Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.

Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.

Diagnosis of Cutaneous Acute Graft­Versus­Host Disease Through Circulating Plasma miR-638, miR-6511b-5p, miR-3613-5p, miR-455-3p, miR-5787, and miR-548a-3p as Prospective Noninvasive Biomarkers Following Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: There are currently no laboratory tests that can accurately predict the likelihood of developing acute graft-versus-host disease (aGVHD), a patient's response to treatment, or their survival chance. This research aimed to establish circulating miRNAs as diagnostic, prognostic, or predictive biomarkers of aGVHD. METHODS: In a prospective cohort, we studied the incidence of cutaneous aGVHD in AML patients undergoing allo-HSCT at Shariati Hospital in Tehran, Iran during 2020-2023. Patients with cutaneous aGVHD were labeled as the case group, while patients without cutaneous aGVHD were selected as the control group. Accordingly, the expression levels of six significant miRNAs (miR-638, miR-6511b-5p, miR-3613-5p, miR-455-3p, miR-5787, miR-548a-3p) were evaluated by quantitative reverse transcription-polymerase chain reaction (RTqPCR) in three different time-points: before transplantation, on day 14 and day 21 after transplantation. RESULTS: The levels of plasma miR-455-3p, miR-5787, miR-638, and miR-3613-5p were significantly downregulated, while miR-548a-3p, and miR-6511b-5p were significantly upregulated in individuals with cutaneous aGVHD in comparison to patients without GVHD. Additionally, the possibility for great diagnostic accuracy for cutaneous aGVHD was revealed by ROC curve analysis of differentially expressed miRNAs (DEMs). CONCLUSION: The study findings encourage us to hypothesize that the aforementioned miRNAs may contribute to the predominance of aGVHD, particularly low-grade cutaneous aGVHD.

Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML).

BACKGROUND: KIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy. RESULTS: In contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+ R and KIR2DS2D/C1+ R mismatch versus KIR2DL1D/C2- R mm, KIR2DL2/3D/C1- R mm and KIR3DL1D/Bw4- mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04). CONCLUSION: This analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

Circulating miR-455-3p, miR-5787, and miR-548a-3p as potential noninvasive biomarkers in the diagnosis of acute graft-versus-host disease: a validation study.

Currently, acute graft-versus-host disease (aGVHD) diagnosis is based on clinical features and pathological findings. Until now, there is no non-invasive diagnostic test for aGVHD. MicroRNAs may act as promising predictive, diagnostic, or prognostic biomarkers for aGVHD. The purpose of the current study was to validate circulating microRNAs as diagnostic biomarkers to assist clinicians in promptly diagnosing aGVHD, so that treatment can be initiated earlier. In the present study, we evaluated six microRNAs (miR-455-3p, miR-5787, miR-6729-5p, miR-6776-5p, miR-548a-3p, and miR-6732-5p) selected from miRNA array data in 40 aGVHD patients compared to 40 non-GVHD patients with RT-qPCR. Target genes of differentially expressed microRNAs (DEMs) were predicted using Targetscan, miRanda, miRDB, miRWalk, PICTAR5, miRmap, DIANA, and miRTarBase algorithms, and their functions were analyzed using EnrichNet, Metascape, and DIANA-miRPath databases. The expressions of plasma miR-455-3p and miR-5787 were significantly downregulated, whereas miR-548a-3p was significantly upregulated in aGVHD patients compared to non-GVHD patients. Moreover, DEMs showed potentially high diagnostic accuracy for aGVHD. In silico analysis of DEMs provided valuable information on the role of DEMs in GVHD, immune regulation, and inflammatory response. Our study suggested that miR-455-3p, miR-5787, and miR-548a-3p could be used as potential noninvasive biomarkers in the diagnosis of aGVHD in addition to possible therapeutic targets in aGVHD.

MicroRNAs as Potential Diagnostic, Prognostic, and Predictive Biomarkers for Acute Graft-versus-Host Disease.

Successful treatment of various hematologic diseases with allogeneic hematopoietic stem cell transplantation is often limited due to the occurrence of acute graft-versus-host disease (aGVHD). So far, there are no approved molecular biomarkers for the diagnosis and prediction of aGVHD at the clinical level due to our incomplete understanding of the molecular biology of the disease. Various studies have been conducted on animal models and humans to investigate the role of microRNAs in aGVHD pathogenesis to implicate them as biomarkers and therapeutic targets. Because of their high stability, tissue specificity, ease of measurement, low cost, and simplicity, they are excellent targets for biomarkers. In this review, we focused on microRNA expression profiling studies that were performed recently in both animal models and human cases of aGVHD to identify diagnostic and predictive biomarkers for this disease. The expression pattern of microRNAs can be specific to cells and tissues. Because aGVHD affects several organs, microRNA signatures in target tissues may help to understand the molecular pathology of the disease. Identification of organ-specific microRNAs in aGVHD can be promising to categorize patients for organ-specific therapies. Thus, microRNAs can be used as noninvasive diagnostic tests in clinic to improve prophylaxis, predict incidence and severity, and reduce morbidity.

Identification of MiR-125a as a Novel Plasma Diagnostic Biomarker for Chronic Lymphoblastic Leukemia.

Background: Chronic lymphocytic leukemia (CLL) is a type of malignancy in which the bone marrow makes too many lymphocytes. MicroRNAs (miRNAs) are endogenous short (~22-nucleotides) non-protein-coding regulatory RNA molecules with key roles in cellular and molecular processes linked to different cancers including CLL. Re-cently, some investigations have demonstrated that miR-125a downregulation is correlated with the expression of P53, NRG1 and ERBB2. Methods: In this study, samples including 38 patients with CLL and 25 healthy individuals were collected. We used quantitative real-time PCR (qRT-PCR) to assess the expression of miR-125a in plasma of the CLL patients in comparison with healthy controls. Moreover, we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis on miR-125a targets in the DAVID database in order to investigate the potential role of miR-125a in cancer pathways. MiR-125a exerted a variety of roles in the cancer pathway via downregulating target genes including ERBB2. Results: The expression of miR-125a dramatically decreased (~2-fold) in the patients with CLL compared with the healthy controls (p = 0.03). Furthermore, overexpression of miR-125a was associated with different CLL staging and B symptoms (all at p < 0.05). The KEGG pathway enrichment analysis demonstrated the eight statistically related KEGG signaling pathways with miR-125a targetome. Conclusions: The results suggested that the miR-125a expression level could be a novel potential biomarker for CLL prognosis.

Liver fibrosis alleviation after co-transplantation of hematopoietic stem cells with mesenchymal stem cells in patients with thalassemia major.

The aims of this study are to determine the replacement rate of damaged hepatocytes by donor-derived cells in sex-mismatched recipient patients with thalassemia major and to determine whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells (HSCs) can alleviate liver fibrosis. Ten sex-mismatched donor-recipient pairs who received co-transplantation of HSCs with mesenchymal stem cells were included in our study. Liver biopsy was performed before transplantation. Two other liver biopsies were performed between 2 and 5 years after transplantation. The specimens were studied for the presence of donor-derived epithelial cells or hepatocytes using fluorescence in situ hybridization by X- and Y-centromeric probes and immunohistochemical staining for pancytokeratin, CD45, and a hepatocyte-specific antigen. All sex-mismatched tissue samples demonstrated donor-derived hepatocyte independent of donor gender. XY-positive epithelial cells or hepatocytes accounted for 11 to 25% of the cells in histologic sections of female recipients in the first follow-up. It rose to 47-95% in the second follow-up. Although not statistically significant, four out of ten patients showed signs of improvement in liver fibrosis. Our results showed that co-transplantation of HSC with mesenchymal stem cells increases the rate of replacement of recipient hepatocytes by donor-derived cells and may improve liver fibrosis.

Minimal residual disease (MRD) detection using rearrangement of immunoglobulin/T cell receptor genes in adult patients with acute lymphoblastic leukemia (ALL).

MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage. An ASO-qPCR technique was then applied for 2.5-year monthly MRD quantification for detection of patient-specific Ig/TCR receptor rearrangements as a molecular target. From 98 patients who were diagnosed as ALL, 72 (73.5%) were enrolled in the present study for MRD detection. MRD was successfully quantified in patients with 1-month interval time. MRD level at the end of induction therapy up to day 88 was the only significant prognostic factor. Regarding MRD level, patients were categorized into two groups of low and high-risk. 2.5-year OS in all three time points (days 28, 58 and 88) were significantly lower in high-risk group (P < 0.008). The results of the 2.5-year MRD detection indicate that MRD level at the end of induction up to about 6 months after the first diagnosis was associated with clinical outcome. This study may highlight the usefulness of PB and the definitions of cut-off level for early prediction of relapse and for stratifying ALL patients. Short-interval time points and frequent PB sampling to monitor MRD level is suggested for early clinical relapse prediction and clinical management of the disease.

Deregulation of miR-1, miR486, and let-7a in cytogenetically normal acute myeloid leukemia: association with NPM1 and FLT3 mutation and clinical characteristics.

Cytogenetically normal acute myeloid leukemia (CN-AML) constitutes the largest subgroup of AML patients that is associated with molecular alteration. MiRNAs have been shown to be aberrantly expressed in CN-AML. In addition, specific miRNA (miR) expression patterns were found to be associated with certain genetic alterations in these patients. This study investigated the expression level of miR-1, miR-486, and let-7a in 45 CN-AML patients well characterized for FLT3 and/or NPM1 mutations using real-time quantitative RT-PCR and evaluated the association between candidate miRs expression and clinical features. Our data revealed that miR-1 was significantly overexpressed in CN-AML patients, and increasing expression of miR-1 correlated with NPM1 mutation (P < 0.05) and lower hemoglobin level was also observed in patients with miR-1 overexpression (P < 0.05). The expression of miR-1 was much higher in AML-M2 compared with other subtypes. Further, we found significantly increasing miR-486 expression in 40 of 45 (89 %) CN-AML patients. There was no significant association of upregulation of miR-486 with clinical parameters. The expression level of miR-486 was increased in AML-M2 subtype. The levels of let-7a were significantly increased in CN-AML patients compared to the healthy control and significantly higher in the NPM1 ± CN-AML patients. There was no correlation detected between the level of let-7a and FLT3+. An increasing expression level of let-7a was demonstrated in M2 subtype. In addition, our data showed no significant association between increasing let-7a and clinical characteristic. Comparison of peripheral blood and bone marrow results in 30 CN-AML patients showed that there is a considerable concordance between PB and BM in the results of candidate miR levels (P < 0.001). In conclusion, further studies should also be performed to detect functional mechanism of these miRs.

Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway.

Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi-tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway.

FLT3 Gene Mutation Profile and Prognosis in Adult Acute Myeloid Leukemia.

BACKGROUND: Internal tandem duplication (ITD) of FMS-related tyrosine kinase 3 (FLT3) gene, which occurs in exons 14 and 15, is one of the most prevalent somatic mutations in adult acute myeloid leukemia (AML) and has biological, prognostic, and therapeutic implications. The prognostic importance of codon 835 tyrosine kinase domain (TKD) mutation (exon 20), which occurs relatively frequently in adult AML, is often debated. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML. METHODS: We determined the status of ITD and TKD mutations using fragment analysis and the polymerase chain reaction-restriction fragment polymorphism method, respectively. In addition, we used direct sequencing to confirm the results of TKD mutation analysis. RESULTS: Twenty five percent of the patients had an ITD mutation. The mean size of the inserted fragment was 63.5 base pairs. Twenty percent of the ITD-positive patients showed more than one mutated population upon polymerase chain reaction. Statistical analyses showed that the ITD mutation was associated with a decreased overall survival among patients in the intermediate cytogenetic risk group (p-value = 0.013). The size of the ITD was not correlated with overall survival. Eight out of 139 patients (5.7%) had the codon 835 mutation. One new mutation of the insertion/deletion type was discovered. Analyses did not show any relationship between the TKD mutation and overall survival. Two patients (1.4%) showed concurrent TKD and ITD mutations. The TKD and ITD mutation rates of the FLT3 gene were consistent with previous studies on AML patients. CONCLUSIONS: This study supports the results of previous studies regarding the association of the FLT3-ITD mutation and poor prognosis.

AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy.

Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer.

GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.

Cytogenetically normal acute myeloid leukemia (CN-AML) with biallelic CEBPA gene mutations (biCEPBA) represents a distinct disease entity with a favorable clinical outcome. So far, it is not known whether other genetic alterations cooperate with biCEBPA mutations during leukemogenesis. To identify additional mutations, we performed whole exome sequencing of 5 biCEBPA patients and detected somatic GATA2 zinc finger 1 (ZF1) mutations in 2 of 5 cases. Both GATA2 and CEBPA are transcription factors crucial for hematopoietic development. Inherited or acquired mutations in both genes have been associated with leukemogenesis. Further mutational screening detected novel GATA2 ZF1 mutations in 13 of 33 biCEBPA-positive CN-AML patients (13/33, 39.4%). No GATA2 mutations were found in 38 CN-AML patients with a monoallelic CEBPA mutation and in 89 CN-AML patients with wild-type CEBPA status. The presence of additional GATA2 mutations (n=10) did not significantly influence the clinical outcome of 26 biCEBPA-positive patients. In reporter gene assays, all tested GATA2 ZF1 mutants showed reduced capacity to enhance CEBPA-mediated activation of transcription, suggesting that the GATA2 ZF1 mutations may collaborate with biCEPBA mutations to deregulate target genes during malignant transformation. We thus provide evidence for a genetically distinct subgroup of CN-AML. The German AML cooperative group trials 1999 and 2008 are registered with the identifiers NCT00266136 and NCT01382147 at www.clinicaltrials.gov.

Rewiring of miRNA-mRNA bipartite co-expression network as a novel way to understand the prostate cancer related players.

The differential expression and direct targeting of mRNA by miRNA are two main logics of the traditional approach to constructing the miRNA-mRNA network. This approach, could be led to the loss of considerable information and some challenges of direct targeting. To avoid these problems, we analyzed the rewiring network and constructed two miRNA-mRNA expression bipartite networks for both normal and primary prostate cancer tissue obtained from PRAD-TCGA. We then calculated beta-coefficient of the regression-model when miR was dependent and mRNA independent for each miR and mRNA and separately in both networks. We defined the rewired edges as a significant change in the regression coefficient between normal and cancer states. The rewired nodes through multinomial distribution were defined and network from rewired edges and nodes was analyzed and enriched. Of the 306 rewired edges, 112(37%) were new, 123(40%) were lost, 44(14%) were strengthened, and 27(9%) weakened connections were discovered. The highest centrality of 106 rewired mRNAs belonged to PGM5, BOD1L1, C1S, SEPG, TMEFF2, and CSNK2A1. The highest centrality of 68 rewired miRs belonged to miR-181d, miR-4677, miR-4662a, miR-9.3, and miR-1301. SMAD and beta-catenin binding were enriched as molecular functions. The regulation was a frequently repeated concept in the biological process. Our rewiring analysis highlighted the impact of ß-catenin and SMAD signaling as also some transcript factors like TGFB1I1 in prostate cancer progression. Altogether, we developed a miRNA-mRNA co-expression bipartite network to identify the hidden aspects of the prostate cancer mechanism, which traditional analysis -like differential expression- was not detect it.

Investigation of Expression Profile of Placenta-specific 1 (PLAC1) in Acute Myeloid and Lymphoid Leukemias.

Background: Placenta-specific 1 (PLAC1) is one of the cancer-testis-placenta antigens that has no expression in normal tissue except placenta trophoblast and testicular germ cells, but is overexpressed in a variety of solid tumors. There is a lack of studies on the expression of PLAC1 in leukemia. We investigated expression of PLAC1 in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). Methods: In this study, we investigated expression pattern of PLAC1 gene in peripheral blood and bone marrow mononuclear cells of newly-diagnosed patients with AML (n=31) and ALL (n=31) using quantitative real-time PCR. Normal subjects (n=17) were considered as control. The PLAC1 protein expression in the samples were also detected using western blotting. Results: Our data demonstrated that PLAC1 transcripts had 2.7 and 2.9 fold-change increase in AML and ALL, respectively, compared to normal samples. PLAC1 transcript expression was totally negative in all studied normal subjects. Level of PLAC1 mRNA expression in ALL statistically increased compared to normal samples (p=0.038). However, relative mRNA expression of PLAC1 in AML was not significant in comparison to normal subjects (p=0.848). Furthermore, relative mRNA expression of PLAC1 in AML subtypes was not statistically significant (p=0.756). PLAC1 gene expression showed no difference in demographical clinical and para-clinical parameters. Western blotting confirmed expression of PLAC1 in the ALL and AML samples. Conclusion: Considering PLAC1 expression profile in acute leukemia, PLAC1 could be a potential marker in leukemia which needs complementary studies in the future.

The Influence of KIR Gene Polymorphisms and KIR-ligand Binding on Outcomes in Hematologic Malignancies following Haploidentical Stem Cell Transplantation: A Comprehensive Review.

Natural killer (NK) cell behavior and function are controlled by a balance between negative or positive signals generated by an extensive array of activating and inhibiting receptors, including killer cell immunoglobulin-like receptor (KIR) proteins, main components of the innate immune system that contribute to initial responses against viral infected-transformed cells through generation of the release of cytokines and cytotoxicity. What is certain is that KIRs are genetically polymorphic and the extent of KIRs diversity within the individuals may have the potential outcomes for hematopoietic stem cell transplantation (HSCT). In this regard, recent studies suggest that KIR is as imperative as its ligand (HLA) in stem cell transplantation for malignant diseases. However, unlike HLA epitope mismatches, which are well-known causes of NK alloreactivity, a complete understanding of KIR genes' role in HSCT remains unclear. Because of genetic variability in KIR gene content, allelic polymorphism, and cell-surface expression among individuals, an appropriate selection of donors based on HLA and KIR profiles is crucial to improve outcomes of stem cell transplantation. In addition, the impact of the KIR/HLA interaction on HSCT outcomes needs to be investigated more comprehensively. The present work aimed to review the NK cell regeneration, KIR gene polymorphisms, and KIRligand binding on outcomes in hematologic malignancies following haploidentical stem cell transplantation. Comprehensive data gathered from the literature can provide new insight into the significance of KIR matching status in transplantations.

Spontaneous Complete Remission of Acute Myeloid Leukemia in the Absence of Disease-Modifying Therapy following Severe Pulmonary Involvement by Coronavirus Infectious Disease-19.

Coronavirus infectious disease-19 (COVID-19) usually alters the innate and adaptive immune setting by excessive production of proinflammatory cytokines, leading to a deviation in the natural course of simultaneous malignant disease. In the absence of disease-modifying therapy, complete remission of acute myeloid leukemia (AML) is an extraordinary event caused mainly by an immune-related mechanism secondary to a severe infectious process. We present a 57-year-old woman with a new diagnosis of AML associated with a 11q23/KMT2A abnormality who had achieved temporary spontaneous remission in the absence of disease-modifying therapy following the severe pulmonary infection with coronavirus lasting for six months. We review the literature and explain the potential impact of stimulated immune responses by COVID-19 on induction of remission in a patient with AML that could provide an excellent opportunity for new immune-based therapies to evolve for the hematologic malignancies. Despite the high ability of the immune process to destroy the malignant cells, the remission of duration is usually short. Therefore, it seems that continuing treatment after SR of AML by a consolidation regimen or bone marrow transplantation, based on a risk-adapted treatment approach, may reduce the recurrence risk.

A Comparison of Dexamethasone Plus Vincristine versus Standard Regimen in Induction Therapy of Adult Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplantation.

Background: Current treatment options of acute lymphoblastic leukemia(ALL) include chemotherapy alone or hematopoietic stem cell transplantation (HSCT) following induction chemotherapy both along with CNS prophylaxis. The usual and standard induction regimens currently administered could have severe complications and mortality. Materials and Methods: To lessen induction regimen complications in ALL patients who undergo HSCT, we used a cytoreduction induction regimen including dexamethasone (8 mg, IV, three times a day, for 28 days) and vincristine(1.4 mg/m2, IV, on days 1,8,15 and 22) for 49 newly diagnosed adult ALL patients followed by an early sibling donor HSCT within two months. The results were matched with outcomes of HSCT in 172 ALL patients inducted by standard induction regimen. Results: Median follow-up time was 5.41 years in the standard group and 5.27 years in the other. All patients of the case group (100%) achieved complete remission. Landmark analyses were performed to scrutinize the effect of treatments on different time intervals: first two years and 2nd to end years. Type of treatment had no significant effect on the hazard of death in the first landmark (HR=0.87, P=0.64). Cytoreduction regimen amplified the hazard of death 3.43 times more than the standard regimen in the second landmark (HR=3.43 P=0.035). Multivariate analysis showed that the cytoreduction regimen reduced the hazard of relapse about 22%, but not statistically significant (HR=0.78, P-value=0.24). Conclusion: Overall, it seems despite achieving complete remission in induction therapy, depth of response is a critical predictor for long-term outcomes of HSCT in ALL patients, and the use of multiple agents may be necessary to decrease tumor cell burden and minimal residual disease(MRD).

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis.

Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. A total of 122 patients (median age: 8 years, range: 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day, days -9 to -6), cyclophosphamide (15 mg/kg/day, days -5 to -2), and in vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease prophylaxis with cyclosporine combined with methotrexate. We used the Kaplan-Meier method, log-rank test, and Cox proportional hazards models to analyze patient survival. Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched siblings in 48 (39.3%), matched other relatives in 56 (45.9%), and matched unrelated persons in 18 (14.8%) patients. With a median follow-up time of 24.25 months, graft rejection occurred in only one patient. The 1- and 5-year overall survival rates were 84.14% (95% confidence interval: 76.02-89.70) and 82.16% (95% confidence interval: 73.01-88.45), respectively. Of the patient characteristics documented before transplant, the presence of cardiopulmonary, genitourinary tract, central nervous system, and limb malformations significantly affected survival rates. Our results indicate excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable to aim at optimizing the outcome of HSCT in FA patients in future studies.

A Panel of Circulating microRNAs as a Potential Biomarker for the Early Detection of Gastric Cancer.

Background: The high mortality rate of Gastric Cancer (GC) is a consequence of delayed diagnosis. The early diagnosis of GC could increase the five-year survival rate among patients. We aimed to find a panel of microRNAs (miRNA) for the detection of GC in the early stages. Methods: In this case-control study, we selected consistently upregulated miRNAs from the results of 12 high-throughput miRNA profiling studies in GC. In the profiling phase, the differential expressions of 13 candidate miRNAs were analyzed by quantitative reverse-transcription PCR (qRT-PCR) in two pooled RNA samples prepared from the plasma of eight GC patients and eight matched controls. In the validation phase, significantly upregulated miRNAs from the profiling phase were further evaluated in the plasma samples of 97 patients with stage I-IV gastric adenocarcinoma and 100 healthy controls. Results: In the profiling phase, six miRNAs (miR-18a, 21, 25, 92a, 125b and 221) were significantly upregulated in the GC patients compared to the controls (p<0.05). However, in the validation phase, only significant up-regulation of miR-18a, 21 and 125b was confirmed (p<0.05). A panel of miR-18a/21/125b was able to detect GC patients with stage I-IV from the controls (p<0.001; AUC=0.92, sensitivity=86%; specificity=85%). In addition, the panel could distinguish the early-stage GC (I+II) from the control group with an AUC of 0.83, a sensitivity of 83%, and a specificity of 75%. Conclusion: A panel of circulating miR18a/21/125b could be suggested as a potential biomarker for the early detection of GC.