Current Research in Translational Medicine最新文献

Introduction

In the era of JAK inhibitors, allogeneic stem cell transplantation (HSCT) remains the only curative treatment for patients with Myelofibrosis (MF). Splenic irradiation (SI) may be used to reduce spleen size and related symptoms.

Methods

We conducted a retrospective analysis on 14 patients with MF who underwent HSCT with SI from any donor source at our center between June 2016 and March 2021. All patients received a conditioning backbone based on treosulfan and fludarabine, with post-transplant cyclophosphamide (PTCy) and sirolimus as graft-versus-host disease (GvHD) prophylaxis. Patients received SI with 10 Gy involved-field radiotherapy in five 2-Gy fractions over the course of a week prior to the beginning of conditioning.

Results

At transplant all patients were transfusion-dependent and had splenomegaly (median bipolar diameter by ultrasound: 20.75 cm). Overall, 12 patients had received ruxolitinib prior to transplant. Re-evaluation of spleen dimensions was available for 13 patients: median splenic bipolar diameter after at least 3 months from transplant decreased by a median of 25%. With a median post-transplant follow-up of 25 months, 6 patients remain in CR with full-donor chimerism, 3 patients died due to NRM. Overall, 4 patients relapsed. At last follow-up, nine patients are currently alive and achieved transfusion-independence.

Conclusions

In a small cohort of mostly ruxolitinib pre-treated patients, SI and treosulfan-based conditioning appeared a safe and effective tool to reduce spleen dimensions and ameliorate symptoms. Future prospective studies with adequate sample size are warranted to further investigate the usefulness and safety of this approach in MF.

Cancer-associated venous thrombosis (CAT) is a common, multifactor event known to complicate the course of cancer and jeopardize a patient's prognosis. The current guidelines regarding the prevention of CAT are sometimes considered insufficiently precise about specific situations, or are poorly applied. The expected benefits of thromboprophylaxis are balanced by the risk of major bleeding induced by anticoagulation, which implies a need to accurately identify ambulatory patients at high risk of thrombosis or hemorrhage. The Khorana score is commonly used for this, but is limited by the non-reproducibility of predicted performance across cancer types, and by the fact that antitumor treatment and cardiovascular risks are not included. The COMPASS-CAT score, which includes those two aspects, was found to be a more accurate predictor of venous thromboembolism in patients with lung cancer, and to better distinguish between patients at low or high risk of thrombosis. The frailty of patients with cancer is also a major issue, and should be taken into account when thromboprophylaxis is considered. According to current guidelines, CAT prophylaxis should be considered for hospitalized patients, those for whom surgery is scheduled, or those with pancreatic cancers. In ambulatory patients, decisions should be made according to patient, cancer and antitumoral treatment characteristics. Low molecular weight heparin is the gold standard of CAT prophylaxis. Despite increased risks of bleeding or drug-drug interactions in cancer patients, direct oral anticoagulants could be alternate options for high-risk ambulatory patients that should be accompanied by a careful global analysis of benefits, harms, and patient preferences.

Introduction

The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow.

Method

To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms "COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia.

Results

Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations.

Conclusion

To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.

Adoptive T cell therapy (ACT) is a fast developing, niche area of immunotherapy (IO), which is revolutionising the therapeutic landscape of solid tumour oncology, especially metastatic melanoma (MM). Identifying tumour antigens (TAs) as potential targets, the ACT response is mediated by either Tumour Infiltrating Lymphocytes (TILs) or genetically modified T cells with specific receptors – T cell receptors (TCRs) or chimeric antigen receptors (CARs) or more prospectively, natural killer (NK) cells. Clinical trials involving ACT in MM from 2006 to present have shown promising results. Yet it is not without its drawbacks which include significant auto-immune toxicity and need for pre-conditioning lymphodepletion. Although immune-modulation is underway using various combination therapies in the hope of enhancing efficacy and reducing toxicity. Our review article explores the role of ACT in MM, including the various modalities – their safety, efficacy, risks and their development in the trial and the real world setting.

Purpose

Chimeric antigen receptor T-cell (CAR-T) therapy has been proven very effective in treating hematologic malignancies. Ciltacabtagene autoleucel (cilta-cel), a second-generation CAR-T cell with double B cell maturation antigen (BCMA) targeting binding domains, showed an 88% overall response rate (ORR) in patients with relapsed/refractory multiple myeloma (MM), which were carried out in our institute. This study aimed to assess the prognostic potential of soluble BCMA (sBCMA) in serum as a biomarker in MM after CAR-T therapy.

Patients and methods

Serum samples (n = 44) from MM patients were collected before and after CAR-T therapy. The level of sBCMA was analyzed by enzyme-linked immunosorbent assay (ELISA). Additionally, three patients’ long-term longitudinal analysis were performed.

Results

Serum sBCMA level was correlated with the percentage of malignant plasma cells in bone marrow (r = 0.613). After CAR-T infusion, the sBCMA level in serum of MM patients decreased markedly (median: 508,513 pg/mL before CAR-T infusion, 89,198 pg/mL in the first month, 8448 pg/mL in the second months, and 6010 pg/mL in the third month after CAR-T infusion). In patients who obtained objective response (≥ PR), re-elevated sBCMA indicated the possibility of disease recurrence. At a cutoff 69,326.27 pg/mL, sBCMA shows high sensitivity (87.5%) and specificity (88.5%) for identifying relapse of MM after CAR-T therapy.

Conclusion

Our results suggested that serum sBCMA level changes in response to the clinical status of MM patients after anti-BCMA CAR-T therapy. Furthermore, sBCMA may be a auxiliary biomarker for disease monitoring in MM patients after CAR-T therapy.

Children with acute myeloid leukemia (AML) face a relapse of the disease in 30% of all cases. AML relapse is difficult to predict, and existing risk scales are often ineffective. Using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET-AML) project, we defined an expression signature based on matrix RNAs (mRNAs) and long non-coding RNAs (lncRNAs) that could predict relapse in pediatric AML patients.

We used a comprehensive bioinformatics analysis that included the identification of functionally significant differentially expressed genes in AML relapse, several rounds of association with relapse-free survival (RFS) mRNAs and lncRNAs selection, and evaluation of the obtained expression signatures to predict recurrence at the primary tumor level.

Two mRNAs (ENSG00000149289.11 (ZC3H12C) and ENSG00000075213.11 (SEMA3A)) and one lncRNA (ENSG00000287569.1) were associated with a decreased RFS. Models including changes in the expression of ZC3H12C and ENSG00000287569.1, as well as all three markers, demonstrated very good quality and could predict the recurrence of pediatric AML.

Human mesenchymal stem cells (hMSCs) are multipotent cells and an attractive therapeutic agent in regenerative medicine and intensive clinical research. Despite the great potential, the limitation that needs to be overcome is the necessity of ex vivo expansion because of insufficient number of hMSCs presented within adult organs and the high doses required for a transplantation. As a result, numerous research studies aim to provide novel expansion methods in order to achieve appropriate numbers of cells with preserved therapeutic quality. Bioreactor-based cell expansion provide high-level production of hMSCs in accordance with good manufacturing practice (GMP) and quality standards. This review summarizes current knowledge about the hMSCs manufacturing platforms with a main focus to the application of bioreactors for large-scale production of GMP-grade hMSCs.

Purpose of the study

Calreticulin is an endoplasmic reticulum chaperone protein, which is involved in protein folding and in peptide loading of major histocompatibility complex class I molecules together with its homolog calnexin. Mutated calreticulin is associated with a group of hemopoietic disorders, especially myeloproliferative neoplasms. Currently only the cellular immune response to mutated calreticulin has been described, although preliminary findings have indicated that antibodies to mutated calreticulin are not specific for myeloproliferative disorders. These findings have prompted us to characterize the humoral immune response to mutated calreticulin and its chaperone homologue calnexin.

Patients and methods

We analyzed sera from myeloproliferative neoplasm patients, healthy donors and relapsing-remitting multiple sclerosis patients for the occurrence of autoantibodies to wild type and mutated calreticulin forms and to calnexin by enzyme-linked immunosorbent assay.

Results

Antibodies to mutated calreticulin and calnexin were present at similar levels in serum samples of myeloproliferative neoplasm and multiple sclerosis patients as well as healthy donors. Moreover, a high correlation between antibodies to mutated calreticulin and calnexin was seen for all patient and control groups. Epitope binding studies indicated that cross-reactive antibodies bound to a three-dimensional epitope encompassing a short linear sequence in the C-terminal of mutated calreticulin and calnexin.

Conclusion

Collectively, these findings indicate that calreticulin mutations may be common and not necessarily lead to onset of myeloproliferative neoplasm, possibly due to elimination of cells with mutations. This, in turn, may suggest that additional molecular changes may be required for development of myeloproliferative neoplasm.