Citations

6509 Background: Accrual of underrepresented populations (URPs-racial and ethnic minorities, women, rural populations, and younger and older populations) to clinical trials has been historically low, hampering progress in cancer treatment, symptom intervention and prevention for all. In 2018, the Alliance for Clinical Trials in Oncology (Alliance), as a part of the NCI's National Clinical Trials Network (NCTN) and a Research Base for the NCI Community Oncology Research Program (NCORP) began a multi-pronged strategy to increase accrual of underrepresented minorities by race and ethnicity (URMs) to both treatment and cancer control trials conducted by the Alliance. Methods: Alliance leadership set a goal of 20% accrual for racial and ethnic minorities to all trials in 2018. The Health Disparities Committee (HDC) implemented several strategies over time including leadership promotion/expectation of goals; funding junior investigators and special projects focusing on URPs; working groups for specific populations in HDC; HDC co-chairs to selected protocols; translation services of patient facing materials; opening studies at NCORP Minority Underserved Sites; real time monitoring of accrual demographics, by Alliance and by site; protocols addressing aims for specific populations; closing protocol enrollment to majority populations; and increasing the study sample size to enroll additional minority participants to allow for analyzing intervention effects by subgroups. Results: Accrual data from 117 NCTN and NCORP trials led by Alliance was included from 2014-2022. Over time, accrual of racial and ethnic minorities increased from 13.6% to 25.3% for treatment and 13% to 21.5% for cancer control trials. This results in overall increase from 13.5 % to 23.6% of URMs for all trials, a 74.8% improvement. Conclusions: Intentional approaches to increase URMs has led to an increase in URM accruals to Alliance trials. Future strategies include implementation of the Alliance Patient Questionnaire to prospectively measure the prevalence of specific social determinants of health among patients enrolled to further expand the understanding and address the needs of unique population accrued to Alliance trials. In addition, accrual of women, rural populations, and younger and older adults (65+ years) are now being monitored over time to increase all URP accruals.

4597 Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]

AbstractAn increasing number of machine learning applications are being developed and applied to digital pathology, including hematopathology. The goal of these modern computerized tools is often to support diagnostic workflows by extracting and summarizing information from multiple data sources, including digital images of human tissue. Hematopathology is inherently multimodal and can serve as an ideal case study for machine learning applications. However, hematopathology also poses unique challenges compared to other pathology subspecialities when applying machine learning approaches. By modeling the pathologist workflow and thinking process, machine learning algorithms may be designed to address practical and tangible problems in hematopathology. In this article, we discuss the current trends in machine learning in hematopathology. We review currently available machine learning enabled medical devices supporting hematopathology workflows. We then explore current machine learning research trends of the field with a focus on bone marrow cytology and histopathology, and how adoption of new machine learning tools may be enabled through the transition to digital pathology.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

AbstractGlucagon‐like peptide 1 receptor agonists (GLP‐1 RAs) reduce elevated blood glucose levels and induce weight loss. Multiple GLP‐1 RAs and one combined GLP‐1/glucose‐dependent insulinotropic polypeptide agonist are currently available. This review was conducted with the aim of summarising direct comparisons between subcutaneous semaglutide and other GLP‐1 RAs in individuals with type 2 diabetes (T2D), particularly with respect to efficacy for inducing weight loss and improving other markers of metabolic health. This systematic review of PubMed and Embase from inception to early 2022 was registered on PROSPERO and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and Meta‐Analysis of Observational Studies in Epidemiology guidelines. Of the 740 records identified in the search, five studies fulfilled the inclusion criteria. Comparators included liraglutide, exenatide, dulaglutide and tirzepatide. In the identified studies, multiple dosing regimens were utilised for semaglutide. Randomised trials support the superior efficacy of semaglutide over other GLP‐1 RAs with respect to weight loss in T2D, but tirzepatide is more effective than semaglutide.

AbstractOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

(1) Introduction: Traumatic brain injury (TBI) is a leading cause of injury and mortality worldwide, carrying an estimated cost of $38 billion in the United States alone. Neutrophil to lymphocyte ratio (NLR) has been investigated as a standardized biomarker that can be used to predict outcomes of TBI. The aim of this review was to determine the prognostic utility of NLR among patients admitted for TBI. (2) Methods: A literature search was conducted in PubMed, Scopus, and Web of Science in November 2022 to retrieve articles regarding the use of neutrophil to lymphocyte ratio (NLR) as a prognostic measure in traumatic brain injury (TBI) patients. Inclusion criteria included studies reporting outcomes of TBI patients with associated NLR values. Exclusion criteria were studies reporting only non-primary data, those insufficiently disaggregated to extract NLR data, and non-English or cadaveric studies. The Newcastle-Ottawa Scale was utilized to assess for the presence of bias in included studies. (3) Results: Following the final study selection 19 articles were included for quantitative and qualitative analysis. The average age was 46.25 years. Of the 7750 patients, 73% were male. Average GCS at presentation was 10.51. There was no significant difference in the NLR between surgical vs. non-surgical cohorts (SMD 2.41 95% CI −1.82 to 6.63, p = 0.264). There was no significant difference in the NLR between bleeding vs. non-bleeding cohorts (SMD 4.84 95% CI −0.26 to 9.93, p = 0.0627). There was a significant increase in the NLR between favorable vs. non-favorable cohorts (SMD 1.31 95% CI 0.33 to 2.29, p = 0.0090). (4) Conclusions: Our study found that NLR was only significantly predictive for adverse outcomes in TBI patients and not surgical treatment or intracranial hemorrhage, making it nonetheless an affordable alternative for physicians to assess patient prognosis.

475 Background: Emerging evidence supports use of neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for appropriately selected patients with upper tract urothelial carcinoma (UTUC). However, oncologic outcomes have not been well characterized for patients with residual muscle-invasive disease after NAC. Methods: We used a multi-institutional cohort from 24 centers in the U.S., Europe, and Japan to retrospectively identify patients who underwent RNU for UTUC from 1985-2022 and had high-grade muscle-invasive disease. We stratified the cohort based on receipt of NAC (>ypT2 vs. >pT2). Exclusion criteria included receipt of adjuvant chemotherapy, concurrent cystectomy with RNU, and distant metastatic disease. Baseline characteristics were compared between groups. Kaplan-Meier survival analysis with log-rank test was used to compare differences in recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Multivariable Cox regression and Fine-Gray competing risk regression were used to determine predictors of these outcomes. Results: A total of 1,233 patients were included, 62 of whom received NAC prior to RNU. A platinum-based regimen was used in 90% of NAC recipients, and the median number of cycles administered was 4 (IQR: 3-5). Median follow-up time among all patients was 22 months (IQR: 8-47 mo.). NAC recipients were more likely to have pathologic node positivity (35% vs. 13%) and less likely to have positive tumor margins (8% vs. 28%). On Kaplan-Meier analysis, NAC recipients with residual >ypT2 disease had poorer outcomes than those with >pT2 disease (2-year RFS [NAC vs. no NAC]: 52% vs. 80%, p<0.001; 2-year OS: 60% vs. 78%, p=0.003; 2-year CSS: 61% vs. 86%, p<0.001). Multivariable analyses also showed a statistically significant association between residual muscle-invasive disease after NAC and poorer RFS, OS, and CSS (Table). Conclusions: NAC recipients with >ypT2 disease at RNU after exhibit poorer outcomes than stage-matched chemotherapy naïve counterparts. This may reflect effects of occult micrometastatic disease or chemoresistant primary tumors in non-responders. Our data highlight the need to improve prospective identification of candidates most likely to respond to NAC prior to RNU for UTUC in order to maximize its therapeutic benefit. [Table: see text]

Background: Despite the well-established potent benefit of mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke, access to MT has not been studied globally. We conducted a worldwide survey of countries on 6 continents to define MT access (MTA), the disparities in MTA, and its determinants on a global scale. Methods: Our survey was conducted in 75 countries through the Mission Thrombectomy 2020+ global network between November 22, 2020, and February 28, 2021. The primary end points were the current annual MTA, MT operator availability, and MT center availability. MTA was defined as the estimated proportion of patients with LVO receiving MT in a given region annually. The availability metrics were defined as ([current MT operators×50/current annual number of estimated thrombectomy-eligible LVOs]×100 = MT operator availability) and ([current MT centers×150/current annual number of estimated thrombectomy-eligible LVOs]×100= MT center availability). The metrics used optimal MT volume per operator as 50 and an optimal MT volume per center as 150. Multivariable-adjusted generalized linear models were used to evaluate factors associated with MTA. Results: We received 887 responses from 67 countries. The median global MTA was 2.79% (interquartile range, 0.70–11.74). MTA was <1.0% for 18 (27%) countries and 0 for 7 (10%) countries. There was a 460-fold disparity between the highest and lowest nonzero MTA regions and low-income countries had 88% lower MTA compared with high-income countries. The global MT operator availability was 16.5% of optimal and the MT center availability was 20.8% of optimal. On multivariable regression, country income level (low or lower–middle versus high: odds ratio, 0.08 [95% CI, 0.04–0.12]), MT operator availability (odds ratio, 3.35 [95% CI, 2.07–5.42]), MT center availability (odds ratio, 2.86 [95% CI, 1.84–4.48]), and presence of prehospital acute stroke bypass protocol (odds ratio, 4.00 [95% CI, 1.70–9.42]) were significantly associated with increased odds of MTA. Conclusions: Access to MT on a global level is extremely low, with enormous disparities between countries by income level. The significant determinants of MT access are the country’s per capita gross national income, prehospital LVO triage policy, and MT operator and center availability.

Abstract Background In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR‐Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR‐Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence‐based findings and recommendation from the full document. Methods ICAR‐Allergic Rhinitis 2023 employed established evidence‐based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results ICAR‐Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion The ICAR‐Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.