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PURPOSE: Pelvic lymph node metastases (ypN+) after multiagent neoadjuvant chemotherapy (NAC) is a poor prognostic sign in nonmetastatic muscle-invasive bladder cancer (nmMIBC). We sought to create a nomogram predicting probability of ypN+ after NAC for cN0 nmMIBC and determine association with overall survival (OS). METHODS AND MATERIALS: We reviewed the National Cancer Database for patients with cT2-4N0M0 urothelial carcinoma of the bladder receiving multiagent NAC and surgery from 2004 to 2020. Following a data split, univariate logistic regression identified variables associated with ypN+ at P < .05. Eligible variables were used for multivariate logistic regression and nomogram generation. A threshold for 95% sensitivity defined high- and low-risk groups for ypN+. Fine-Gray models assessed ypN+ risk group and OS, accounting for competing risks of surgical mortality. RESULTS: A total of 6194 patients were identified with a median follow-up of 39.5 months (interquartile range [IQR], 20.5-67.2 months). Most patients had high-grade (97.7%) cT2 disease (70.8%) with nonpapillary urothelial histology (67.3%) and initiated NAC at a median of 41.0 days after diagnosis (IQR, 28.0-59.0 days).The nomogram included age in decades (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.87-1.03; P = .172), weeks from diagnosis to NAC (OR, 1.02; 95% CI, 1.01-1.04; P = .004), nonpapillary histology (OR, 1.17; 95% CI, 0.99-1.39; P = .068), and clinical T-stage. Within the testing cohort, ypN+ was found in 392 (22.8%) high-risk and 12 (8.0%) low-risk patients (P < .001), with median OS of 36.1 and 74.0 months, respectively (P < .001). High-risk patients had worse OS despite competing risks of 30-day (subdistribution hazard ratio [SHR], 1.80; 95% CI, 1.49-2.18; P < .001) and 90-day surgical mortality (SHR, 1.68; 95% CI, 1.39-2.04; P < .001). CONCLUSIONS: This is the first study to provide a tool for predicting ypN+ and prognosticate worse OS in primarily high-grade nmMIBC and could select patients for alternative neoadjuvant therapy and facilitate future study.

BACKGROUND: The COVID-19 pandemic prompted a surge in telehealth utilization. However, language barriers have emerged as a potential obstacle to effective telemedicine engagement, impacting millions of limited English proficient (LEP) individuals. Understanding the role of language spoken in telehealth outcomes is critical, particularly in cancer care, in which consistent follow-up and communication are vital. The primary objective was to assess the impact of telehealth utilization and primary language spoken on clinical outcomes in cancer patients. METHODS: This study utilized a retrospective cohort design, encompassing cancer patients seen at the Chao Family Comprehensive Cancer Center between March 1, 2020, and December 31, 2022. The study incorporated both in-person and telehealth visits, examining the association between encounter type and clinical outcomes. RESULTS: The study included 7890 patients with more than one outpatient visit during the study period. There was decreased telehealth utilization in non-English speaking cancer patients throughout the pandemic. Increased telehealth utilization was associated with higher rates of admission, irrespective of cancer type. Additionally, telehealth visits were associated with longer duration of subsequent admissions compared to in-person visits. Spanish-speaking patients utilizing telehealth had higher rates of re-admission compared to English speakers utilizing telehealth. Patients who died had higher rates of telehealth utilization compared to patients who survived. CONCLUSIONS AND RELEVANCE: This study demonstrates that primary language spoken is associated with differences in telehealth utilization and associated outcomes in cancer patients. These differences suggest that the interplay of telehealth and language could contribute to widening of disparities in clinical outcomes in these populations. The study underscores the need to optimize telehealth usage and minimize its limitations to enhance the quality of cancer care in a telehealth-driven era.

Purpose This study aimed to identify factors associated with delays in initiating early salvage radiation therapy in prostate cancer patients with prostate-specific antigen (PSA) failure after prostatectomy. Methods We conducted a single-institution, retrospective study of patients receiving salvage radiation therapy after radical prostatectomy from 2011 to 2022. Patient demographics and clinical data were examined to identify factors that may have influenced the time to start of radiation therapy after surgery. Utilizing a PSA cut off of 0.25 ng/ml or less, we classified patients as receiving either early PSA low or late PSA high salvage therapy depending on their PSA at the time of initiating treatment. Results Of the 81 patients evaluated, the median age was 61.9 years (IQR 57.9 - 66.5), with most presenting with pT3 (65.4%), Grade Group 2 disease (35.8%), and positive margins 55%). Median PSA at salvage radiation therapy commencement was 0.30 ng/mL (0.18 - 0.48). 40 patients completed early salvage and 41 patients completed late salvage in the overall cohort. A significant association was found between patient insurance carrier and pre-radiation PSA levels. Patients with HMO (Health Maintenance Organization) or PPO (Preferred Provider Organization) insurance were more likely to complete late salvage radiation compared to non-managed Medicare patients (HMO OR 4.0, p

INTRODUCTION: Ethics consultations are often needed at difficult junctures of medical care. However, data on the nature of how patient characteristics, including race/ethnicity, language, and diagnosis, affect ethics consult outcomes are lacking. METHODS: We performed a retrospective cohort study of all patients who were seen by the Ethics Consult Service between 2017 and 2021 at a large tertiary academic center with the aim of determining whether patient demographic and clinical factors were associated with the timing of ethics consult requests and recommendations of the ethics team. RESULTS: We found that patients admitted for COVID-19 had significantly longer median times to consult from admission compared with other primary diagnoses (19 vs 8 days respectively, p = 0.015). Spanish-speaking patients had longer median times to consult from admission compared to English speaking patients (20 vs 7 days respectively, p = 0.008), indicating that language barriers may play a role in the timing of ethics consultation. CONCLUSIONS: This study demonstrates the need to consider clinical and demographic features when planning and prioritizing ethics consultations at large institutions to enhance consult efficiency, resource utilization, and patient experience and autonomy.

Platinum-based chemotherapy is known to cause taste and smell changes (TSCs) via a host of mechanisms, including altered receptor activity, saliva/mucus production, and induction of receptor destruction via mitotic inhibition. In the literature to date, these changes have primarily resulted in worsening of taste and smell. In this case report, we document the first instance of an individual regaining their sense of olfactory detection following treatment with oxaliplatin for colorectal adenocarcinoma. We theorize that the improvement in his sense of smell may have resulted from oxaliplatin-induced destruction of his nasal polyps through the caspase-9/procaspase-9 apoptotic pathway, a pathway shared with other mechanisms of nasal polyp destruction. These findings were supported by nasal endoscopy and sphenoid sinusoscopy, which demonstrated no clinical persistence of nasal polyps, in contrast to nasal endoscopy prior to chemotherapy which demonstrated persistent nasal polyposis. Objective smell testing post-treatment revealed a diminished ability to discriminate odors. Chemotherapy-induced TSCs play a key role in poor weight gain, food aversion, emotional distress, and an overall decrease in quality of life, and patients should be informed of these potential consequences prior to starting treatment. However, in patients with anosmia secondary to nasal polyposis, treatment with platinum-based chemotherapy may provide an additional therapeutic benefit. Further studies may help elucidate the potential therapeutic benefits of these agents in managing steroid-resistant polyposis for patients suffering from olfactory dysfunction.

UNLABELLED: The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis. SIGNIFICANCE: We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265.

BackgroundTumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway.ResultTo develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior.ConclusionThese results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

Introduction Acute myeloid leukemia (AML) remains one of the most difficult cancers to treat, with a low cure rate (~25%) and a 5-year survival rate of 28% (1, 2). High-throughput [...], Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and RBC transfusionindependence in patients with acute myeloid leukemia (AML) treated with the isocitrate dehydrogenase 2 (IDH2) mutantspecific inhibitor enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRISPR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed [CD71.sup.+] progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapsespecific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherap. [ABSTRACT FROM AUTHOR]

Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of the human body. Human MPPs remain ill-defined whereas mouse MPPs have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single cell analyses and complementary functional assays, we identified new human MPPs and oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow with distinct biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We show that within the canonical Lin-CD34+CD38dim/loCD90CD45RA-MPP population, there is a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69-erythroid-biased MPP. We also show that the canonical Lin-CD34+CD38dim/loCD90-CD45RA+ LMPP population can be separated into a CD2+ LMPP with lymphoid and myeloid potential, a CD2-LMPP with high lymphoid potential, and a CLL1+ GMP with minimal lymphoid potential. We used these new HSPC profiles to study human and mouse bone marrow cells and observe limited cell type specific homology between humans and mice and cell type specific changes associated with aging. By identifying and functionally characterizing new adult MPP sub-populations, we provide an updated reference and framework for future studies in human hematopoiesis.

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy., Competing Interests: Declaration of Interests R.M. is on the Advisory Boards of Kodikaz Therapeutic Solutions, Orbital Therapeutics, and 858 Therapeutics and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.A.L. is a consultant for Cartography Biosciences.