فهرست مطالب

Iranian Journal of Pediatric Hematology and Oncology
Volume:13 Issue: 2, Spring 2023

  • تاریخ انتشار: 1402/03/08
  • تعداد عناوین: 7
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  • Amirreza Jahanshahi, Amirataollah Hiradfar, Shabnam Mahboubi, Abbasali Hosseinpour Feizi, Abolhassan Shakeri Bavi, Ali Mostafavijabbari, HamidReza Yousefi Nodeh, Sina Raeisi* Pages 79-86
    Background

    Given the children's susceptibility to the harmful radiation of computerized tomography (CT) scans, ultrasonography can be a good alternative in staging pediatric lymphoma. The present study aimed to assess the predictive value of abdominal ultrasonography compared to CT scan in children with lymphoma.

    Materials and Methods

    Fifty-two children with confirmed lymphoma were included in the present cross-sectional analytical study and underwent CT scan. The staging was performed based on the involvement pattern, lymph nodes, liver involvement, spleen involvement, and lymph node sizes. Then, the patients underwent ultrasonography followed by re-staging. The data were analyzed by SPSS 26. p-value less than 0.05 was considered statistically significant.

    Results

    The included patients consisted of 32 (61.5%) boys and 20 (38.5%) girls with the median age of 6.0 years (4.3-8.0). The number of the patients with positive paraaortic lymphadenopathy, iliac chain lymphadenopathy, mesenteric lymphadenopathy, increased liver size, changed liver parenchyma, increased spleen size, changed spleen parenchyma, increased kidney size, and changed kidney parenchyma evaluated by sonography and CT scan were 24 (46.2%) and 26 (50.0%), 3 (5.8%) and 3 (5.8%), 34 (65.4%) and 34 (65.4%), 49 (94.2%) and 48 (92.3%), 23 (44.2%) and 23 (44.2%), 45 (68.2%) and 21 (31.8%), 48 (92.3%) and 48 (92.3%), 50 (96.2%) and 50 (96.2%), and 49 (94.2%) and 48 (92.3%), respectively (p ≤ 0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of abdominal ultrasonography staging compared to CT scan were 100%, more than 90%, more than 75%, and 100%, respectively.

    Conclusion

    Due to the sufficient sensitivity and specificity, ultrasonography has the potential to be applied instead of CT scan for the abdominal staging of pediatric lymphoma.

    Keywords: Computed Tomography, Lymphoma, Lymphadenopathy, Ultrasonography
  • Masumeh Sanaei, Fraidoon Kavoosi* Pages 87-98
    Background

      The aberrant and altered patterns of gene expression play an important role in the biology of cancer and tumorigenesis. DNA methylation and histone deacetylation are the most studied epigenetic mechanisms. Histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA) and trichostatin A (TSA) are a group of anticancer compounds for the treatment of solid and hematological cancers. Previously, we reported the effect of two HDACIs, valproic acid (VPA) and TSA, on colon cancer and hepatocellular carcinoma (HCC), respectively. The aim of the current in vitro study is to investigate the effects of TSA on the intrinsic apoptotic pathway, p21/Waf1/Cip1 (p21), p53, and histone deacetylases (HDACs) 1, 2 and 3 in human neuroblastoma LAN-1, glioblastoma GBM-29, HCC SMMC7721, and colon cancer COLO 201 cell lines.

    Materials and methods

    In this lab-trial study, all three cell lines were seeded at the density of 3 × 105 cells per well and incubated for 24 hours. Then, the cells were treated with TSA based on IC50 values for 24 hours except in the control groups; the control cells were treated with the equal amounts of the DMSO solvent. Subsequently, cell viability, cell apoptosis and gene expression were determined by three techniques including MTT assay, flow cytometry assay, and qRT-PCR.

    Results

    The result of qRT-PCR indicated that TSA could increase the expression levels of Bid, BimEL, Noxa, p21, and p53 genes and decrease those of Bcl-xL, RIP, Mcl-1, XIAP, HDACs 1, 2 and 3 significantly (P < 0.0001) by which it inhibited cell growth and induced significant cell apoptosis in LAN-1, GBM-29, SMMC7721, and COLO 201 cell lines (p value<0.001).

    Conclusion

    TSA can affect cell apoptotic via the intrinsic apoptotic pathway in LAN-1, GBM-29, SMMC7721, and COLO 201 cell lines.

    Keywords: Apoptosis, Histone deacetylase, Mitochondrial, Trichostatin A
  • Ali Amini, Mohammad Faranoush, Mostafa Paridar, Ahmad Kazemi, MohammadReza Rezvani, Majid Safa* Pages 99-118
    Background

    The ubiquitin-proteasome system (UPS) plays a crucial role in regulating the levels and functions of a large number of proteins in the cell, which are important for cancer cell growth and survival. The proteasome is highly activated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is the most common malignancy in children. The attempt to inhibit proteasome as a therapeutic strategy has been successful for some malignancies.

    Materials and Methods

    In this experimental study, human BCP-ALL cell lines NALM-6 and SUP-B15 were treated with carfilzomib with and without the chemotherapeutic agents. The XTT assay evaluated the viability of the cells. Cell cycle analysis and apoptosis assay were assessed by flow cytometry. RQ-PCR and western blotting evaluated the expression of pro-/anti-apoptotic signals. A drug combination study for synergistic or additive effects of carfilzomib with doxorubicin or dexamethasone was performed.

    Results

    We observed that carfilzomib alone induced G2/M cell cycle arrest and caspase-dependent apoptosis in the human BCP-ALL cells (NALM-6 and SUP-B15). Gene and protein expression analysis indicated the upregulation of pro-apoptotic as well as downregulation of the cell survival and proliferative signals (P-value<0.05). The synergy of carfilzomib with doxorubicin or dexamethasone was revealed in BCP-ALL cells.

    Conclusion

    Our results indicated that proteasome inhibition induces p53-mediated apoptosis in BCP-ALL cells. Since carfilzomib has a synergistic effect with anti-leukemic agents doxorubicin and dexamethasone in BCP-ALL cells, this combined-modality approach might be befitting for patients who do not respond well to conventional chemotherapy.

    Keywords: Acute lymphoblastic leukemia, Carfilzomib, Dexamethasone, Doxorubicin, Proteasome
  • Hassan Boustani, Nasser Abbasi, Abbas Ghotaslou, Omid Kiani Ghalesardi, Farhad Zaker, Minoo Shahidi* Pages 119-131
    Background

    Although significant advances have been made in the treatment of cancer, a significant number of patients with acute lymphoblastic leukemia (ALL) show resistance to treatment. Thus, it is necessary to seek novel therapeutic agents to overcome this problem. Studies have indicated that the expression level of mouse double minute 2 (MDM2), a negative regulator of p53, is markedly elevated in patients with refractory or recurrent ALL. Thus, targeting MDM2 using a specific inhibitor, Idasanutlin, can increase the activity of p53. This study evaluated the possible synergistic effect of Idasanutlin and Daunorubicin on the induction of apoptosis in NALM-6 cells.

    Materials and methods

      In this fundamental study, the anti-proliferative effects of Idasanutlin on NALM-6 cells, either alone or in combination with Daunorubicin, were confirmed by MTT(methyl-thiazol-tetrazolium) assay, Annexin/PI apoptosis assay, and cell cycle analysis. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-leukemic activity of Idasanutlin.

    Results

    Idasanutlin synergistically enhanced Daunorubicin-induced apoptosis and activated caspase-3, thereby activating programmed cell death in a dose-dependent manner (P<0.001). The treatment of NALM-6 cells with Idasanutlin caused cell cycle arrest in the G1 phase by an increase in the expression of p21 (P<0.001).  Moreover, a significant increase was detected in the expression of pro-apoptotic genes (P<0.001), as well as a remarkable decrease in the expression of anti-apoptotic (P<0.01) and multidrug resistance1 (MDR1) genes (P<0.01).

    Conclusions

    It seems that Idasanutlin can cooperatively promote daunorubicin-induced apoptosis in NALM-6 cells. These findings open up a new horizon in the application of Idasanutlin in combination with Daunorubicin to overcome drug resistance in patients with ALL.

    Keywords: Acute lymphoblastic leukemia, Apoptosis, Daunorubicin, Drug resistance, Idasanutlin
  • Zahra Moradi, Mahmood Barati, Mehdi Azad, Alieh Safari, Bahram Chahrdovali, Farhad Zaker, MohammadReza Rezvany* Pages 132-143
    Background

    Acute lymphoblastic leukemia (ALL) is the most prevalent hematologic malignancy among children. DNA methylation is well known to play a role in the initiation and progression of cancer. This research aimed to characterize the epigenetic inactivation and gene expression of Protocadherin-10 (PCDH10) and Reprimo (RPRM) in pediatric acute lymphoblastic leukemia, which is associated with epigenetic silencing in human cancers.

    Materials and Methods

    This case-control study included 21 children (mean age, 4.5 years) with new cases of ALL. In addition, 15 patients with ALL were selected following treatment. Samples of bone marrow were extracted from each patient. Prior to and following treatment, 15 paired samples were analyzed. In addition, ALL patients were compared to 18 normal controls in a case study. MS-HRM and quantitative real-time PCR were utilized to examine the DNA-promoter methylation and gene expression of two TSGs from each group.

    Results

    Expression of PCDH10 was significantly up regulated in treatment ALL group compared to the new cases of ALL patients (P= 0.0119), PCDH10 gene expression was higher in the normal control group than in the new cases of ALL (P <0.0001).  RPRM gene, also had a slightly increase in gene expression in treatment ALL group compared to the new cases of ALL (P =0.0412). RPRM gene expression was higher in the normal control group than in the new cases of ALL) P = 0.0372). There was an increase in methylation in both PCDH10 and RPRM genes in new cases of ALL groups compared with treatment ALL group and normal group (P<0.0001 for both genes).

    Conclusions

    New cases of ALL were associated with high DNA methylation level and low gene expression of PCDH10 and RPRM genes.

    Keywords: Acute lymphoblastic leukemia, Methylation, PCDH10, RPRM
  • Muhammad Sadeqi Nezhad, Alireza Rajabzadeh*, Ali Dehghani Firoozabadi Pages 144-160

    Immunotherapy with genetically engineered T-cells that express the chimeric antigen receptor (CAR) has raised hopes for the treatment of pediatric malignancies. Although CAR T-cell development is on a fast-moving pace and evolution, the context of exploring novel targetable antigens has been neglected. In this review study, we analyze the prominent hematologic antigens targeted by engineered T-cells in both preclinical and clinical aspects. Furthermore, we discuss the outcomes of CAR-based therapy in hematologic cancers from different viewpoints of treatment and provide some critical features for additional considerations.  Almost certainly, most of the engineered T-cells redirected against hematologic disorders aim at conventional target antigens rather than targeting an ideal target antigen that is exclusively expressed on cancerous cells and restricted to normal tissues. CAR-based clinical trials in hematologic cancers have often dealt with CD19, followed by BCMA, CD22, and CD20 antigens. Besides, most of the scFvs used in the CAR structure are derived from murine antibodies, which may raise the concern about immunogenicity by reducing the persistence of modified T-cells. Nevertheless, short- and long-term life-threatening toxicities and the development of escape mechanisms that result in resistance and antigen loss are not thoroughly understood yet. The ultimate goal of using modified CAR T-cells is to make them effective and curative. Therefore, a better understanding of all the features pertaining to target antigens is imperative. Also, the methods to identify candidate target antigens and manage the associated obstacles of CAR T-cells should be evaluated and prioritized.

    Keywords: Chimeric antigen receptor, Hematologic malignancies, Immunotherapy, T-cells
  • Collin Dubick*, Vishwas Sakhalkar, Sushmita Nair, Mark Boudreau, Om Sakhalkar Pages 161-165

    Acute Disseminated Encephalomyelitis (ADEM) is a monophasic demyelinating disease most often triggered by infection or immunization, though associations with malignancy and stem cell transplant have been described. We described the case of a four-year-old boy with new-onset neurological symptoms associated with ADEM, acute leukemia, and equivocal evidence of Mycoplasma pneumoniae infection. He responded to a short course of antibiotics and chemotherapy for B cell acute lymphoblastic leukemia (B-ALL) that included a prolonged course of high dose steroids with immunosuppressive therapy. This case illustrated a possible association between paraneoplastic ADEM and leukemia in pediatric patients.

    Keywords: Encephalomyelitis, Leukemia, Paraneoplastic