Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.

Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.

Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.     

Effective radiation dose in coronary imaging modalities

• This study demonstrated that in a single center experience, effective radiation dose received by patients is higher when the combination of coronary computed tomographic angiography (CTA) and single‐photon emission computed tomography (SPECT) imaging were used together, than when a combination of a non‐invasive modality was coupled with an invasive modality (coronary angiography ± FFR).
• Although significant improvements in non‐invasive imaging have emerged to help further risk stratify patients with coronary artery disease, coronary angiography remains a powerful tool, and still appears to deliver a lower effective radiation dose when used to risk stratify patients appropriately.
• Further studies in dose reduction with nuclear imaging, coronary CTA, and virtual FFR are needed to reduce the dose of radiation and improve the diagnostic power of non‐invasive imaging.

     

Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms

Little is known about the outcomes of Philadelphia-negative myeloproliferative neoplasms (MPNs) in adolescents and young adults (AYA). We reviewed all patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) treated at our institution from 1988 to 2016 who were aged 16 to 39 years (AYA) and described their outcomes in comparison to older MPN population. Of 2206 patients, 185 (8.3%) were identified as AYA: 105 (57%) ET, 43 (23%) PV, and 37 (20%) MF. The median age was 33 years [range, 16–39], and median follow-up time 3 years [range, 0.04–25]. JAK2 allele burdens were significantly lower among AYA JAK2V617F-mutated patients in both PV (p?=?0.001) and MF (p?=?0.005). Seven percent of MPN AYA patients were diagnosed with a thrombotic event at, or prior to, diagnosis. Over the short median follow-up, 4 thrombotic (PV?=?1, MF?=?3) and 3 leukemia (ET?=?2, MF?=?1) events occurred. In multivariate analysis, AYA did not predict for thrombotic or transformational events across three cohorts. In the MF cohort, there was a reduced frequency of negative prognostic variables of anemia (p?=?0.011) and leukocytosis (p?=?0.048) in AYA when compared with non-AYA. Overall survival was significantly superior in the AYA cohorts in all three MPN groups, namely MF (p?<?0.001), PV (p?<?0.001), and ET (p?=?0.002). Our findings suggest that MPN AYA patients exhibit an indolent clinical phenotype characterized by favorable survival outcomes.     

Molecular pathogenesis of acquired aplastic anemia

The application of next‐generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)‐associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA‐related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.     

Prognostic Factors in the Era of Targeted Therapies in CLL

Purpose of Review

Chronic lymphocytic leukemia is heterogeneous disease characterized by a variable clinical course that is greatly influenced by various patient and disease characteristics. Over the last two decades, advent of new diagnostic methodologies has led to the identification of several factors of prognostic and predictive relevance. Furthermore, recent advances in next-generation sequencing techniques has identified recurrent novel mutations in NOTCH1, SF3B1, BIRC3, and ATM genes whose role as prognostic and predictive markers is currently being investigated. These biologic markers carry new prognostic information and their incorporation into prognostic scoring systems will likely lead to refined multi-parameter risk models.

Recent Findings

While the prognostic impact of many of the most commonly used markers on clinical outcomes in patients treated with chemo-immunotherapy is well documented, it is important to review their predictive and prognostic role in the era of novel targeted therapies.

Summary

This article will discuss the currently available information on the clinical relevance of prognostic markers in patients treated with novel targeted therapies.

     

Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism

Iterations in Ca2+ and Mg2+ balance accompany aldosteronism (inappropriate for dietary Na+ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined. (1) To study the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO3 excretion. (2) To assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn2+]i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress were examined. (3) Oxidative stress and cardiac pathology in response to ZnSO4 supplement (40 mg/d) were also studied. Comparison of controls and rats receiving 4 weeks ALDOST revealed the following: (1) an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; (2) a rise in cardiac Zn, including increased [Zn2+]i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91(phox), coupled with oxidative stress in plasma and urine; (3) ZnSO4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO4 attenuated cardiomyocyte necrosis; however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contributes to cardiac pathology.     

Microbiota and caspase-1/caspase-8 regulate IL-1β-mediated bone disease

A leucine-to-proline missense mutation at residue 98 in the proline-serine-threonine phosphatase interacting protein 2 (Pstpip2) gene leads to autoinflammatory disease that is characterized by splenomegaly, necrosis, and spontaneous development of osteomyelitis in mice (Pstpip2^cmo). Disease progression in these mice resembles that of chronic recurrent multifocal osteomyelitis in humans. Our group and others have shown that disease progression in Pstpip2^cmo mice is mediated by the cytokine IL-1β, independently of inflammasomes or IL-1α. Our recent publication highlighted herein establishes that diet-induced changes in intestinal microbiota provide protection against the development of osteomyelitis in Pstpip2^cmo mice. Moreover, the proteases caspase-1 and caspase-8 have redundant roles in cleaving IL-1β and promoting disease. This addendum reviews the current literature on the Pstpip2^cmo murine disease model and the clinical significance of the role of PSTPIP2 in regulating autoinflammatory osteomyelitis, which is mediated by innate components of immune cells.