Citations

IMPORTANCE: Aggressive fluid resuscitation remains a cornerstone of the Surviving Sepsis Campaign (SSC) guidelines, but there is growing controversy regarding the recommended 30 mL/kg IV fluid dosage. It is contended that, in selected patients, this volume confers an increased risk of volume overload without either concomitant benefit or strong evidence in support of the recommended IV fluid dosage. OBJECTIVES: Assessment of practice patterns and their impact on patient outcomes following the surviving sepsis guidelines for fluid resuscitation. DESIGN: Large, multisite retrospective cohort study. SETTING AND PARTICIPANTS: The retrospective study included all adult patients who presented to the emergency department at one of 19 different Mayo Clinic sites throughout the Midwest, Southeast, and Southwest from August 2018 to November 2020 with suspected sepsis. MAIN OUTCOMES AND MEASURES: Eight-thousand four-hundred fourteen patients suspected to have sepsis were assessed regarding fluid resuscitation and outcomes among patients receiving 30 mL/kg IV fluid dosing compared with patients who did not. Patient demographics and clinical information were collected via electronic health records. Patients were divided into two cohorts: those who received 0–29.9 mL/kg of IV fluid and those who received 30.0+ mL/kg of IV fluid. Statistical analyses were performed to evaluate the impact of fluid dose on in-hospital death, 30-day mortality, ICU admission after diagnosis, dialysis initiation after diagnosis, ventilator use, vasopressor use, as well as ICU and hospital length of stay. RESULTS: We observed lower in-hospital mortality and 30-day mortality risk in the 30+ mL/kg dosing group. Increased fluid dosage did, however, carry a much greater chance of ICU admission. Most patients (72% after propensity score weighting) in our population received less than 30 mL/kg fluid (based on ideal body weight). CONCLUSIONS AND RELEVANCE: IV fluid dosing for sepsis resuscitation greater than 30 mL/kg was associated with decreased risk of in-hospital mortality, 30-day mortality, and reduced risk of requiring mechanical ventilation. Our data does ultimately seem to support the SSC recommendation.

Objectives Palliative Medicine involvement in MICU patients have improved length of stay and mortality, but with varying effects on specific patient decision outcomes, such as, advance care planning. These studies have utilized Palliative Medicine later in the hospital or ICU course, with some evidence showing that earlier involvement resulted in better results. The purpose of this study was to evaluate the benefits of early (within 24 hours) palliative care consultation in medical ICU (MICU) patients to clinical and satisfaction outcomes. Methods An unblinded randomized study performed in the MICU in one academic hospital in the USA. Ninety-one adult patients admitted to MICU received a Palliative care medicine consultation within 24 hours as the intervention. Measurements and results Ninety-one patients admitted to the MICU underwent randomization with 50 patients randomly assigned to receive Palliative Medicine consultation and 41 patients randomly assigned to receive standard-of-care based on predefined criteria. The median satisfaction score was 23 points higher for the patients in the intervention group (P < .001). The median length of MICU stay was 5 days shorter in the intervention group compared to the control group (95% CI; 1 day to 18 days, P = .018). Advance care planning was completed in the hospital for 34% of patients in the intervention arm and 12% of patients in the controls arm (absolute risk difference 22%, 95% CI 4% to 37%, P = .016). Conclusion Early Palliative Medicine consultation within 24 hours of MICU admission showed significant benefits to patients by improving satisfaction and decreasing length of stay. This study provides evidence that Palliative Medicine involvement earlier in the course of severe disease is important. Further studies in other types of intensive care units (neurological and Cardiovascular) are necessary to determine their impact.

Abstract Background Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. Methods We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. Results Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78–2.15; P = .32). Conclusions Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

e19007 Background: While clinical outcomes of patients (pts) with TP53 mutated (m) acute myeloid leukemia (AML) are dismal, subsets of pts with eligibility to curative intent therapies can do better. As racial disparities are known to impact outcome in hematological malignancies, we sought to explore disparities in TP53m AML. Methods: We conducted a multicenter study of 304 TP53m AML pts, divided into 2 groups, White (n= 240) and Black/Hispanic (n=64), to compare difference in disease characteristics and clinical outcome. We grouped Black and Hispanic together as the number of pts were small in each group and our aim was to evaluate outcome in under-represented races/ethnicities. Results: Baseline characteristics are summarized in Table. The median age of the pts was comparable between White and Black/Hispanic (p= 0.97). A significantly higher proportion of Black/Hispanic pts (23%) had diabetes mellitus when compared with White (14%) pts (p= 0.02). A higher proportion of Black/Hispanic pts had therapy-related AML (33% vs. 20%, p= 0.03), complex cytogenetics (98% vs. 87%, p= 0.003) and co-mutations (70% vs. 57%, p= 0.02). The proportion of pts who received hypomethylating agent + venetoclax (29% vs 20%, p= 0.20) or CPX-351 (22% vs 20%, p= 0.13) were comparable between White and Black/Hispanic, respectively. A higher proportion of Black/Hispanic pts received supportive care (17% vs. 4%, p= 0.002). White pts had higher rates of complete remission with or without count recovery (25% vs. 19%, p= 0.07). Only 6% of Black/Hispanic pts received allogeneic stem cell transplantation (alloHCT) compared to 16% for White pts (p= 0.01). The median event free survival was 2 months (mo) (95% CI;1.52-2.41) and 2.5 mo (95% CI:1.62-3.31) in White and Black/Hispanic pts, respectively (p= 0.71). The median overall OS was shorter for Black/Hispanic (6.37 mo [95% CI:2.88-9.85]) than for White (6.90 mo [95% CI:5.55-8.24] [p= 0.009]). Conclusions: Our study demonstrates poorer OS in Black/Hispanic pts with TP53m AML. Potential drivers of this disparity include lower alloHCT rates, higher rates of pts receiving supportive care, and higher-risk disease in Black/Hispanic pts.[Table: see text]

TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.

e16550 Background: Improved computational power and modern algorithms have generated significant interest in radiomics for cancer diagnosis and staging. Here we assess the performance of deep learning (DL) models as a means for feature extraction in combination with supervised machine learning (ML) algorithms for accurate staging and chemotherapy response assessment of bladder cancer. Methods: Deidentified grayscale CT images from bladder cancer patients scheduled to undergo radical cystectomy were included in this retrospective study. These images were manually annotated with two regional masks (normal region and cancer region). Five DL models- namely, AlexNet, GoogleNet, InceptionV3, ResNet-50, and XceptionNet pre-trained on the ImageNet dataset, a public dataset, were then fine-tuned on our bladder CT scan data to extract features. Through feature selection process, the subset of the features was used to build ML classifiers for classification. The classification was performed using five different ML classifiers, namely k-Nearest Neighbor (KNN), Naïve-Bayes (NB), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and Decision Tree (DT). The classification task was performed with 10-fold cross-validation, and each of the experiments contained a different but not mutually exclusive subset of samples. The evaluation metrics include accuracy, sensitivity, specificity, precision, and F1-score. Results: A total of 200 deidentified grayscale CT images of 100 patients with histologically proven bladder cancer, were included in this study. For experiment (1) normal vs. cancer, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 86.07%, sensitivity of 96.75%, specificity of 69.65%, precision of 83.07%, and F1-score of 89.39%. For experiment (2) non-muscle invasive Cancer (NMIBC) vs. muscle invasive bladder cancer (MIBC), the LDA classifier on XceptionNet based features provided the best performance with an accuracy of 79.72%, sensitivity of 66.62%, specificity of 87.39%, precision of 75.58%, and F1-score of 70.81%. For experiment (3) T0 lesion vs. MIBC, the LDA classifier on XceptionNet based features provides the best performance with an accuracy of 74.96%, sensitivity of 80.51%, specificity of 70.22%, precision of 69.78%, and F1-score of 74.73%. Conclusions: Our proposed model has shown good results in differentiating normal vs cancer and promising performance in differentiating T0 vs MIBC after chemotherapy treatment. We are expanding our dataset to further improve the performance in differentiating T0 vs MIBC. In addition, we will investigate the applicability of GAN for data augmentation to address data limit. We believe the hybrid DL and ML framework may facilitates radiologists' decisions and clinical decision-making in patients with bladder cancer.

518 Background: Cisplatin (C) based neoadjuvant chemotherapy (NAC) has been the mainstay treatment for muscle invasive bladder cancer (MIBC). However, the optimal choice of NAC is not well-established. We therefore conducted a network-meta-analysis (NMA) to assess comparative efficacy of different treatment options. Methods: Several electronic databases (MEDLINE, and EMBASE) and conference proceedings were systematically used to identify randomized trials evaluating first-line treatments in neoadjuvant MIBC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and pathologic complete response (pCR). DerSimonian-Laird random-effects meta-analysis was used to compute direct comparisons between NAC and local therapy (LT) only. Fixed effect NMA was conducted within the frequentist framework for mixed treatment comparisons. P-scores were used to assess relative treatment rankings. All statistical analyses were conducted in R (v 4.1.1). Results: This systematic review included 23 trials (25 references) with a total of 5313 patients with 10 unique treatments. Direct comparisons showed significant benefit in PFS (HR: 0.82; 95% CI: 0.71-0.94), and in OS (HR: 0.85; 95% CI: 0.78-0.92) with NAC when compared to LT only. However, the likelihood of achieving an objective response (RR: 1.18; 95% CI: 0.72-1.95: I2: 85%) or CR (RR: 1.51; 95% CI: 0.87-2.61; I2: 79%) was not different between the two arms. Data available in 15 trials contributed to the network for PFS outcome while only eight trials contributed to OS outcome. Mixed treatment comparisons showed significantly improved PFS with nintedanib-gemcitabine-cisplatin (NinGC; HR: 0.42; 95% CI: 0.20-0.87) and dose-dense-methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC; HR: 0.61; 95% CI: 0.43-0.88) compared to LT only. Consistent benefit was observed when NinGC (HR: 0.48; 95% CI: 0.24-0.97) and ddMVAC (HR: 0.70; 95% CI: 0.51-0.96) were compared to GC only. However, no significant differences were observed between NinGC (rank 1) and ddMVAC (rank 2) or among other mixed treatment comparisons. Similarly, OS was significantly improved with NinGC (rank 1) relative to MVAC (HR: 0.41; 95% CI: 0.17-0.97), MVC (HR: 0.37; 95% CI: 0.16-0.88), MC (HR: 0.38; 95% CI: 0.16-0.92), AC (HR: 0.36; 95% CI: 0.15-0.91), and GC (HR: 0.39; 95% CI: 0.17-0.90). While similar results were observed with ddMVAC (rank 2) when compared to MVC (HR: 0.63; 95% CI: 0.42-0.94), MC (HR: 0.64; 95% CI: 0.42-0.98), and GC (HR: 0.66; 95% CI: 0.47-0.92), no significant differences were observed with ddMVAC when compared to MVAC (HR: 0.62; 95% CI: 0.38-1.01) and NinGC (HR: 1.70; 95% CI: 0.69-4.19). Conclusions: Current evidence shows improved PFS and OS with the use of neoadjuvant ddMVAC and Nin-GC in patients with MIBC relative to other treatment options.

481 Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]