Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia.

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

Progression-free survival, disease-free survival and other composite end points in oncology: improved reporting is needed.

Composite outcome measures such as progression-free survival and disease-free survival are increasingly used as surrogate end points in oncology research, frequently serving as the primary end point of pivotal trials that form the basis for FDA and EMA approvals. Such outcome measures combine two or more distinct events (for example, tumour (re)growth, new lesions and/or death) into a single, time-to-event end point. The use of a composite end point can increase the statistical power of a clinical trial and decrease the follow-up period required to demonstrate efficacy, thus lowering costs; however, these end points have a number of limitations. Composite outcomes are often vaguely defined, with definitions that vary greatly between studies, complicating comparisons of results across trials. Altering the makeup of events included in a composite outcome can alter study conclusions, including whether treatment effects are statistically significant. Moreover, the events included in a composite outcome often vary in clinical significance, reflect distinct biological pathways and/or are affected differently by treatment. Therefore, knowing the precise breakdown of the component events is essential to accurately interpret trial results and gauge the true benefit of an intervention. In oncology clinical trials, however, such information is rarely provided. In this Perspective, we emphasize this deficiency through a review of 50 studies with progression-free survival as an outcome published in five top oncology journals, discuss the advantages and challenges of using composite end points, and highlight the need for transparent reporting of the component events.

Severe proptosis during cataract surgery.

Purpose: We report an unusual case of severe proptosis during phacoemulsification in a 58-year-old female with a history of Crohn's disease, bilateral chronic panuveitis, prior bilateral central retinal vein occlusion, and uncontrolled steroid-associated ocular hypertension requiring bilateral Ahmed glaucoma drainage device (GDD) implantation with pars plana tube placement. Observations: During phacoemulsification of the right eye, the patient developed significant proptosis. Following lid speculum removal and mechanical eyelid manipulation, the proptosis resolved within 20 minutes without requiring a lateral canthotomy. The patient had no permanent visual complications. Conclusions and Importance: The likely pathophysiology of intraoperative proptosis in this case was accumulation of fluid in the retrobulbar space due to a functioning Ahmed tube shunt with the tube placed in the vitreous cavity. To avoid this complication, concurrent cataract surgery may be considered for patients with pars plana tube placement GDD surgery.

Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification.

Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.

Adjuvant and neoadjuvant use of immune checkpoint inhibitors in NSCLC.

The neoadjuvant and adjuvant use of immune checkpoint inhibitors (ICIs) in early stage non-small cell lung cancer (NSCLC) is increasing, with pembrolizumab approved as adjuvant therapy following surgical resection and chemotherapy by the U.S. Food and Drug Administration in early 2023. However, clinical trials of these agents have several key limitations including the use of surrogate endpoints that have not been validated and a lack of demonstrated survival benefit. Further data supporting the benefits of ICIs in this setting are necessary to justify their use at the cost of greater financial burdens, time, and adverse effects.

FDA validation of surrogate endpoints in oncology: 2005-2022.

INTRODUCTION: The number of oncologic drugs approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints is rising. However, many surrogates have not demonstrated a correlation with clinically meaningful outcomes like overall survival. We sought to investigate surrogate validation studies conducted by the FDA over the past 17 years. METHODS: We reviewed analyses of surrogate outcomes published by the FDA from 2005 to 2022. Data extracted included the number of clinical trials included in each analysis, the associations of surrogate outcomes with OS or other surrogates, and the authors' interpretation of these associations. RESULTS: Of the 15 surrogate analyses conducted by the FDA, only one demonstrated a strong correlation between a surrogate outcome and overall survival. 87% only included clinical trials submitted to the FDA in their analysis, and all were published from 2014 onwards. DISCUSSION: The vast majority of FDA analyses of surrogate outcomes did not find strong correlations between surrogates and overall survival, raising concern about the use of such outcomes as endpoints in clinical trials. As most studies were based on limited data, further research is required to assess the true validity of surrogate outcomes. POLICY SUMMARY: Drugs approved on the basis of surrogates that are not associated with clinically meaningful outcomes can cause significant harm to patients. Until surrogate outcomes have been thoroughly and robustly validated, they should be used with caution in drug approval decisions.