Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.

Quantitation of rare somatic mutations is essential for basic research and translational clinical applications including minimal residual disease (MRD) detection. Though unique molecular identifier (UMI) has suppressed errors for rare mutation detection, the sequencing depth requirement is high. Here, we present Quantitative Blocker Displacement Amplification (QBDA) which integrates sequence-selective variant enrichment into UMI quantitation for accurate quantitation of mutations below 0.01% VAF at only 23,000X depth. Using a panel of 20 genes recurrently altered in acute myeloid leukemia, we demonstrate quantitation of various mutations including single base substitutions and indels down to 0.001% VAF at a single locus with less than 4 million sequencing reads, allowing sensitive MRD detection in patients during complete remission. In a pan-cancer panel and a melanoma hotspot panel, we detect mutations down to 0.1% VAF using only 1 million reads. QBDA provides a convenient and versatile method for sensitive mutation quantitation using low-depth sequencing.

Objective: The objective of this study is to determine the preoperative patient characteristics predicting prolonged length of hospital stay (pLOS) following robotic-assisted radical prostatectomy (RARP). Methods: The National Surgical Quality Improvement Program (NSQIP) database was used to select patients who underwent RARP without other concomitant surgeries between 2008 and 2016. Patients’ demographics, comorbidities, and laboratory markers were collected to evaluate their role in predicting pLOS. The pLOS was defined as length of stay (LOS) >2 days. A multinomial logistic regression was constructed adjusting for postoperative surgical complications to assess for the predictors of pLOS. Results: We obtained data for 31,253 patients of which 20,774 (66.5%) patients stayed ⩽1 day, 6993 (22.4%) patients stayed for 2 days, and 3486 (11.2%) patients stayed for >2 days. Demographic variables – including body mass index (BMI) <18.5: odds ratio (OR) = 2.8, 95% confidence interval (CI) = [1.7–4.8]; smoking: OR = 1.2, 95% CI = [1.1–1.4]; and dependent functional status: OR = 3.1, 95% CI = [1.6–6.0] – were predictors of pLOS. Comorbidities – such as heart failure: OR = 4.6, 95% CI = [2.0–10.8]; being dialysis dependent: OR = 2.7, 95% CI = [1.4–5.0]; and predisposition to bleeding: OR = 2.0, 95% CI = [1.5–2.7] – were the strongest predictors of extended hospitalization. In addition, pLOS was more likely to be associated with postoperative bleeding, renal, or pulmonary complications. Conclusion: Preoperative patient characteristics and comorbidities can predict pLOS. These findings can be used preoperatively for risk assessment and patient counseling.

Hereditary hemorrhagic telangiectasia (HHT) is a common bleeding disorder, but little is known regarding prevalence and risk factors for bleeding. Adult discharges with HHT and bleeding were identified by International Classification of Disease, 10th edition (ICD-10) codes in the National Inpatient Sample (NIS), 2016-2018. Prevalence estimates were weighted using NIS discharge-level weights to reflect national estimates. Risk factors for bleeding were determined by weighted multivariable logistic regression. Among 18 170 849 discharges, 2528 (0.01%) had HHT, of whom 648 (25.6%) had bleeding. Arteriovenous malformation (AVM) (31.9% vs 1.3%), angiodysplasia (23.5% vs 2.3%), telangiectasia (2.3% vs 0.2%), and epistaxis (17.9% vs 0.6%) were more common in HHT than in non-HHT patients (non-HHT), each P < .001. In contrast, menstrual (HMB) and postpartum bleeding (PPH) were less common in reproductive-age HHT than non-HHT, each P < .001. Anemia associated with iron deficiency (IDA), was equally common in HHT with or without bleeding (15.7% vs 16.0%), but more common than in non-HHT (7.5%), P < .001. Comorbidities, including gastroesophageal reflux (25.9% vs 20.0%) and cirrhosis (10.0% vs 3.6%) were greater in HHT than non-HHT, each P < .001. In multivariable logistic regression, peptic ulcer disease (OR, 8.86; P < .001), portal vein thrombosis (OR, 3.68; P = .006), and hepatitis C, (OR, 2.13; P = .017) were significantly associated with bleeding in HHT. In conclusion, AVM and angiodysplasia are more common and HMB and PPH less common in patients in those with HHT than non-HHT. IDA deficiency is as common in HHT with and without bleeding, suggesting ongoing blood loss and need for universal iron screening.