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Objectives: To develop a desirability of outcome ranking (DOOR) scale for use in children with septic shock and determine its correlation with a decrease in 3-month postadmission health-related quality of life (HRQL) or death., Design: Secondary analysis of the Life After Pediatric Sepsis Evaluation prospective study., Setting: Twelve U.S. PICUs, 2013-2017., Patients: Children (1 mo-18 yr) with septic shock., Interventions: None., Measurements and Main Results: We applied a 7-point pediatric critical care (PCC) DOOR scale: 7: death; 6: extracorporeal life support; 5: supported by life-sustaining therapies (continuous renal replacement therapy, vasoactive, or invasive ventilation); 4: hospitalized with or 3: without organ dysfunction; 2: discharged with or 1: without new morbidity to patients by assigning the highest applicable score on specific days post-PICU admission. We analyzed Spearman rank-order correlations (95% CIs) between proximal outcomes (PCC-DOOR scale on days 7, 14, and 21, ventilator-free days, cumulative 28-day Pediatric Logistic Organ Dysfunction-2 (PELOD-2) scores, and PICU-free days) and 3-month decrease in HRQL or death. HRQL was measured by Pediatric Quality of Life Inventory 4.0 or Functional Status II-R for patients with developmental delay. Patients who died were assigned the worst possible HRQL score. PCC-DOOR scores were applied to 385 patients, median age 6 years (interquartile range 2, 13) and 177 (46%) with a complex chronic condition(s). Three-month outcomes were available for 245 patients (64%) and 42 patients (17%) died. PCC-DOOR scale on days 7, 14, and 21 demonstrated fair correlation with the primary outcome (-0.42 [-0.52, -0.31], -0.47 [-0.56, -0.36], and -0.52 [-0.61, -0.42]), similar to the correlations for cumulative 28-day PELOD-2 scores (-0.51 [-0.59, -0.41]), ventilator-free days (0.43 [0.32, 0.53]), and PICU-free days (0.46 [0.35, 0.55])., Conclusions: The PCC-DOOR scale is a feasible, practical outcome for pediatric sepsis trials and demonstrates fair correlation with decrease in HRQL or death at 3 months., Competing Interests: Dr. Logan’s institution received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (K23HD096018) (R01HD073362 and cooperative agreements U10-HD050012, U10-HD050096, U10-HD063108, U10-HD049983 U10-HD049981, U10-HD063114, and U10-HD063106). Drs. Logan, Banks, Reeder, Meert, Zimmerman, and Maddux received support for article research from the National Institutes of Health (NIH). Drs. Banks, Bennett, and Zimmerman’s institutions received funding from the NICHD. Dr. Banks disclosed government work. Drs. Reeder and Meert’s institutions received funding from the NIH. Dr. Bennett’s institution received funding from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute. Dr. Zimmerman’s institution received funding from Immunexpress; he received funding from Elsevier Publishing. Dr. Maddux’s institution received funding from the NICHD (K23 HD096018) and the Francis Family Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities., Methods: We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set., Results: DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors., Conclusion: Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.

Objectives: Cytokine release syndrome (CRS) is a potentially lethal toxicity associated with chimeric antigen receptor T cell therapy for pediatric acute lymphoblastic leukemia (ALL). Outcomes after critical illness due to severe CRS are poorly described. Our aim was to characterize critical illness outcomes across a multicenter cohort of PICU patients with ALL and CRS., Design: Multicenter retrospective cohort study., Setting: Twenty-one PICUs contributing data to Virtual Pediatric Systems, LLC (January 2020-December 2021)., Patients: PICU patients with ALL or unclassified leukemia and CRS., Interventions: None., Measurements and Main Results: We identified 55 patients; 34 (62%) were 12 years or older, 48 (87%) were admitted from a hospital inpatient ward, and 23 (42%) received advanced organ failure support or monitoring. Fifty-one survived to PICU discharge (93%) including 19 of 23 (83%) who received advanced organ failure support or monitoring defined as receipt of noninvasive or invasive ventilation, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, continuous renal replacement therapy, or placement of a tracheostomy, arterial catheter, hemodialysis catheter, or intracranial catheter. Twelve patients (22%) received invasive ventilation, nine of whom survived to PICU discharge. Two of four patients who received continuous renal replacement therapy and one of three patients who required cardiopulmonary resuscitation survived to PICU discharge. Lengths of PICU stay were median 3.0 days (interquartile range, 1.4-7.8 d) among PICU survivors, 7.8 (5.4-11.1) among those receiving advanced organ failure support or monitoring, and 7.2 days (interquartile range, 2.9-14.7 d) among nonsurvivors. Of the 51 patients who survived to PICU discharge, 48 (94%) survived the hospitalization., Conclusions: PICU patients with CRS frequently received a high level of support, and the majority survived their PICU stay and hospitalization. Additional multicenter investigations of severe CRS are necessary to inform evidence-based practice., Competing Interests: Drs. Kohler and Maddux received support for article research from the National Institutes of Health; they disclosed the off-label products use of tocilizumab, glucocorticoids, siltuximab, and anakinra. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation/Parker B. Francis Fellowship. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer., Methods: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures., Results: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression., Conclusions: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming., Trial Registration: Not applicable (non-interventional study). CRUK Internal Database Number 14232., (© 2021. The Author(s).)