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OBJECTIVES Early warning scores detecting clinical deterioration in pediatric inpatients have wide-ranging performance and use a limited number of clinical features. This study developed a machine learning model leveraging multiple static and dynamic clinical features from the electronic health record to predict the composite outcome of unplanned transfer to the ICU within 24 hours and inpatient mortality within 48 hours in hospitalized children. METHODS Using a retrospective development cohort of 17 630 encounters across 10 388 patients, 2 machine learning models (light gradient boosting machine [LGBM] and random forest) were trained on 542 features and compared with our institutional Pediatric Early Warning Score (I-PEWS). RESULTS The LGBM model significantly outperformed I-PEWS based on receiver operating characteristic curve (AUROC) for the composite outcome of ICU transfer or mortality for both internal validation and temporal validation cohorts (AUROC 0.785 95% confidence interval [0.780–0.791] vs 0.708 [0.701–0.715] for temporal validation) as well as lead-time before deterioration events (median 11 hours vs 3 hours; P = .004). However, LGBM performance as evaluated by precision recall curve was lesser in the temporal validation cohort with associated decreased positive predictive value (6% vs 29%) and increased number needed to evaluate (17 vs 3) compared with I-PEWS. CONCLUSIONS Our electronic health record based machine learning model demonstrated improved AUROC and lead-time in predicting clinical deterioration in pediatric inpatients 24 to 48 hours in advance compared with I-PEWS. Further work is needed to optimize model positive predictive value to allow for integration into clinical practice.

Context.— Cytologic-histologic correlation (CHC) is a Clinical Laboratory Improvement Amendments–mandated requirement for gynecologic cytology, but no similar requirement exists for nongynecologic cytology. This study presents the findings from a College of American Pathologists survey of nongynecologic cytology practice patterns. Objective.— To survey the current CHC practices for nongynecologic cytology. Design.— Data were analyzed from a survey developed by the committee and distributed to participants in the Nongynecologic Cytopathology Education Program mailing. Results.— Adoption of CHC for nongynecologic cytology cases is worldwide, with 88.5% of institutions performing CHC on these specimens, a substantial increase from previous years. Performance of CHC varied by institution type, with clinic or regional/local independent laboratories and national/corporate laboratories performing CHC significantly less frequently than hospitals, university hospitals/academic medical centers, and Veterans Administration/Department of Defense hospital institutions. Most CHC was performed concurrently in real time, when the corresponding surgical specimen was reviewed. Selection for real-time concurrent CHC was by the interpreting pathologist, the pathologist diagnosing the surgical biopsy sample or cytopathology case, or both. Sampling was by far the most common reason for discordance. A 2-step difference was the most frequent threshold for discordance between cytology and surgical specimens, but this criterion varied among institutions, with no majority definition. The positive predictive value of a positive cytology finding was calculated rarely in North American institutions but was calculated more frequently in international institutions. Conclusions.— CHC practices for nongynecologic cytopathology mirror those found for CHC of gynecologic cytopathology.

ImportanceIncarcerated patients admitted to the hospital face threats to their rights to privacy and self-determination in medical decision-making. Little is known about medical decision-making processes for hospitalized incarcerated persons who lack decisional capacity.ObjectiveTo characterize the prevalence of incapacity among hospitalized incarcerated patients and describe the decision-making processes, including who served as surrogate decision-makers, involvement of prison employees in medical decisions, and ethical concerns emerging from the patients’ care.Design, Setting, and ParticipantsRetrospective descriptive and qualitative study of medical records for all patients admitted from prison for at least 24 hours between January 1, 1999, and September 1, 2019, at a large Midwestern academic medical center. Data analysis was performed from March 15, 2021, to December 14, 2022.Main Outcomes and MeasuresPrevalence of prison-to-hospital admissions for patients with a loss of capacity and characteristics of medical decision-making.ResultsDuring the 20-year study period, 462 patients from the prison were admitted to the hospital, totaling 967 unique admissions. Of these, 131 admissions (14%) involved patients with a loss of capacity and 43 admissions (4%, representing 34 unique patients) required surrogate decision-making. Ten of these patients had advance directives. Surrogate decision-makers often faced decisions about end-of-life care (n = 17) or procedural consent (n = 23). A family member was identified as surrogate decision-maker in 23 admissions. In 6 cases with a kindred surrogate, additional consent was requested from a prison employee. In total, prison employees were documented as being present during or participating in major medical decisions for half of the admissions. Five themes emerged from thematic analysis: uncertainty and misinformation about patient rights and the role of prison employees in medical decision-making with respect to these two themes, privacy violations, deference to prison officials, and estrangement from family and friends outside of the prison.Conclusions and RelevanceIn this first in-depth description, to date, of decision-making practices for hospitalized incarcerated patients lacking decisional capacity, admissions of these patients generated uncertainty about their rights, sometimes infringing on patients’ privacy and autonomy. Clinicians will encounter incarcerated patients in both hospital and clinic settings and should receive education on how to support ethically and legally sound decision-making practices for this medically vulnerable population.

Background: Endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) have an unclear benefit in those with pre-stroke dementia or cognitive impairment, as these patients were often excluded from landmark stroke trials. We performed a systematic review and meta-analysis to assess the outcomes of IVT and EVT in these populations. Aims: Our systematic review, conforming to the Meta-Analysis of Observational Studies in Epidemiology guidelines, investigated studies on acute ischemic stroke patients with pre-stroke dementia or cognitive impairment treated with IVT or EVT. Primary outcome was favorable 90-day outcome (mRS 0–2). Secondary outcomes included 90-day mortality, symptomatic intracranial hemorrhage (SICH), and radiographic intracranial hemorrhage (ICH). Summary of review: Nine articles were identified, with five observational studies of IVT use in patients with (n = 1078) and without dementia (n = 2805) being selected for the meta-analysis. There were no significant differences in favorable outcome (adjusted OR: 0.61, 95% CI 0.24–1.59), mortality (unadjusted OR: 1.19, 95% CI 0.86–1.64), ICH (unadjusted OR: 1.32, 95% CI 0.79–2.19), and symptomatic ICH (unadjusted OR: 0.94, 95% CI 0.70–1.25) for patients undergoing IVT with pre-stroke dementia versus those without. One EVT study (n = 615 with dementia vs n = 9600 without) found no significant differences in outcomes apart from an increased odds of ICH for those with pre-existing dementia (adjusted OR: 1.57, 95% CI 1.03–2.40). A pooled analysis of three IVT studies showed no significant association of cognitive impairment (n = 93 vs n = 211 without) with all assessed outcomes, whereas a study of EVT found that pre-stroke cognitive impairment was associated with poor 90-day outcomes (mRS 3–6). Conclusion: These results suggest no substantial safety issues in the use of IVT or EVT for patients with pre-existing dementia or cognitive impairment compared to those without. However, the efficacy of these therapies in this demographic remains uncertain. Further rigorous studies that include a more nuanced outcome measurement approach are warranted. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42021240499.

Introduction: The use of standardized, evidence-based classification systems is crucial for the accurate diagnosis and treatment of diseases. Moreover, standardized classification facilitates research and epidemiologic studies and promotes consistency in communication among healthcare professionals. Since 2016, the revised 4 th edition of the World Health Organization classification (WHO-HAEM4R) has been the global standard for diagnosis of lymphoid malignancies. With the emergence of new data, 2 new classification systems were developed and published in 2022: the 5 th edition of the WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC). Both WHO-HAEM5 and ICC maintain a shared fundamental concept of disease classification that integrates clinical, pathologic, and molecular data. However, they differ on nomenclature, establishment of new entities, and/or diagnostic criteria for some disease categories. To evaluate the impact of these differences on real-world diagnosis of non-Hodgkin lymphoma (NHL), we examined the diagnostic classification of NHL in the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study (NCT02736357). Methods: Initiated in 2015, LEO is an ongoing prospective observational study of patients aged ≥18 years with newly diagnosed NHL. Patients are enrolled at 8 major U.S. medical centers. Clinical, epidemiologic, pathologic, and treatment data are abstracted at baseline and active follow-up is conducted for all patients. Lymphoma subtype is coded for each case based on expert hematopathology re-review of the diagnostic pathology slides, the pathology report, biomarker data, and clinical data. Of note, NHL subtype distribution is similar to SEER data. We studied all patients enrolled in LEO between 7/1/2016 (the date LEO pathology review started using WHO-HAEM4R diagnostic codes) and 5/31/2020. WHO-HAEM4R diagnoses and additional clinicopathologic data, when relevant, were used to map cases into the corresponding WHO-HAEM5 and ICC diagnoses. Differences between WHO-HAEM5 and ICC were annotated for each case as: None - same disease entity; Minor - difference in nomenclature with similar diagnostic criteria; Major - difference in disease category and/or diagnostic criteria; or Unevaluable - insufficient data to assign WHO-HAEM5 and/or ICC diagnosis. Results: LEO enrolled 6143 patients during the study period. Of these, comparison between WHO-HAEM5 and ICC was evaluable in 5730 (93.3%). Unevaluable cases included those without a specific WHO-HAEM4R diagnosis at enrollment (N=384; e.g., patients with a low-grade B-cell lymphoma that could not be definitively sub-classified) and those with a specific WHO-HAEM4R diagnosis, but with insufficient clinicopathologic data to assign a specific WHO-HAEM5 and/or ICC diagnosis (N=29). Of the 5730 evaluable cases, 5376 (93.8%) showed no difference between WHO-HAEM5 and/or ICC diagnosis, 311 (5.4%) showed minor differences (nomenclature only), and 43 (0.8%) showed major differences (Table 1). The 43 major differences all involved B-cell NHLs; 20 (46.5%) were attributable to different approaches to classifying double-hit lymphomas, 21 (48.9%) to classification of splenic/leukemic B-cell lymphomas, and 2 (4.6%) to classification of B-cell lymphomas occurring at specific anatomic sites (Table 2). Conclusion: In a large, prospective lymphoma cohort reflecting real-world clinical practice at 8 major U.S. medical centers, major diagnostic differences in the classification of NHL using WHO-HAEM5 or ICC classification criteria were seen in 0.8%, whereas the remaining 99.2% of diagnoses were either the same or showed differences in nomenclature only. The existence of 2 concurrent classification systems presents potential for discrepancies in pathologic diagnosis, clinical practice, clinical trials, and other lymphoma research. Furthermore, some of the differences between WHO-HAEM5 and ICC are clinically and potentially therapeutically significant, and their resolution requires further study. Nevertheless, our findings argue that the proportion of patients affected would be small in real-world practice settings. This appears largely related to incidence rates of specific lymphoma subtypes, with major differences between the 2 classifications predominantly affecting rare entities, while there is general concordance on the most common forms of NHL.

Background: The use of CAR-T cell therapy has transformed treatment paradigms in B-cell malignancies. Ciltacabtagene autoleucel (cilta-cel) was approved for use in RRMM after four or more prior lines of therapy in 2022. While the pivotal studies exclusively treated patients in an inpatient setting, robust infrastructure planning at some centers across US has fostered outpatient administration of the commercially available product. Outpatient administration of CAR-T is more desirable due to superior financial sustainability, lower healthcare resource utilization, and greater patient autonomy during the treatment. Hence, we conducted a qualitative study to evaluate clinical and administrative perspectives and trends in outpatient administration of commercialized cilta-cel with an aim to understand best practices from certified CAR-T centers in the USA. Methods: A targeted literature review was conducted to better understand current practices around outpatient administration of CAR-T, and inform the development of primary research materials for designing subsequent interviews. Next, two 60-minute exploratory interviews were conducted with multi-stakeholder participants (n=5) from two certified cilta-cel centers, each with significant volume of outpatient administration of cilta-cel. Following the qualitative analysis of interviews, two 90-minute panels were conducted with multi-stakeholder participants (n=14) from six certified cilta-cel centers, including centers from exploratory interviews, focusing on clinical and administrative topics across the patient journey. Results: Each center in the study treated approximately 15-30 patients with cilta-cel in the outpatient setting. Using Likert scales, participants from all centers ranked space/capacity as the most important factor in decision-making process for outpatient cilta-cel administration, and ranked reimbursement incentives as a highly (67% of participants) or a moderately (33%) important factor. All participants agreed that having a dedicated outpatient infrastructure (dedicated space such as bed availability and internal processes including standard operating procedures (SOPs)), 24/7 support, outpatient bone marrow transplant (BMT) or cell therapy experience, and robust multidisciplinary teams were key to setting-up successful outpatient centers for cilta-cel therapy. The participants agreed that cilta-cel can be administered safely in an outpatient setting due to generally predictable, delayed onset of potential AEs, except in patients with significant comorbidities or organ dysfunction. Participants also considered caregiver support and lodging availability as factors of importance for outpatient administration. Institutionally established AE monitoring protocols are critical for safe use of cilta-cel in an outpatient setting. Over 50% of the centers interviewed have recently started to administer tocilizumab to treat mild grade 1 cytokine release syndrome (CRS) in an outpatient setting. Based on the findings across the phases of research, the patient journey for outpatient administration of cilta-cel was updated (Figure 1). While patients may be admitted for toxicity events, 100% of centers interviewed had 24-hour coverage and bed availability for these patients if needed. Conclusions: Overall, this study further supports the notion that centers can safely administer cilta-cel in an outpatient setting, if appropriate infrastructure is in place. Additional best practices for new outpatient sites include adequate infrastructure, SOPs, a well-trained and multidisciplinary team, and education of patients and caregivers (Table 1). Outpatient management and earlier intervention for low-grade AEs is currently evolving, with more real-world research required. Continued expert sharing of best practices can aid centers in implementing outpatient administration of CAR-T therapies. Funding: This analysis was supported by Janssen Research & Development, LLC and Legend Biotech USA, Inc

Introduction: PET/CT is the standard-of-care for staging and therapy response assessment in lymphoma. Fluorodeoxyglucose (FDG)-avidity in extranodal marginal zone lymphoma (EMZL) remains controversial with some variability by extranodal location. The current Lugano classification recommends the use of CT scans only in staging and follow-up for EMZL. However, emerging data from small studies have challenged this suggestion. In this study we aimed to determine the ability of PET/CT to detect FDG-avid EMZL during staging work-up. Methods: First, we retrospectively analyzed the University of Miami (UM) MZL database (period 2/2016-1/2023) searching for patients who underwent staging PET/CT. Images were reviewed by expert radiologists to ascertain avidity of tumor and not surrounding tissue, with specific attention to ocular and GI locations; if scans were not available (n=15), we retrieved data from reports (results presented in part at ICML2023). Next, we aimed to validate the initial UM results additionally analyzing data from imaging reports for patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) MZL cohort (period 7/2015-5/2020), excluding LEO patients from Miami to avoid overlap. Patients with high-grade transformation at diagnosis were excluded. For patients with >1 extranodal site, each location was counted independently. We considered FDG-avid disease if SUVmax was ≥2 as this value is commonly observed between mediastinal blood pool (BP) and liver background. To normalize data, we calculated ratios of lymphoma SUVmax versus both BP and liver background, as available. Patients without measurable disease were excluded from analysis. Results: Among 210 patients with EMZL in the UM cohort, 152 had staging PET/CT and were analyzed. Twenty-two patients demonstrated >1 extranodal site providing a total of 187 locations. The LEO cohort included 411 patients from 7 centers, with 235 having available imaging reports. Fifty-two patients in this cohort demonstrated >1 extranodal site providing a total of 306 locations. Disease distribution is depicted in Table 1. Among 187 EMZL locations in the UM cohort, the most common were gastric (n=33, 17.6%), ocular (n=31, 16.6%), lung (n=30, 16%), skin and soft tissue (n=16, 8.6%, each). Similarly, lung (n=63; 20.6%), soft tissue (n=46; 15%), gastric and ocular (n=34 each; 11%) were common locations in the LEO cohort. EMZL demonstrated FDG-avidity (SUVmax ≥2) across all locations with identical values in both cohorts (UM= 78.1% & LEO= 76.5%). FDG-avidity by location is shown in Table 1A & B with salivary gland (100% & 100%), lung (93.3% & 95.2%), soft tissue (93.8% & 100%), and airways (90.9% & 100%) demonstrating high avidity in both cohorts. Contrarily, skin was commonly non-FDG avid (93.8% & 81%). The median size of FDG-avid lesions was 2.4cm (range, 0.7-17.4) in UM and 2.9cm (range, 0.1-12) in LEO cohorts. In patients with >1 extranodal site FDG-avidity was nearly universal across sites (UM=93% & LEO=100%). We observed a significant correlation between lymphoma size and FDG-avidity for UM (r=0.33; P=0.001), and for LEO (r=0.55; P<0.0001). In patients with background FDG-avidity data in the UM cohort (n=150), a BP index and liver index ≥1 detected lymphoma in 79.3% & 71.5% cases, respectively. We were unable to calculate indexes in LEO cohort since only limited data on BP (n=26) and liver (n=19) background was available in imaging reports. Conclusions: This study represents the largest analysis evaluating accuracy of PET/CT to determine initial tumor burden in 387 patients with EMZL. We demonstrate that EMZL is largely an FDG-avid disease across two cohorts, and PET/CT should be included in the staging of these patients while acknowledging possible limited sensitivity in GI locations due to physiologic uptake. Furthermore, we observed that patients with multiple extranodal locations demonstrate uniform FDG-avidity across all sites except for skin involvement. Based on our results we recommend the incorporation of PET/CT into standard staging of EMZL in planned revised Lugano classification guidelines. In those demonstrating initial FDG-avidity, a lower SUVmax threshold of SUVmax ≥2, comparison to mediastinal BP rather than to liver background activity and evaluating for resolution of focal FDG-avidity should be considered to assess treatment response in routine care and clinical trials.