Decoding cardiogenic shock: assessing shock index and its variants as prognostic indicators for in-hospital mortality.

BACKGROUND: Cardiogenic shock (CS) is associated with high in-hospital mortality. Objective assessment of its severity and prognosis is paramount for timely therapeutic interventions. This study aimed to evaluate the efficacy of the shock index (SI) and its variants as prognostic indicators for in-hospital mortality. METHODS: A retrospective study involving 1282 CS patients were evaluated. Baseline patient characteristics, clinical trajectory, hospital outcomes, and shock indices were collected and analysed. Receiver operating characteristic (ROC) curves were employed to determine the predictive accuracy of shock indices in predicting in-hospital mortality. RESULTS: Of those evaluated, 866 (67.6%) survived until discharge. Non-survivors were older (66.0 ± 13.7 vs. 57.4 ± 16.2, P < 0.001), had a higher incidence of cardiac risk factors, and were more likely to present with acute coronary syndrome (33.4% vs. 16.1%, P < 0.001) and out-of-hospital cardiac arrest (11.3% vs. 5.3%, P < 0.001). All mean shock indices were significantly higher in non-survivors compared with survivors. ROC curves demonstrated that adjusted shock index (ASI), age-modified shock index (AMSI), and shock index-C (SIC) had the highest predictive accuracy for in-hospital mortality, with AUC values of 0.654, 0.667, and 0.659, respectively. Subgroup analysis revealed that SIC had good predictive ability in patients with STEMI (AUC: 0.714) and ACS (AUC: 0.696) while AMSI and ASI were notably predictive in the OHCA group (AUC: 0.707 and 0.701, respectively). CONCLUSIONS: Shock index and its variants, especially ASI, AMSI, and SIC, may be helpful in predicting in-hospital mortality in CS patients. Their application could guide clinicians in upfront risk stratification. SIC, ASI, and AMSI show potential in predicting in-hospital mortality in specific CS subsets (STEMI and OHCA). This is the first study to evaluate SI and its variants in CS patients.

Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia.

In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1+ preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms.

A clinical laboratory-developed LSC17 stemness score assay for rapid risk assessment of patients with acute myeloid leukemia.

Leukemia stem cells (LSCs) are linked to relapse in acute myeloid leukemia (AML). The LSC17 gene expression score robustly captures LSC stemness properties in AML and can be used to predict survival outcomes and response to therapy, enabling risk-adapted, upfront treatment approaches. The LSC17 score was developed and validated in a research setting. To enable widespread use of the LSC17 score in clinical decision making, we established a laboratory-developed test (LDT) for the LSC17 score that can be deployed broadly in clinical molecular diagnostic laboratories. We extensively validated the LSC17 LDT in a College of American Pathologists/Clinical Laboratory Improvements Act (CAP/CLIA)-certified laboratory, determining specimen requirements, a synthetic control, and performance parameters for the assay. Importantly, we correlated values from the LSC17 LDT to clinical outcome in a reference cohort of patients with AML, establishing a median assay value that can be used for clinical risk stratification of individual patients with newly diagnosed AML. The assay was established in a second independent CAP/CLIA-certified laboratory, and its technical performance was validated using an independent cohort of patient samples, demonstrating that the LSC17 LDT can be readily implemented in other settings. This study enables the clinical use of the LSC17 score for upfront risk-adapted management of patients with AML.

Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.

Combined loss of function of two different loci of miR-15/16 drives the pathogenesis of acute myeloid leukemia.

Double knockout of the two miR-15/16 loci in mouse resulted in the development of acute myeloid leukemia (AML). This result suggested that, at least, a fraction of human AMLs could be due to a similar mechanism. We analyzed the role of the two miR-15/16 clusters in 93 myelodysplastic syndrome (MDS) patients divided in three subgroups: patients with MDS, patients with MDS before transforming into AML (MDS-T), and patients with AML evolving from MDS (MDS-AML). Then, we tested 139 AML cases and 14 different AML cell lines by assessing microRNA (miRNA) expression, target protein expression, genetic loss, and silencing. MDS-T and MDS-AML patients show a reduction of the expression of miR-15a/-15b/-16 compared to MDS patients. Each miRNA can significantly predict MDS and MDS-T groups. Then, 79% of primary AMLs show a reduced expression of miR-15a and/or miR-15b. The expression of miR-15a/-15b/-16 significantly stratified AML patients in two prognostic classes. Furthermore, 40% of AML cell lines showed a combined loss of the expression of miR-15a/-15b and overexpression of their direct/indirect targets. As potential mechanisms involved in the silencing of the two miR-15/16 loci, we identified a genetic loss of miR-15a and miR-15b and silencing of these two loci by methylation. We identified a potential driver oncogenic role in the loss of expression of both miR-15/16 clusters in the progression of MDS into AML and in AML pathogenesis. The stratification of AML patients, based on miR-15/16 expression, can lead to targeted and combination therapies for the treatment of this incurable disease.

The utility and safety of flexible bronchoscopy in critically ill acute leukemia patients: a retrospective cohort study.

PURPOSE: Flexible bronchoscopy with bronchoalveolar lavage (BAL) is commonly performed in immunocompromised patients. Nevertheless, it remains unclear whether bronchoscopy with BAL leads to changes in medical management or is associated with procedural complications among critically ill acute leukemia (AL) patients. METHODS: We evaluated 71 AL patients who underwent diagnostic bronchoscopy with BAL in the intensive care unit (ICU) between 1 January 2007 and 31 December 2012. We recorded baseline characteristics, vital signs (before, during, and after the procedure), changes in medical management following the procedure, and procedural complications. Using a multivariable logistic regression model, we explored the relationship between patient characteristics and whether bronchoscopy changed management or caused complications. Patient characteristics included as predictors in the regression model were age, sex, immunosuppression status (those undergoing active chemotherapy), and the Acute Physiology And Chronic Health Evaluation II score. RESULTS: The most common indication for ICU admission was respiratory failure (51 patients, 72%), followed by sepsis (14 patients, 20%). Overall, the results obtained from bronchoscopy with BAL were associated with a change in management in 32 patients (45%), most commonly a change in antimicrobial therapy as a result of an infectious pathogen being identified (17 patients, 24%). Complications were documented in nine patients (13%) and included post-procedural hypoxia (six patients, 8%), the need for intubation (one patient, 9% of non-intubated patients), and tracheal perforation (one patient, 1%). No clinically significant changes in patient vital signs were observed during or immediately following the procedure. Patient characteristics did not predict whether bronchoscopy was associated with changes in medical management or procedural complications in multivariable analyses. CONCLUSIONS: Flexible bronchoscopy with BAL is relatively safe and helps to guide medical management among patients with AL admitted to the ICU.

A 17-gene stemness score for rapid determination of risk in acute leukaemia.

Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC+ and 89 LSC- cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

Outcomes and Predictors of Mortality for Patients with Acute Leukemia Admitted to the Intensive Care Unit.

Purpose. The objectives were to describe the management and outcomes of acute leukemia (AL) patients admitted to the ICU and to identify predictors of ICU mortality. Methods. Data was retrospectively collected from the medical records of all patients with AML or ALL admitted to the Mount Sinai Hospital ICU from August 2009 to December 2012. Results. 151 AL patients (117 AML, 34 ALL) were admitted to the ICU. Mean age was 54 (SD 15) years, median APACHE II score was 27 (IQR 22-33), and 50% were female. While in ICU, 128 (85%) patients had sepsis and 56 (37%) had ARDS. The majority of patients required invasive organ support: 94 (62%) required mechanical ventilation while 23 (15%) received renal replacement therapy. Multivariable analysis identified SOFA score (OR 1.18, 95% CI 1.01-1.38) and invasive ventilation (OR 9.64, 95% CI 3.39-27.4) as independent predictors of ICU mortality. Ninety-four (62%) patients survived to ICU discharge. Only 39% of these 94 patients discharged were alive 12 months after ICU admission. Conclusions. AL patients admitted to the ICU had a 62% ICU survival rate; yet only 25% of cohort patients were alive 12 months after ICU admission. Higher admission SOFA scores and invasive ventilation are independently associated with a greater risk of dying in the ICU.