. GFR was measured using urinary clearance of iothalamate (mGFR). We calculated eGFR-NMR using serum creatinine, valine, myo-inositol, and cystatin C, age, and sex. We compared the reliability of eGFR-NMR with current eGFR equations (2021 Chronic Kidney Disease Epidemiology Collaboration equations for creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. In particular, we evaluated its performance in age, sex, and race subgroups. Results In the overall cohort, mean age was 63 (±8) years, 54% were females, 49% were Black individuals, and mean mGFR was 78.7 (±24.3) ml/min/1.73 m2. eGFR-NMR overestimated mGFR by 2 mL/min/1.73 m2 (95% CI, 4 to 0.7) while eGFR-Cr-CysC underestimated mGFR by −5 mL/min/1.73 m2 (95% CI, −2 to −7). All equations had acceptable accuracy metrics. When stratified by age, sex, and race, eGFR-NMR performed the best among Black males age <65 years compared to current equations (Figure 1). In this subgroup, eGFR-NMR was unbiased (bias, 2mL/min/1.73 m2 [95% CI, -3 to 10]) compared to substantial biases of eGFR-Cr (bias, 17 mL/min/1.73 m2 [95% CI, 9 to 24]) and eGFR-Cr-CysC (bias, 15 mL/min/1.73 m2 [95% CI, 6 to 20]). In other subgroups, measures of accuracy for eGFR-NMR, eGFR-Cr, eGFR-Cr-CysC were generally similar. Conclusion eGFR-NMR can be used to estimate mGFR and was more accurate than CKD-EPI equations among Black males age <65 years.

e17009 Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p < 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.

Background: The purpose of this study was to validate the Foot and Ankle Outcome Score (FAOS) for osteochondral lesions of the talus (OLTs). We hypothesize that the FAOS will meet all 4 psychometric criteria for validity in this patient population. Methods: From 2008 to 2014, a total of 208 patients with OLTs were included in the construct validity portion of the study. All patients completed FAOS and 12-Item Short-Form Health Survey (SF-12) scores. Twenty additional patients were prospectively recruited and were asked to complete questionnaires to determine the relevance of each of the FAOS questions as it related to their OLT. Forty-four patients completed the FAOS 1 month after the first FAOS to assess reliability via Spearman correlation coefficient. Responsiveness of the FAOS was assessed with 54 patients who had both preoperative and postoperative FAOS scores via Student paired t test with significance determined as P < .05. In total, 229 unique patients were included in this study. Results: Statistically significant associations were found between all FAOS and SF-12 subscales ( P < .01). The FAOS symptoms subscale demonstrated the lowest correlation with the SF-12 physical health domains. No floor or ceiling effects were identified. Weak correlations were calculated between the 5 FAOS subscales and the SF-12 mental component summary score. All FAOS domains met the threshold for acceptable content validity (score > 2.0). All FAOS subscales demonstrated acceptable test-retest reliability, with ICC values ranging from 0.81 (ADL) to 0.92 (Pain). Conclusion: This study demonstrates the acceptable yet moderate construct and content validity, reliability, and responsiveness of the FAOS for patients with OLTs of the ankle joint. We endorse the use of the FAOS in evaluating ankle OLTs in both the research and clinical setting and consider it a useful patient-reported, self-administered instrument following surgical intervention. Level of Evidence: Level IV, retrospective case study.

Abstract Background: Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in OC, immune checkpoint blockade therapy has been ineffective. Recently studies have shown that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity. One target involved in the DDR that has the potential to be of therapeutic value is protein phosphatase 4 (PP4); however, the effect of PP4 deficiency on anti-tumor immunity remain unknown. Results: Our results show that PP4 inhibition combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using a panel of ovarian cancer cells, we show that PP4 inhibition triggers inflammatory signaling via NF-κB and STAT1 activation resulting in increased expression of pro-inflammatory cytokines including IFNβ1, CCL5, CXCL10, and IL-6. Moreover, conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and NK cells over carboplatin treatment alone. Knockdown of STING in OC cells significantly abrogated the increase in CD8 T cell migration induced by PP4 inhibition. PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell IFN-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of ovarian cancer resulted in significant reduction of tumor growth in vivo. PP4C low tumors had increased infiltration of CD161+ NK cells and CD4+ T cells. Addition of low dose carboplatin treatment in vivo led to increased CD8+ T cell infiltration in PP4C low tumors when compared to the untreated groups. Conclusions: Our work has identified a role for PP4 inhibition in promoting anti-tumor immune activation. These findings provide the rationale for combining PP4 inhibitors with immunotherapy as a new approach in ovarian cancer treatment. Citation Format: Remya Raja, Christopher Wu, Esen Y. Bassoy, Thomas Rubino, Emma Utagawa, Paul Magtibay, Kristina Butler, Marion Curtis. Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4455.

Abstract Artificial intelligence (AI) based digital pathology has been getting rapid adoption over the last 2 to 3 years These AI based digital pathology models can analyze samples at high resolution and scale Retaining that resolution at scale through molecular analysis is key to the discovery of novel biomarkers We have developed a technology that can integrate AI-supported digital pathology (DP) algorithms to identify informative tissue regions for selective microdissection to improve molecular analysis of FFPE material The system is capable of extracting DNA, RNA or proteins with cellular (10 micron) resolution from FFPE tissue sections. The samples are ready for use in off-the-shelf molecular analysis workflows (qPCR, Next Gen Sequencing, etc) The system decreases the tumor cellularity requirements for clinical analysis by extracting only the area enriched for informative biomarkers To demonstrate the capability of the system we used an AI based digital pathology model that was developed to identify multiple cellular phenotypes from a H&E stained colorectal cancer FFPE tissue sections We used the digital pathology output to guide the microdissection of RNA from tumor buds, carcinoma, immature stroma and inflammatory stroma in a paired designed RNA seq experiment The data showed that the system is capable of enriching the tumor-bud tissue content from&lt;1% in the tissue to ~50% purity in the crude lysate Bioinformatic analysis of the RNAseq signatures showed that the tumor buds had a distinct RNAseq signature relative to the other three cell types and that the gene expression pattern was consistent with EMT pathways. The methodology is scalable, robust, and simpler than current microdissection techniques. This technology can be used to develop novel tests by integrating with AI algorithms, targeting tissue enriched for predictive biomarkers, and enabling low tumor cellularity samples to be analyzed with high precision. Citation Format: John H. Butler, Bidhan Chaudhuri, Katie Konigsfeld, Rish Pai. A novel digitally directed tissue microdissection platform integrates digital pathology with molecular analysis: Case study in metastatic colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4320.