Successful Blinatumomab treatment in an allogeneic hematopoietic stem cell transplant recipient with EBV-related post-transplant lymphoproliferative disorder: A case report and literature review.

Post-transplant lymphoproliferative disorder (PTLD) is a condition in which patients experience the unrestrained proliferation of B cells as a consequence of impaired immune surveillance, almost always as a consequence of Epstein-Barr virus (EBV) infection. It remains one of the most serious potential complications that patients can experience after undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). While treatment with rituximab can significantly improve the prognosis of individuals with EBV-PTLD, those patients in whom rituximab fails to provide appreciable clinical benefit generally exhibit very poor outcomes. In the present report, we describe the case of an EBV-PTLD patient who was successfully treated with blinatumomab and received maintenance therapy consisting of venetoclax combined with azacytidine (AZA). The present case highlights the potential utility of blinatumomab as an effective treatment option for individuals with high-risk EBV-PTLD, although further explanation of the optimal dosing and treatment duration is warranted in the future.

MicroRNA-211 attenuates cell proliferation in T-cell lymphoblastic lymphoma through targeting TCF12.

T-cell lymphoblastic lymphoma (T-LBL) is a class of highly aggressive hematologic neoplasms originating from progenitor T-lymphocytes. MicroRNA (miRNA) is an endogenous RNA molecule with 22 nucleotides in length. Accumulated evidence suggests that miRNA functions as a key regulator in human cancer. Herein, by in silico analysis, we found that miR-211 was a decreased miRNA in T-LBL in high-throughput sequencing data, which was subsequently verified in our cohort. Low miR-211 was closely correlated with bulky disease, high ann arbor stage, relapse and poor prognosis. miR-211 was regulated by N6-methyladenosine (m6A) modification, specifically, m6A methyltransferase METTL14 methylated primary miR-211 (pri-miR-211), expediting pri-miR-211 processing via recruiting DGCR8. Functionally, miR-211 overexpression significantly reduced T-LBL cell viability, DNA synthesis rate and spheroid formation ability, whereas silencing of miR-211 had the opposite effects. In addition, we established the xenograft tumor model and found that miR-211 remarkably inhibited tumor growth in vivo. Further, TCF12 was the direct target of miR-211, miR-211 bound to TCF12 mRNA 3`-untranslated region (UTR) and increased its decay, overexpression of TCF12 could effectively rescue the weakened malignant behavior of T-LBL cells caused by miR-211 overexpression. Collectively, our data clearly demonstrate that miR-211 is a novel tumor suppressor in T-LBL, targeting of miR-211/TCF12 axis may be a potential treatment for T-LBL patients.

Clinical Characteristics and Optimal Therapy of Acute Myeloid Leukemia with Myelodysplasia-Related Changes: A Retrospective Analysis of a Cohort of Chinese Patients

Objective: This study aimed to investigate the clinical characteristics of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) according to the 2016 World Health Organization classification and the preferred therapy for patients with AML-MRC aged 60-75 years. Materials and Methods: We retrospectively analyzed differences in clinical data among 190 patients with AML-MRC and 667 patients with AML not otherwise specified (AML-NOS). We also compared different therapeutic regimens among patients with AML-MRC aged 60-75 years. Results: Compared with AML-NOS, patients with AML-MRC had significantly different clinical characteristics as well as worse overall survival (OS) (9.2 vs. 13.6 months; p<0.001) and complete remission rates (65.3% vs. 76.2%; p=0.005). Multivariate analysis performed for the whole group (patients with both AML-MRC and AML-NOS) showed that AML-MRC was the independent prognostic factor (p=0.002). Additional multivariate analysis performed for 190 patients with AML-MRC indicated that age (p<0.001) and lactate dehydrogenase (p=0.031) were independent prognostic factors. Compared with the IA/DA regimen [idarubicin and cytarabine (IA) or daunorubicin and cytarabine (DA)], the DAC+CAG regimen [decitabine and half-dose CAG regimen (cytarabine, aclarubicin, and granulocyte colony-stimulating factor)] was associated with better OS (4.5 vs. 6.2 months; p=0.021) in patients aged 60-75 years and categorized into the unfavorable risk group. Conclusion: AML-MRC cases exhibited worse clinical outcomes compared to AML-NOS. Compared to the IA/DA regimen, the DAC+CAG regimen was the optimal choice for patients with AML-MRC in the unfavorable risk group and aged 60-75 years.

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma.

Refractory/relapsed B cell lymphoma patients who received the available anti-CD19 chimeric antigen receptor (CAR) T cells may still experience a short duration of remission. Here in this study, we evaluated the safety and efficacy of a novel dominant-negative programmed cell death-1 (PD-1) armored anti-CD19 CAR T cells. A total of 9 patients (including 4 diffuse large B cell lymphomas, DLBCL, 2 transformed follicular lymphomas, TFL, and 3 follicular lymphomas, FL) received the novel CAR T cells infusion at a dose of more than 1 × 106/kg. Grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity were observed in 11.1% (n = 1/9) and 11.1% (n = 1/9) of patients, respectively. The overall response rate (ORR) was 77.8% (n = 7/9) and complete response (CR) rate was 55.6% (n = 5/9). Two patients have ongoing CR (all at 20+ months). CAR T cells expanded after infusion and continued to be detectable at 12+ months in patients with ongoing CR. This novel CD19-CAR T cell was safe and effective with durable remissions in patients with refractory/relapsed B cell lymphoma.

The mouse model of hepatic veno-occlusive disease.

With the application of hematopoietic stem cell transplantation, Subacute or acute increase in the incidence of hepatic veno-occlusive disease (HVOD) becomes more common and it can lead to fatal complications. This article characterizes a mouse model of HVOD induced by monocrotaline. After gavage with monocrotaline was performed on BALB/c mice, On the 3rd, 4th, 6th, 8th and 10th days, mice were anesthetized, blood was collected and the liver was removed. Liver slices were processed by HE stain, Masson's trichrome stain or immunohistochemical stain. From days 3 through 4, histopathology and cytokine changes were determined as severe, early HVOD. From days 6 through 8, the changes were considered to represent late HVOD. On the 10th day, the above changes showed that late HVOD gradually improved.

[Analysis of the Effect of TET2 Mutation and SNP on Clinical Characteristics and Prognosis of AML Patients].

OBJECTIVE: To evaluate the clinical significance of TET2 mutation(TET2mut) and SNP in adult acute myeloid leukemia (AML) and its effect on prognosis. METHODS: A total of 24 genes, including TET2, FLT3-ITD and NPM1, were detected in 124 adult AML patients using second-generation sequencing technology, and their clinical characteristics and effect on prognosis of patients were analyzed. RESULTS: A total of 25 TET2 gene mutations were detected in 124 AML patients, the mutation rate was 20.2%, there were 75 cases of TET2 single nucleotide polymorphisms(SNP), accounting for 60.5%. There were 47 cases of SNPrs2454206(G>A), accounting for 37.9%. Compared with TET2 wild-type(TET2wt) patients, TET2mut patients were mostly elderly. TET2SNP was commonly seen in male, with statistically significant differences (P＜0.05). SNP rs2454206 had no significant correlation with sex and age (P＞0.05). However, the analysis found that the complete remission rate of 1 course and the total complete rate (CR) of patients with TET2AG/GG were both obviously superior to those with TET2AA (P＜0.05). In the univariate analysis, the overall survival(OS) rate of the patients with TET2mut was lower than that of patients with TET2wt, and the event free survival (EFS) rate was higher than that of TET2wt patients, but the difference was not statistically significant (P＞0.05).The 1-year OS rate and EFS rate of the patients with TET2AA were significantly lower than those of the patients with TET2AG/GG (P＜0.05). Multivariate analysis showed that TET2AA was an independent risk factor for OS and EFS in AML patients. CONCLUSION: TET2 SNPrs2454206(G＞A) commonly appears in patients with acute myeloid leukemia, and these patients have the better response to chemotherapy and a better prognosis.

[Proventive and Therapentic Effects of Endothelial Progenitor Cells on Monocrotaline-Induced Hepatic Vein Occlusion Disease].

OBJECTIVE: To investigate the preventive and therapeutic effects of endothelial progenitor cells on monocrotaline-induced hepatic vein occlusion disease in mice. METHODS: C57BL/6 mice were randomly divided into 3 groups: saline group (n=15), monocrotaline group (n=15), and endothelial progenitor cell infusion group (n=15). Liver function (TBIL, ALT, AST), liver index, and serum levels of TNF-α and IL-6 were measured on the 8th day after intragastric administration. Hepatic sinusoidal endothelial cells, hepatic central venous endothelial cells and hepatocytes were observed by both HE and immunohistochemical staining. Hepatic fibrosis was observed by Masson's trichrome staining. RESULTS: By the light microscopy, the liver of the monocrotaline group showed moderate to the severe injuries of hepatic sinusoidal and central venous endothelial cells, and hepatic venous congestion. Masson staining showed moderate to severe hepatic fibrosis of central vein and hepatic sinus. In the endothelial progenitor cell group, hepatic sinusoidal and central venous endothelial cell injuries, and the fibrosis of central hepatic vein and hepatic sinus were mild to moderate. Hepatic venous congestion was reduced in comparison with that in the mice of the monocrotaline group. Compared with the endothelial progenitor cell group, the liver index was higher, the liver function was more abnormal, and the serum expression levels of TNF-α and IL-6 were higher in the monocrotaline group. CONCLUSION: The monocrotaline-induced damage of hepatic sinusoidal and central venous endothelial cells is an linitiating factor for hepatic vein occlusive disease. Infusion of endothelial progenitor cells can play a role in preventing and treating hepatic vein occlusion.

Nasal NK/T cell lymphoma mimicking mucosa-associated lymphoid tissue lymphoma in morphology: A case report.

The objective of the present study was to describe the clinicopathological features of a patient with nasal NK/T cell lymphoma that was similar in morphology to mucosa-associated lymphoid tissue lymphoma (MALToma). The clinicopathological data of a patient diagnosed with nasal NK/T cell lymphoma mimicking MALToma was collected, and the clinicopathological characteristics were discussed. The female patient was 43 years old and had suffered from persistent congestion for ten days. The mucosa in the left nasal cavity was inflamed, resulting in congestion and it was also purulent on the surface, as observed by nasal endoscopy. The disease was considered to be inflammatory based on CT scan. A biopsy after operation showed that the tumor consisted of small lymphoid cells that resembled MALToma in morphology. On the basis of the immunohistochemistry and in situ hybridization laboratory tests, a diagnosis of left nasal NK/T cell lymphoma was made. The patient received chemotherapy and radiotherapy, and remission was achieved six months after diagnosis. The patient was in a good condition at 16 months follow-up. In conclusion, NK/T cell lymphoma composed of small cells may be a type of indolent lymphoma with special characteristics of clinical presentation, image, pathology and prognosis. This case highlights that more attention is required by radiologists, pathologists and hematologists to diagnose this type of lymphoma.

Co-existence of t(9;22) and t(8;21) in primary blast phase of chronic myelogenous leukemia: clinical experience and literature review.

Rare chronic myelogenous leukemia (CML) patients manifested as the primary blast phase without a chronic and accelerated phase. The occurrence of a t(8;21) translocation in secondary blast phase of CML or Philadelphia chromosome positive acute myelogenous leukemia (Ph+ AML) has been reported previously. No case of primary blast phase of chronic myelogenous leukemia (CML-BP) bearing one clone with t(9;22) and t(8;21) simultaneously has been reported. One Chinese patient presenting with extensive spontaneous ecchymosis and enlarged spleen diagnosed as acute myelogenous leukemia (AML) by smear and immunophenotype was given chemotherapy including daunorubicin 3 days and cytarabine 7 days without a tyrosine kinase inhibitor (TKI) drug at the beginning. Fresh frozen plasma and 4-factor prothrombin complex concentrate was also transfused for coagulation disorder. However, fusion genes BCR/ABL p210 and AML1/ETO were both positive and karyotype analysis showed the abnormalities of t(9;22) and t(8;21) in the same clones. Bone marrow aspirate on 7th day of chemotherapy indicated hypocellularity with 45% blasts remaining. Cytarabine was prolonged to nine days combined with imatinib 600 mg per day. His bone marrow aspirate after complete remission revealed t(8;21) clones disappearing, especially FISH of bone marrow smear detecting the BCR/ABL fusion signals in the basophilic erythroblasts, which confirmed his diagnosis as primary blast phase of CML rather than Ph+ AML. Thus, we report for the first time one patient diagnosed as primary blast phase of CML presenting with t(9;22) and t(8;21) simultaneously.

Mechanisms of immune injury and heterogeneity of bone marrow hematopoietic cells island in patients with auto-immuno-related hematocytopenia.

Because of environmental pollution more and more people are suffered with auto-immuno-related hematocytopenia (AIRH). Serum IL-12, IL-17, and IFN-γ levels were detected by ELISA and lymphocyte subsets were analyzed by flow cytometry. Peroxidase (POX) and HLA-DR of immune cells were detected by cytochemical and immunochemical staining. Cells expressing anti-human IgG, FcγR II, MR, and other molecules in HI were detected by immunofluorescence. Serum IL-12, IL-17, and IFN-γ levels of patients were significantly higher than control group. Lymphocyte subsets of patients showed that the percentages of CD19+ B cells and CD3+ CD8+ T cell in peripheral blood were both significantly elevated. HI were mainly classified into three types, in these three types of hematopoietic cells island, peroxidase, and HLA-DR expression varied. Hematopoietic cells with pathological changes expressed anti-human IgG. The immunocytes with different levels of immunomolecules adhered captured and devoured abnormal hematopoietic cells. Immune cells expressed IL-12, IL-17A, and IL-17RA, leading to inflammatory injury of hematopoietic cells. HI destroys cells which connect auto-antibodies. Immune cells in HI express a variety of immune molecules, promote cell immune responses, and amplify the inflammatory reaction by ADCC effect or phagocytosis. These ultimately destruct directly and damage indirectly hematopoietic cells.

A murine model of hepatic veno-occlusive disease induced by allogeneic hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (HVOD) is a life-threatening complication of bone marrow stem cell transplantation. The understanding of this clinical condition is hampered by the lack of suitable animal models. Here, we present a murine (BALB/c-based) model of HVOD induced by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chimerism rate of bone marrow was measured on days 5 and 10, while the chimerism rate of peripheral blood was measured on day 15 after allo-HSCT. Percentages of peripheral reticulocytes and serum levels of bilirubin and alanine aminotransferase (as liver function tests) were measured on days 5, 10, 15, 20, and 30. Livers were obtained on days 5, 10, 15, 20, and 30, and fixed in formaldehyde or glutaric dialdehyde. Liver slices were processed using the hematoxylin-eosin, Masson's trichrome, or immunohistochemistry staining, and examined by light or transmission electron microscopy. Sinusoidal damages were the earliest pathological changes occurring in the allo-HSCT-induced HVOD, followed by coagulative necrosis of liver cells. The liver cell necrosis was later attenuated and sinusoidal endothelial cell morphology improved. However, on day 30, the edema and necrosis of liver cells became aggravated again. Furthermore, sinusoidal lining cell regeneration and partly attenuated liver cell necrosis were followed by the moderate to severe central vein fibrosis. In conclusion, we have successfully established a murine model of HSCT-HVOD. This model develops moderate to severe HVOD which cannot heal without intervention.

[Effects of liver sinusoid endothelial cell injury in mouse hepatic veno-occlusive disease].

This study was purposed to investigate the role of monocrotaline-inducing mouse liver sinusoid endothelial cell (SEC) injury in hepatic veno-occlusive disease. BALB/c mice were randomly divided into 2 groups: control group and monocrotaline group, mice were orally administrated with normal saline or monocrotaline with concentration of 200 mg/kg at days 0, 1, 2, respectively. At days 3, 4, 6, 8 and 10 after oral administration with normal saline or monocrotaline, the liver function (ALT, TBIL, AKP) and liver index were examined, and the percentage of activated platelets were detected by flow cytometry. The SEC, vascular endothelial cells and hepatic fibrosis were observed by staining with hematoxylin-eosin and Masson. Transmission electron microscopy was used to observe sinusoidal endothelial cell damage and platelet adhesion. The results showed that compared with control group, mice in monocrotaline group were characterized by severe damage of SEC, numbers of platelet aggregation and adhesion, central number and sinusoidal fibrosis. The percentage of activated platelets and liver index increased (P < 0.05). The characterization of portal hypertension was presented later, such as dysfunction of liver and ascites. It is concluded that SEC injury induced by monocrotaline may be the first step of hepatic veno-occlusive disease, and this kind of SEC injury is self-limiting, but fibrosis is always observed.