News Update on Hematological Malignancies : Nov 2020

JAK/STAT signaling in hematological malignancies

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that recognize specific cytokines, and is critical in blood formation and immune response. Many of those receptors transmit anti-apoptotic, proliferative and differentiation signals, and their expression and functions are critical for the formation of blood lineages. Several cancers, including blood malignancies, have been associated with constitutive activation of members of the STAT family, which normally require JAK-mediated tyrosine phosphorylation for transcriptional activation. More recently, human myeloproliferative neoplasms were discovered to be associated with a unique acquired somatic mutation in JAK2 (JAK2 V617F), rare exon 12 JAK2 mutations, or thrombopoietin receptor mutations that constitutively activate wild-type JAK2. Prompted by these observations, many studies have explored the possibility that JAKs, cytokine receptors, or other components of the JAK/STAT pathway are mutated or upregulated in several hematological malignancies. This has been observed in certain pediatric acute lymphoblastic leukemias and adult T-cell lymphoblastic leukemias, and overexpression of JAK2 seems to be important in Hodgkin lymphoma. Here we discuss the nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies and present examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage. JAK inhibitors are making their way into the therapeutic arsenal (for example, in myelofibrosis), and we discuss the possibility that other hematological diseases might benefit from treatment with these inhibitors in combination with other agents. [1]


Mechanism of action of lenalidomide in hematological malignancies

Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Lenalidomide has been shown to be an immunomodulator, affecting both cellular and humoral limbs of the immune system. It has also been shown to have anti-angiogenic properties. Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of MDS. Even though the exact molecular targets of lenalidomide are not well known, its activity across a spectrum of neoplastic conditions highlights the possibility of multiple target sites of action. [2]

Role of RUNX1 in hematological malignancies

RUNX1 is a member of the core-binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. RUNX1 is one of the most frequently mutated genes in a variety of hematological malignancies. Germ line mutations in RUNX1 cause familial platelet disorder with associated myeloid malignancies. Somatic mutations and chromosomal rearrangements involving RUNX1 are frequently observed in myelodysplastic syndrome and leukemias of myeloid and lymphoid lineages, that is, acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia. More recent studies suggest that the wild-type RUNX1 is required for growth and survival of certain types of leukemia cells. The purpose of this review is to discuss the current status of our understanding about the role of RUNX1 in hematological malignancies. [3]

Blood Stream Infections in Children with Malignancies: A Single Center Experience Risk Factors, Microbiological Isolates and Sensitivity Pattern

Aim: To determine risk factors, microbiological isolates and antibiotic sensitivity pattern of blood stream infections of pediatric malignancies.

Study Design: A prospective single center cohort study included Children with malignancies that developed one or more episodes of septicemia during the period of their treatment and follow up.

Place and Duration of Study: We included 46 children who were admitted to the Pediatric oncology Unit of Tanta University Hospitals, Egypt, over the period of six months. The included children had a microbiologically confirmed blood stream infections.

Methodology: Positive blood cultures by BacT/ALERT were sub cultured on MacConkey agar, blood agar, chocolate agar, and sabouraud agar. VITEK 2TM Compact 15 was used for verification of bacterial identification and MIC determination.

Results: Sixty seven blood stream infections were detected in 46 patients. Hematological malignancies (67.4%) and neutropenia (69.7%) were the major risk factors. Gram positive bacteria represented (53.7%) including mainly coagulase negative Staphylococci (38.9%) and Streptococci (30.6%). Methicillin resistance was detected in all S. aureus, 71.4% of Coagulase negative Staphylococci that were sensitive to ciprofloxacin (85.7%, 100%), gentamycin (85.7%, 100%) and clindamycin (71.4%) respectively. Gram negative bacteria represent (46.3%) mainly Klebsiella pneumoniae (38.7%). ESBL in Enterobacteriaceae was (81.3%) with sensitivity to ciprofloxacin, amikacin, piperacillin/ tazobactam and sulbactam/ cefoperazone (100%, 100%, 69.2%, 53.8%) respectively. Carbapenem resistance was detected in one isolate of K. pneumoniae, two P. aeruginosa and two A. baumanii. Intestinal translocation of Klebsiella pneumoniae in (41.7%, 5/12) and P. aeruginosa (40%, 2/5), as well as in the four detected cases of central line blood stream infections.

Conclusion: The application of infection control guidelines and the strict antibiotic policy are mandatory for each institute. Selective digestive decontamination is considered to limit translocation. Carbapenem resistance was alarming and mandating more evaluation of β-lactam/β-lactamase inhibitors in treatment of ESBL Enterobacteriaceae.[4]

Impact of Cancer on Survival of Patients with AKI on CRRT

Background: Few studies have examined cancer patients with acute kidney injury (AKI) who require continuous renal replacement therapy (CRRT). The aim of this study was to compare the characteristics and outcomes of patients with and without cancer requiring CRRT for AKI in general intensive care units (ICUs).

Methods: We studied a retrospective cohort study in an ICU. A total of 200 patients (without cancer 79%; with cancer 21%) were included over a 24 month period. Predictors of all-cause death were examined using Kaplan-Meier and Cox proportional hazards analyses in both treatment groups for statistical analysis.

Results: The 1st contributing factors of AKI was cardiac dysfunction (40%) and 2nd factors was sepsis (38%). The cause of AKI was multifactorial in 78% of cancer patients and in 71% of patients without cancer. Hospital mortality rates were higher in patients with cancer (69%) than in patients without cancer (49.4 %) (P = 0.023). In multivariate analyses, older age, medical admission, poor chronic health status, comorbidities, ICU days until RRT start, number of associated organ dysfunctions, and diagnosis of cancer were associated with hospital mortality. The diagnosis of cancer was independently associated with mortality [odds ratio = 1.68 (95% confidence interval, 1.10–2.59), P = 0.017].

Conclusions: The presence of cancer may be independently associated with mortality in our study. [5]

Reference

[1] Vainchenker, W. and Constantinescu, S.N., 2013. JAK/STAT signaling in hematological malignancies. Oncogene, 32(21), pp.2601-2613.

[2] Kotla, V., Goel, S., Nischal, S., Heuck, C., Vivek, K., Das, B. and Verma, A., 2009. Mechanism of action of lenalidomide in hematological malignancies. Journal of hematology & oncology, 2(1), pp.1-10.

[3] Sood, R., Kamikubo, Y. and Liu, P., 2017. Role of RUNX1 in hematological malignancies. Blood, 129(15), pp.2070-2082.

[4] Amer, W. H., Elrifaey, S. M. and El Sharaby, R. M. (2017) “Blood Stream Infections in Children with Malignancies: A Single Center Experience Risk Factors, Microbiological Isolates and Sensitivity Pattern”, Microbiology Research Journal International, 18(3), pp. 1-12. doi: 10.9734/MRJI/2017/30595.

[5] Kim, Y. N. and Shin, H. S. (2014) “Impact of Cancer on Survival of Patients with AKI on CRRT”, Journal of Advances in Medicine and Medical Research, 5(6), pp. 758-766. doi: 10.9734/BJMMR/2015/12704.

 

 

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