Understanding the Continuum between High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by bone marrow dysplasia, failure of hematopoiesis and variable risk of progression to acute myeloid leukemia (AML). Recent large-scale studies have demonstrated that distinct molecular abnormalities detected at earlier stages of MDS alter disease biology and predict progression to AML. Consistently, various studies analyzing these diseases at the single-cell level have identified specific patterns of progression strongly associated with genomic alterations. These pre-clinical results have solidified the conclusion that high-risk MDS and AML arising from MDS or AML with MDS-related changes (AML-MRC) represent a continuum of the same disease. AML-MRC is distinguished from de novo AML by the presence of certain chromosomal abnormalities, such as deletion of 5q, 7/7q, 20q and complex karyotype and somatic mutations, which are also present in MDS and carry crucial prognostic implications. Recent changes in the classification and prognostication of MDS and AML by the International Consensus Classification (ICC) and the World Health Organization (WHO) reflect these advances. Finally, a better understanding of the biology of high-risk MDS and the mechanisms of disease progression have led to the introduction of novel therapeutic approaches, such as the addition of venetoclax to hypomethylating agents and, more recently, triplet therapies and agents targeting specific mutations, including FLT3 and IDH1/2. In this review, we analyze the pre-clinical data supporting that high-risk MDS and AML-MRC share the same genetic abnormalities and represent a continuum, describe the recent changes in the classification of these neoplasms and summarize the advances in the management of patients with these neoplasms.

Lower Limb Paralysis as Initial Presentation of Arterial Embolism Secondary to Heparin-Induced Thrombocytopenia after Hip Fracture - a Case Report.

Introduction: Prophylactic anticoagulation (AC) with low molecular weight heparins (LMWHs) following hip fracture has reduced the incidence of severe thromboembolic events. However, heparin-induced thrombocytopenia (HIT) remains a serious complication in these patients. Clinical case: We report an unusual case of thrombosis due to severe HIT in a 75-year-old female patient following intramedullary nailing for a hip fracture. The patient was taking Verapamine. On the fourth postoperative day she developed paralysis, paresthesia and mild pain over the right lower extremity; faint pulses were palpated. Computed tomography angiogram identified superficial artery occlusion leading to limb ischemia. Anti-platelet factor 4 (PF4) heparin antibody positivity confirmed the diagnosis of HIT. Urgent embolectomy was performed and the patient achieved full recovery. Discussion: Arterial embolism presenting with severe neurological deficits is a rare complication of HIT. Conclusion:A high index of suspicion and close platelet count monitoring is warranted for early diagnosis and treatment of this devastating condition that can be limb and life threatening.

Outcomes of Refractory Cytomegalovirus Infection in the First Year after Allogeneic Hematopoietic Cell Transplantation.

Outcomes of refractory (Rf) cytomegalovirus (CMV) infection (CMVi) after hematopoietic cell transplantation (HCT) are poor owing to limited treatment options and treatment related toxicities. Maribavir, an orally bioavailable CMV antiviral, was recently approved for treatment of Rf-CMVi. Real-world studies quantifying the burden of Rf-CMVi prior to maribavir provide a benchmark for evaluating the net value of novel treatments. Here we report the incidence, clinical outcomes, and healthcare resource utilization (HRU) associated with Rf-CMVi in the first year post-HCT in a cohort of CMV-seropositive HCT recipients (R+) who underwent HCT between January 1, 2014, and December 31, 2017, at Memorial Sloan Kettering Cancer Center and were managed exclusively by preemptive therapy. CMVi was defined as CMV viremia treated preemptively. Rf-CMVi was defined as a <1 log10 decrease and CMV viral load >1000 U/mL after ≥14 days of appropriately dosed therapy. Welldays were defined as alive days not hospitalized and off CMV antivirals by 1 year post-HCT. The impact of Rf-CMVi on mortality and HRU was examined in multivariable models. Of the 286 R+ patients, 145 (50.7%) developed CMVi (99 no Rf-CMVi and 46 Rf-CMVi). Compared with the no Rf-CMVi group, the Rf-CMVi group had higher rates of CMV EOD (23.9% versus 10.1%; P = .030), CMV-related mortality (9.5% versus .0%; P = .002), and all-cause mortality (33.3% versus 15.6%; adjusted P = .049). Rf-CMVi was an independent predictor for readmission (adjusted odds ratio [aOR], 3.24; 95% confidence interval [CI], 2.19 to 4.87; P < .0001); CMV-related readmission (aOR, 9.48; 95% CI, 5.83 to 15.80; P < .0001), and decreased well days (adjusted arithmetic mean ratio, .72; 95% CI, .58 to .89; P = .001) in the first year post-HCT. Rf-CMVi is associated with increased mortality and increased HRU at 1 year after HCT. Improved therapies for Rf-CMVi have the potential of improving HCT outcomes and reducing HRU.

Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.

PURPOSE: Azacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2-inhibitor venetoclax, have failed in randomized clinical trial (RCT) evaluations. We extract lessons from decades of clinical trials to thereby inform future work. EXPERIMENTAL DESIGN: Serial single-agent clinical trials were analyzed for mechanism and pathway properties of HMAs underpinning their success, and for rules for dose and schedule selection. RCTs were studied for principles, dos and don'ts for productive combination therapy. RESULTS: Single-agent HMA trial results encourage dose and schedule selection to increase S-phase-dependent DNMT1 targeting, and discourage doses that cause indiscriminate antimetabolite effects/cytotoxicity, because these attrit myelopoiesis reserves needed for clinical response. Treatment-related myelosuppression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Administering cytostatic agents concurrently with HMA can antagonize S-phase-dependent DNMT1 targeting. Supportive care that enables on-time administration of S-phase (exposure-time)-dependent HMA could be useful. Agents that manipulate pyrimidine metabolism to increase HMA pro-drug processing into DNMT1-depleting nucleotide, and/or inhibit other epigenetic enzymes implicated in oncogenic silencing of lineage differentiation, could be productive, but doses and schedules should adhere to therapeutic index/molecular-targeted principles already learned. CONCLUSIONS: More than 40 years of clinical trial history indicates mechanism, pathway, and therapeutic index properties of HMAs that underpin their almost exclusive success and teaches lessons for selection and design of combinations aiming to build on this treatment foundation.

Normal anatomy, variants and factors associated with the cervical vagus nerve topography: a high-resolution ultrasound study.

PURPOSE: To describe the cervical vagus nerve (CVN) topography at the thyroid lobe (TL) level using high-resolution ultrasound and to investigate the possible association with anthropometric data, TL size, and thyroid disease. METHODS: We prospectively examined 550 CVNs in 275 (205 female, 70 male) individuals with normal thyroid (53/275, 19.3%), multinodular disease (167/275, 60.7%), and Hashimoto thyroiditis (55/275, 20%). The CVN location relative to the common carotid artery was recorded as typical (lateral position) and atypical (anterior, medial, and posterior position). The shortest distance between CVN and TL margin, the TL dimensions, and volume were measured. RESULTS: Normal thyroid subjects had lateral-positioned right CVNs in 100% and lateral/anterior/medial left CVNs in 81.1%, 15.1%, and 3.8%, respectively. CVN types did not differ significantly bilaterally between study groups. Asymmetry in CVN topography in all subjects was found in 22.2%, of which anterior CVN was the most common atypical position (64%), especially on the left side (82%). Significant gender, age, body mass, and BMI differences among CVN types were observed on the left side only. Among CVN types, no difference in TL dimensions, volume, and CVN-TL distance was found in all study groups. A weak negative correlation was recorded between CVN-thyroid distance and TL volume only on the left side (r = - 0.147, p = 0.01). CONCLUSION: Asymmetry in CVN topography is mainly due to the increased incidence of the anterior location of CVN on the left side. Age and anthropometric parameters are different on the left side possibly due to the increased prevalence of left CVN variants.

Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis comprising 18,506 patients.

PURPOSE: Infectious diseases are more frequent and can be associated with worse outcomes in patients with diabetes. The aim of this study was to systematically review and conduct a meta-analysis of the available observational studies reporting the effect of diabetes on mortality among hospitalized patients with COVID-19. METHODS: The Medline, Embase, Google Scholar, and medRxiv databases were reviewed for identification of eligible studies. A random effects model meta-analysis was used, and I2 was utilized to assess the heterogeneity. In-hospital mortality was defined as the endpoint. Sensitivity, subgroup, and meta-regression analyses were performed. RESULTS: A total of 18,506 patients were included in this meta-analysis (3713 diabetics and 14,793 non-diabetics). Patients with diabetes were associated with a higher risk of death compared with patients without diabetes (OR 1.65; 95% CI 1.35-1.96; I2 77.4%). The heterogeneity was high. A study-level meta-regression analysis was performed for all the important covariates, and no significant interactions were found between the covariates and the outcome of mortality. CONCLUSION: This meta-analysis shows that that the likelihood of death seems to be higher in diabetic patients hospitalized with COVID-19 compared with non-diabetic patients. Further studies are needed to assess whether this association is independent or not, as well as to investigate the role of adequate glycemic control prior to infection with COVID-19.

Impact of Preemptive Therapy for Cytomegalovirus on Hospitalizations and Cost after Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) viremia occurs in 40% to 80% of CMV-seropositive (R+) recipients of allogeneic hematopoietic cell transplantation (HCT). The preemptive therapy (PET) strategy has reduced the risk of CMV end-organ disease (EOD) and associated mortality but may lead to substantial healthcare resource utilization (HCRU) and costs. Real-world data on the economic impact of PET is relevant for the evaluation of alternative strategies for CMV management. We examined the impact of clinically significant CMV treated with PET on inpatient length of stay (LOS), number of readmissions, and associated costs from day 0 through day 180 post-HCT. This was a retrospective study of R+ adults who underwent peripheral blood or marrow allogeneic HCT at Memorial Sloan Kettering Cancer Center between March 2013 and December 2017. Patients were routinely screened for CMV by qPCR and received PET according to institutional standards of care. Data were extracted from electronic medical records and hospital databases. Itemized cost data per patient were obtained from the Vizient database, adjusted to 2017 dollars using inflation indices. Study outcomes included HCRU evaluated by inpatient LOS and inpatient cost in patients who received PET for clinically significant CMV (PET group) compared with those who did not receive PET (no PET group) and the frequency and cost of CMV-related readmissions compared with non CMV-related readmissions. We used generalized linear models to examine the incremental HCRU and costs associated with PET controlling for other potential factors. Of 357 patients, PET was initiated in 208 (58.3%), at a median of 35 days after HCT. By day 180, 23 patients (6.4%) had developed CMV EOD and 3 (.8%) had died of CMV. Compared with the no PET group, the PET group had a longer LOS for HCT admission (P = .0276), longer total LOS by day 180 (P = .0001), a higher number of readmissions (P = .0001), a higher mean inpatient cost for HCT admission ($189,389 versus $151,646; P = .0133), and a higher total inpatient cost ($297,563 versus $205,815; P < .0001). Among PET recipients, CMV-related readmissions were associated with higher mean cost per episode compared with non CMV-related readmissions ($165,455 versus $89,419; P = .005). CMV-related readmissions comprised 40.6% of total all-cause readmissions and incurred 55.9% of total all-cause readmission costs in PET recipients. Our data show that patients treated with currently available PET had greater inpatient HCRU and cost, by day 180 compared with patients who did not receive PET. The cost of CMV-related readmissions accounted for 56% of total readmission cost among PET recipients. Future studies are needed to examine the cost-effectiveness of alternative strategies for CMV management.

Adenovirus Viral Kinetics and Mortality in Ex Vivo T Cell-Depleted Hematopoietic Cell Transplant Recipients With Adenovirus Infection From a Single Center.

BACKGROUND: We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). METHODS: T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. RESULTS: Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age <18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count <300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52-3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83-4.75) correlated with mortality at D +180. CONCLUSIONS: In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.

Liver findings in patients with Carney complex, germline PRKAR1A pathogenic variants, and link to cardiac myxomas.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.

Impact of advanced glycation end products (AGEs) signaling in coronary artery disease.

Coronary artery disease remains the leading cause of mortality in adult diabetic population with however, a high predominance also in non-diabetic subjects. In search of common molecular mechanisms and metabolic by-products with potential pathogenic role, increased advanced glycation end products (AGEs) present a critical biomarker for CAD development in both cases. Interaction of AGEs with their transmembrane cell receptor, RAGE in endothelial and smooth muscle cells as well as in platelets, activates intracellular signaling that leads to endothelial injury, modulation of vascular smooth muscle cell function and altered platelet activity. Furthermore, tissue accumulation of AGEs affects current treatment approaches being involved in stent restenosis. The present review provides an update of AGE-induced molecular mechanisms involved in CAD pathophysiology while it discusses emerging therapeutic interventions targeting AGE reduction and AGE-RAGE signaling with beneficial clinical outcome.

Failure to Thrive in the Context of Carney Complex.

BACKGROUND/AIMS: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). METHODS: A retrospective case series of pediatric patients with CNC presenting with FTT. RESULTS: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. CONCLUSION: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.

Critical Role of IL-8 Targeting in Gliomas.

BACKGROUND: Glioma is a heterogeneous, highly complicated central nervous system (CNS) tumor with uncertain mechanism of initiation and progression, resulting in an unfavorable outcome. An extended network of cytokines is recognized as a major regulator of glioma pathogenesis, either promoting or inhibiting glioma progression based on their type and specificity. Interleukin-8 (IL-8) has been revealed as a critical regulator of CNS function and development with participation in many CNS disorders including gliomas. OBJECTIVE: The aim of the present review is to address the role of IL-8 in glioma pathogenesis focusing on the implicated molecular pathways as well as on its potential targeting for glioma therapy. METHODS AND RESULTS: PubMed-Medline, SCOPUS, and Google Scholar databases were searched for pre-clinical and clinical studies related to IL-8 implication in gliomagenesis and IL-8 targeting strategies for gliomas. Literature data indicate that IL-8 participates in glioma angiogenesis and cell migration and it can serve as a potential biomarker, for early diagnosis, follow-up and response to therapy. CONCLUSION: Several promising approaches that target directly or indirectly IL-8 effects in gliomas are currently in progress while more-in-depth studies are needed to validate its biomarker role and elucidate the underlying molecular mechanisms.