High FAAP24 expression reveals poor prognosis and an immunosuppressive microenvironment shaping in AML.

BACKGROUND: As a core member of the FA complex, in the Fanconi anemia pathway, FAAP24 plays an important role in DNA damage repair. However, the association between FAAP24 and patient prognosis in AML and immune infiltration remains unclear. The purpose of this study was to explore its expression characteristics, immune infiltration pattern, prognostic value and biological function using TCGA-AML and to verify it in the Beat AML cohort. METHODS: In this study, we examined the expression and prognostic value of FAAP24 across cancers using data from TCGA, TARGET, GTEx, and GEPIA2. To further investigate the prognosis in AML, development and validation of a nomogram containing FAAP24 were performed. GO/KEGG, ssGSEA, GSVA and xCell were utilized to explore the functional enrichment and immunological features of FAAP24 in AML. Drug sensitivity analysis used data from the CellMiner website, and the results were confirmed in vitro. RESULTS: Integrated analysis of the TCGA, TARGET and GTEx databases showed that FAAP24 is upregulated in AML; meanwhile, high FAAP24 expression was associated with poor prognosis according to GEPIA2. Gene set enrichment analysis revealed that FAAP24 is implicated in pathways involved in DNA damage repair, the cell cycle and cancer. Components of the immune microenvironment using xCell indicate that FAAP24 shapes an immunosuppressive tumor microenvironment (TME) in AML, which helps to promote AML progression. Drug sensitivity analysis showed a significant correlation between high FAAP24 expression and chelerythrine resistance. In conclusion, FAAP24 could serve as a novel prognostic biomarker and play an immunomodulatory role in AML. CONCLUSIONS: In summary, FAAP24 is a promising prognostic biomarker in AML that requires further exploration and confirmation.

A Rare Morphology Resembling APL with t (11;12) (p15;q13) in Acute Myeloid Leukemia: Case Report and Literature Review.

BACKGROUND: To investigate the clinical features of and therapeutic options for a rare morphology resembling APL with t (11;12) (p15;q13) in acute myeloid leukemia. METHODS: One case of APL-like acute leukemia with a t (11;12) (p15;q13) translocation is reported and related literature is retrospectively reviewed. RESULTS: A rare acute myeloid leukemia with a t (11;12) (p15;q13) translocation was diagnosed by morphology, immunophenotyping, chromosome analysis, and fusion gene detection, without finding a classical t (15;17) (q24.1;q21.1) translocation and the PML-RARa fusion gene. The patient responded poorly to differentiation induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In the three previous cases re-ported, poor results were obtained with ATRA and/or ATO therapy. CONCLUSIONS: We reported a rare meaningful AML patient with t (11;12) (p15;q13). Standard AML regimens may be preferred. These APL-like leukemias may benefit from hematopoietic stem cell transplantation treatment. Further investigation involving more cases is needed to determine the role of t (11;12) (p15;q13) in AML and to find better therapy choices.

Safety and efficacy of PCSK9 inhibitor (evolocumab) in patients with non-ST segment elevation acute coronary syndrome and non-culprit artery critical lesions: a randomised controlled trial protocol (SPECIAL study).

INTRODUCTION: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%). METHODS AND ANALYSIS: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period. ETHICS AND DISSEMINATION: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214. DISSEMINATION: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society. TRIAL REGISTRATION NUMBER: ChiCTR2200066675.

Comprehensive analysis of ERCC3 prognosis value and ceRNA network in AML.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy with high molecular and clinical heterogeneity, and is the most common type of acute leukemia in adults. Due to limited treatment options, AML is prone to relapse and has a poor prognosis. Excision repair cross-complementing 3 (ERCC3) is an important member of nucleotide excision repair (NER) that is overexpressed in types of solid cancers and potentially regarded as a prognostic factor. However, its role in AML remains unclear. The purpose of this study was to explore ERCC3 expression and functions in AML. METHODS: The Cancer Genome Atlas (TCGA) and GEO (Gene Expression Omnibus) were used to test the accuracy of ERCC3 expression levels for AML diagnosis. Using online databases and R packages, we also explored the signaling pathway, epigenetic regulation, infiltration of immune cells, clinical prognostic value, and ceRNA network in AML. RESULTS: Our results revealed that ERCC3 expression was increased in AML and that high ERCC3 expression had good value for disease-free survival and overall survival in AML patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that ERCC3 and co-expressed genes were mainly involved in chemical carcinogenesis/reactive oxygen species, ubiquitin-mediated protein degradation and oxidative phosphorylation. In addition, almost all the m6A-related coding genes (except GF2BP1) were positively associated with ERCC3 expression. We also constructed a ceRNA regulatory network containing ERCC3 in AML and identified 6 pairs of ceRNA networks, indicating that ERCC3 expression is regulated by a noncoding RNA system. CONCLUSION: This study demonstrated that ERCC3 was overexpressed in AML and that high ERCC3 expression can be considered a biomarker conducive to allo-HSCT in AML patients.

A transient receptor potential channel-related model based on machine learning for evaluating tumor microenvironment and immunotherapeutic strategies in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy. Transient receptor potential (TRP) channels in AML still need to be further explored. A TRP channel-related model based on machine learning was established in this study. Methods: The data were downloaded from TCGA-LAML and Genome-Tissue Expression (GTEx). TRP-related genes (TRGs) were extracted from previous literature. With the use of Single-Sample Gene Set Enrichment Analysis (ssGSEA), TRP enrichment scores (TESs) were calculated. The limma package was used to identify differentially expressed genes (DEGs), and univariate Cox regression analysis was performed to identify prognostic DEGs. The above prognostic DEGs were analyzed by Random Survival Forest and least absolute shrinkage and selection operator (Lasso) analysis to create the TRP signature. The Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to investigate the efficiency and accuracy of prognostic prediction. Moreover, genomic mutation analysis was based on GISTIC analysis. Based on ESTIMATE, TIMER, MCPcounter, and ssGSEA, the tumor microenvironment and immunological characteristics were expressly evaluated to explore immunotherapeutic strategies. Enrichment analysis for TRP signature was based on the Kyoto Encyclopedia of Genes Genomes (KEGG), Gene Ontology (GO), over-representation analysis (ORA), and Gene Set Enrichment Analysis (GSEA). Genomics of Drug Sensitivity in Cancer (GDSC) and pRRophetic were used to carry out drug sensitivity analysis. Conclusively, SCHIP1 was randomly selected to perform in vitro cyto-functional experiments. Results: The worse clinical outcomes of patients with higher TESs were observed. There were 107 differentially expressed TRGs identified. Our data revealed 57 prognostic TRGs. Eight TRGs were obtained to establish the prognostic TRP signature, and the worse clinical outcomes of patients with higher TRP scores were found. The efficiency and accuracy of TRP signature in predicting prognosis were confirmed by ROC curves and five external validation datasets. Our data revealed that the mutation rates of DNMT3A, IDH2, MUC16, and TTN were relatively high. The level of infiltrating immune cell populations, stromal, immune, and ESTIMATE scores increased as the TRP scores increased. Nevertheless, AML patients with lower TRP scores exhibited more tumor purity. The TRP scores were found to be correlated with immunomodulators and immune checkpoints, thus revealing immune characteristics and immunotherapeutic strategies. The IC50 values of six chemotherapeutics were lower in the high TRP score (HTS) group. Finally, it was found that SCHIP1 may be the oncogenic gene. Conclusion: The results of this study will help in understanding the role of TRP and SCHIP1 in the prognosis and development of AML.

Survival Benefit and Efficiency of Low Dose Decitabine With CEG Regimen Compared to Decitabine Alone in the Elderly MDS - A Multicenter, Retrospective Study.

BACKGROUND: Decitabine are used in the treatment of myelodysplastic syndrome (MDS), but none trials reported overall survival improvement. METHODS: High-risk MDS and MDS transformed AML (sAML) patients (IPSS-R > 4.5, age above 60 years) in 6 medical centers of China were treated and compared a new regimen (decitabine with CEG) consisted of low dose decitabine (15 mg/m2, days 1-3), low dose etoposide (30 mg/m2, days 4,6,8,10,12), cytarabine (10 mg/m2 per day, days 4-12) and granulocyte colony-stimulating factor (G-CSF, 5ug/kg, adjusted by patients' WBC level, 12 hours prior to decitabine administration) with decitabine alone. The endpoints were death and disease progression. RESULTS: The baseline characteristics of these 2 groups were equivalent and none patients received prior chemotherapy. The treatment response rate (P= .048) and progression free survival (PFS, P = .030) all demonstrated significant improvement compared with decitabine alone. Decitabine with CEG regimen had attained a CR rate of 45.7%, a median OS of 36 (19-53) months and a median PFS of 34 (16.7-51.3) months in high-risk MDS patients, a CR rate of 40% in sAML. While decitabine alone only attained a median OS of 26 (24.5-27.5) months and a CR rate of 18.2% as well as a median progression free survival of 20 (17.6-22.4) months in MDS patients. Treatment response to CR or PR and TP53 mutation were 2 prognostic factor for OS and PFS in decitabine with CEG regimen. CONCLUSION: Decitabine with CEG regimen showed some promising advantage in elderly, high-risk MDS.

Donor-derived anti-CD19 CAR T cells compared with donor lymphocyte infusion for recurrent B-ALL after allogeneic hematopoietic stem cell transplantation.

The efficacy and safety of donor-derived anti-CD19 CAR T cells vs DLI for the management of relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allo-hematopoietic stem cell transplantation (HSCT) remain unclear. Thirteen B-ALL patients with relapsed after allo-HSCT and thus were treated with donor-derived anti-CD19 CAR T-cell (study group). Fifteen B-ALL patients relapsed after allo-HSCT and thus were treated with DLI (DLI group). The rates of MRD-negative complete remission (61.5%) in the study group were significantly higher than those in the DLI group (13.3%) (p = 0.02). The complete remission duration in study group and DLI group were median 8.0 months (range, 3-25 months) and 4.4 months (range, 1-25 months; p = 0.026), respectively. The overall survival of patients in the study group was superior to that of the DLI group: 9.5 months (range,3-25 months) versus 5.5 months (range, 1-25 months; p = 0.030). One patient with grade 1 acute graft-versus-host disease (aGVHD) was identified in the study group. While five (33.3%) patients in the DLI group developed grades III-IV aGVHD. Three patients (23.07%) developed grade 3 or 4 cytokine release syndrome in the study group. This study suggested that donor-derived anti-CD19 CAR T-cell therapy is promising, safe, and potentially effective for relapsed B-ALL after allo-HSCT and may be superior to DLI.

Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for a Pediatric Ph-Like B-ALL Patient That Relapsed After CART-Cell and Haplo-HSCT Therapy: A Case Report and Review of Literature.

Pediatric Philadelphia chromosome-like (Ph-like) acute B-lymphoblastic leukemia (B-ALL), a high-risk subset of B-ALL characterized by a gene expression profile similar to that of Ph-positive ALL, has extremely poor outcome after a relapse following autologous chimeric antigen receptor (CAR)-T and haploidentical (haplo) hematopoietic stem cell transplantation(HSCT)therapy. with very limited treatment options. Donor-derived CAR T-cell therapy, the most vital advanced anticancer technology, may be a promising salvage strategy for patients with Ph-like B-ALL. Here, we presented a relapsed and refractory case of a child with Ph-like B-ALL after autologous anti-CD19 CAR T-cell therapy followed by haplo-HSCT. She successfully achieved the fourth complete remission (CR4) and maintained CR for five months after the sequential infusion of donor-derived anti-CD22 and anti-CD19 CAR T cells, with mild CRS side effects and no obvious graft-versus-host disease. A donor-derived anti-CD22 and -CD19 CAR T-cell therapy combined with a sequential infusion strategy may provide a promising alternative treatment strategy as effective and safe salvage therapy for children with recurrent and refractory Ph-like B-ALL after autologous CD19-directed CAR T-cell therapy followed by haplo-HSCT.

[Comparison of the Curative Efficacy of Elderly Patients with High-Risk MDS and MDS-Transformed AML between Decitabine Combined with Low-Dose CEG Regimen and Decitabine Combined with Low-Dose CAG Regimen].

OBJECTIVE: To evaluate the efficacy of decitabine combined with low-dose CEG regimen (DCEG) and decitabine combined with low-dose CAG regimen (DCAG) in the treatment of elderly patients with MDS and MDS-transformed acute myeloid leukemia (AML). METHODS: A prospective study was conducted in 7 medical centers, 45 patients with MDS (≥ 60 years old) and MDS-transformed AML from October 2016 to January 2019 were enrolled, with the median age of 68.5 years old. The risk stratification of patients was poor or very poor, according to IPSS-R score. The treament results of decitabine combined with CEG and decitabine combined with CAG were compared. RESULTS: The comparison of the two regiem showed that the DCEG regimen had advantages on total effective rate (ORR, 86.4% vs 47.8%, respectively), overall survival time (OS) (10.0 months vs 6.0 months, respectively) and progression-free survival time (PFS) (9.0 months vs 3.0 months, respectively). About 50% of MDS patients treated by DCEG regimen achieved PR or CR, with a median OS of 31 months. Multivariate analysis showed that patients with PR or CR after induction therapy and DCEG regimen had longer survival time (31months). The incidence of bone marrow suppression, infection and treatment-related mortality rate were similar between the two groups. CONCLUSION: Decitabine combined with CEG regimen could improve the survival of patients with high-risk MDS and MDS-transformed AML. The conclusion of the reaserch needs to be validated by a larger prospective randomized clinical trial.

Allogeneic Donor-Derived Anti-CD19 CAR T Cell Is a Promising Therapy for Relapsed/Refractory B-ALL After Allogeneic Hematopoietic Stem-Cell Transplantation.

INTRODUCTION: Currently, effective and safe salvage therapies are limited among patients with relapsed acute lymphoblastic leukemia after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Anti-CD19 chimeric antigen receptor T (CAR T) cell is a promising treatment. PATIENTS AND METHODS: We studied 11 patients with B-cell acute lymphoblastic leukemia that relapsed after allo-HSCT between September 2017 and October 2019. Patients were treated with a dose of single-infusion donor-derived anti-CD19 CAR T cells. RESULTS: Eight patients (72.7%) experienced morphologic remissions. Seven (63.6%) experienced minimal residual disease-negative remission. The ongoing complete remission (CR) duration of 2 patients reached 22 months. The median overall survival was 9 months (range, 2-22 months). Only one patient with grade 1 acute graft-versus-host disease was observed. Two patients (18.2%) developed grade 3/4 cytokine release syndrome. CONCLUSION: This prospective study showed allogeneic donor-derived anti-CD19 CAR T-cell therapy is an effective and safe salvage regimen for patients with relapsed/refractory B-cell acute lymphoblastic leukemia after allo-HSCT. Further randomized and multicenter investigations are needed to evaluate their potential role in relapsed acute lymphoblastic leukemia therapies after allo-HSCT.

Dysfunction of microRNA-32 regulates ubiquitin ligase FBXW7 in multiple myeloma disease.

Dysfunction of microRNA (miRNA) expression has been associated with tumor occurrence, progression, and development. The aim of this work was to study the dysfunction of miR-32 - an miRNA that was abnormally regulated in different tumors - in clinical tissues from patients with multiple myeloma (MM). The tumor tissues in which we assessed miR-32 expression levels were collected during our 5 years of clinical practice. Our study found an increase in miR-32 expression in MM tissues. Assessment of F-box and WD repeat domain-containing 7 (FBXW7) in MM tissues showed an inverse relation between the expression of FBXW7 and miR-32. To further investigate the relation between miR-32 and FBXW7, cells were transfected with miR-32 or anti-miR-32. In vitro studies found that cells transfected with miR-32 showed a lower expression of FBXW7 and a higher expression of cancer-related proteins, c-Jun and c-Myc. In contrast, the cells transfected with anti-miR32 showed a relatively higher expression of FBXW7, but a lower expression of c-Jun and c-Myc. This study may offer perceptive insights into developing new strategies for MM cancer detection and therapy.