A complete oral regimen for induction therapy of patients with high-risk APL: An oral etoposide instead of intravenous infusion for cytoreductive chemotherapy.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Comparison of efficacy between homoharringtonine, aclarubicin, cytarabine (HAA) and idarubicin, cytarabine (IA) regimens as induction therapy in patients with de novo core binding factor acute myeloid leukemia.

To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

COVID-19 infection in patients with haematological malignancies: A single-centre survey in the latest Omicron wave in China.

As the COVID-19 variant Omicron surge in Beijing, China, a better understanding of risk factors for adverse outcomes may improve clinical management in patients with haematological malignancies (HM) diagnosed with COVID-19. The study sample includes 412 cases, mainly represented by acute leukaemia, chronic myeloid leukaemia (CML), plasma cell disorders and lymphoma and chronic lymphocytic leukaemia. COVID-19 pneumonia was observed in 10.4% (43/412) of patients, and severe/critical illness was observed in 5.3% (22/412). Among the 86 cases with advanced malignancies, 17.6% (12/86) of patients developed severe/critical COVID-19, which was significantly higher than reported in patients with stable malignancies (9/326, 2.70%, p < 0.001). Similarly, the advanced malignancy cohort had a higher mortality rate (9/86, 10.5% vs. 0/326, 0%, p < 0.001) and a poor 30-day overall survival (OS) compared with the stable malignancy cohort (74.2% vs. 100.0%, p < 0.0001). Overall, nine patients (2.2%) died. The primary cause of death was progressive HM in four patients and a combination of both COVID-19 and HM in five patients. In the multivariable analysis, over 65 years of age, comorbidities and advanced malignancy were correlated with severe/critical COVID-19 in HM patients. This study sheds light on the poor outcomes among COVID-19 HM patients with the leading cause of advanced malignancy.

Circulating Tumor DNA: Less Invasive, More Representative Method to Unveil the Genomic Landscape of Newly Diagnosed Multiple Myeloma Than Bone Marrow Aspirates.

Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.

T cell landscape and dynamics in immunoglobulin light chain amyloidosis before and after daratumumab-based therapy.

Amyloid light-chain (AL) is characterized by the presence of small, poorly proliferating plasma cell clones with the production and deposition of light chains into tissues. T cell changes within the tumour microenvironment in AL are poorly understood. By sequencing at a single-cell level of CD3+ T cells purified from bone marrow (BM) and blood of newly diagnosed AL patients before and after a combination of daratumumab with cyclophosphamide, bortezomib, and dexamethasone (Dara-BCD), we analysed the transcriptomic features of T cells and found an expansion, activation and type I cytokine upregulation in BM and circulating T cells after the treatment. More prominent changes were shown in CD8+ T cells. In particular, we found the presence of CD8+ BM resident memory T cells (TRM ) with high expression of inhibitory molecules in AL patients at diagnosis. After Dara-BCD, these TRM cells were quickly activated with downregulation of suppressive molecules and upregulation of IFNG expression. These data collectively demonstrate that Dara-based therapy in patients with AL amyloidosis promotes anti-tumour T cell responses. The similar transcriptomic features of BM and circulating T cells before and after therapy further provide a less invasive approach for molecular monitoring of T cell response in AL amyloidosis.

Melanoxylonin A-G, neoflavonoids from the heartwood of Dalbergia melanoxylon and their cardioprotective effects.

Seven undescribed neoflavonoids, named melanoxylonins A-G, were isolated from the heartwood of Dalbergia melanoxylon, and all the non-toxic isolates were evaluated for their cardioprotective effect against ischemia/reoxygenation (I/R) injury in H9c2 cells. Of these, melanoxylonin A-D containing the 8-OH group showed better potent cardioprotective effects than the other four congeners. Molecular docking studies confirmed the capacity of melanoxylonin D to interact with the myeloperoxidase (MPO) protein. These results indicated that the potential cardioprotective effects of melanoxylonin D in H9c2 cells with I/R injury may be imparted through suppression of MPO. These results may provide a new medicinal usage of D. melanoxylon.

Both the subtypes of KIT mutation and minimal residual disease are associated with prognosis in core binding factor acute myeloid leukemia: a retrospective clinical cohort study in single center.

Core binding factor acute myeloid leukemia (CBF-AML), including cases with KIT mutation, is currently defined as a low-risk AML. However, some patients have poor response to treatment, and the prognostic significance of KIT mutation is still controversial. This study aimed to explore the prognostic significance of different KIT mutation subtypes and minimal residual disease (MRD) in CBF-AML. We retrospectively evaluated continuous patients diagnosed with CBF-AML in our center between January 2014 and April 2019. Of the 215 patients, 147 (68.4%) and 68 (31.6%) patients were RUNX1-RUNX1T1- and CBFB-MYH11 positive, respectively. KIT mutations were found in 71 (33.0%) patients; of them, 38 (53.5%) had D816/D820 mutations. After excluding 10 patients who died or were lost to follow-up within a half year, 42.0% (n = 86) of the remaining 205 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). An MRD > 0.1% at the end of two cycles of consolidation predicted relapse (P < 0.001). Multivariate analysis showed that D816 or D820 mutations and MRD > 0.1% at the end of two cycles of consolidation were independent adverse factors affecting relapse-free survival (RFS) and overall survival (OS). Allo-HSCT could improve RFS (74.4% vs. 34.6%, P < 0.001) and OS (78.1% vs. 52.3%, P = 0.002). In conclusion, high-risk CBF-AML patients must be identified before treatment. D816/D820 mutation, MRD > 0.1% at the end of two cycles of consolidation chemotherapy predicted poor survivals, and allo-HSCT can improve the survival of properly identified patients.

The loss or absence of minimal residual disease of <0·1% at any time after two cycles of consolidation chemotherapy in CBFB-MYH11-positive acute myeloid leukaemia indicates poor prognosis.

No consensus has been reached on the relationship between CBFB-MYH11 copies and prognosis. Of 1525 acute myeloid leukemia (AML) patients, 58 with CBFB-MYH11-positive AML (16/58 patients with c-kit mutation) were retrospectively analyzed with a median follow-up duration of 29.8 (range: 4.8-74.4) months. Of these, 25/58 (43.1%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), 10 of whom had the c-kit mutation. Of the 33 patients who did not undergo allo-HSCT, recurrence in patients with CBFB-MYH11/ABL level >0.1% at any time after two consolidation cycles was significantly higher than in patients with CBFB-MYH11/ABL level <0.1% (61.9% vs. 0%, P = 0.001); further, the 3-year relapse-free survival (RFS; 31.4% vs. 100%, P = 0.004) and event-free survival (EFS; 33.1% vs. 100%, P = 0.004) were significantly decreased in patients with CBFB-MYH11/ABL level >0.1% at any time after two consolidation cycles. The 3-year RFS and EFS rates were lower in patients who did not receive allo-HSCT than in those who did (31.4% vs 84.6%, P = 0.000; 31.4% vs. 80.8%, P = 0.001). CBFB-MYH11-positive AML patients with CBFB-MYH11/ABL level >0.1% at any time after two cycles of consolidation had poor prognoses, and allo-HSCT could improve their survival.

The long-term outcomes of tobacco control strategies based on the cognitive intervention for smoking cessation in COPD patients.

OBJECTIVE: To evaluate the long-term efficacy of tobacco control strategies based on cognitive intervention for smoking cessation in chronic obstructive pulmonary disease (COPD) patients, and to provide basis for clinical practice. MATERIALS AND METHODS: 102 COPD patients with a long-term history of smoking from the outpatient clinic were recruited in the study. These smokers were randomly divided into intervention group and control group. The intervention group received a cognitive intervention containing individual consultation, telephone follow-ups and self-help materials, etc. The prevalence of quitting smoking, acute exacerbation (AE), lung function and survival were compared in the groups in 10 years. RESULTS: There were significant differences between the intervention group and the control group in the rate of persistent quitting smoking in half a year (17.6% vs 3.9%) (P < 0.05), the rate of quitting smoking at the 6th month (58.8% vs 33.3%) (P < 0.05). After 3 months (P < 0.01) and 6 months (P < 0.01), the difference in body weight between the intervention group and the control group was statistically significant. Intervention-group patients had fewer AE per year (P < 0.01) and higher FEV1/FVC ratio (P < 0.01) after 5-year and 10-year follow-up. Besides, the FEV1% predicted in the intervention patients was higher than that in control group after 10-year follow-up. The ages of patients in the death group were greater than those in the survival group. Death-group patients had longer smoking times, higher smoking index, and later onset of COPD symptoms. Death-group patients had lower FEV1% predicted (P < 0.05) and FEV1/FVC ratio (P < 0.01). During 10-year follow-up, 30 patient deaths were recorded (the control group: n = 48; 19 deaths, and intervention group: n = 46; 11 deaths), and patients in the control group had lower survival than those in the intervention group. (P < 0.05). CONCLUSION: The method of quitting smoking based on cognitive intervention is an effective way for COPD patients to quit smoking successfully. Quitting smoking can slower deterioration in lung function and improve the survival of COPD patients. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2000031239 (Chinese clinical trial registry).

Serum Lactate Dehydrogenase Can Be Used as a Factor for Re-Evaluating First-Relapsed Multiple Myeloma.

BACKGROUND: Serum lactate dehydrogenase (LDH) is an adverse prognostic factor for newly diagnosed multiple myeloma (MM). However, the role of LDH in the prognosis of MM patients with relapse has not yet been thoroughly explored. OBJECTIVES: To explore the prognostic value of LDH in patients with first-relapsed MM. METHODS: Data for 112 MM patients who had a first relapse between January 2012 and December 2017 were retrospectively reviewed. Patients were classified into two groups based on the level of serum LDH at relapse (≥240 and <240 U/L). Characteristics and outcomes of the two groups were compared. RESULTS: During the first relapse, patients with high LDH levels had higher serum ß2-microglobulin (p = 0.001), lower serum albumin (p = 0.006), lower platelet counts (p < 0.001), and a higher percentage of extramedullary relapse (p < 0.001) compared with patients with normal LDH levels. According to multivariate analysis, elevated serum levels of LDH (p = 0.001) and re-ISS stage 2/3 (p = 0.001) in relapsed MM patients were two key prognostic factors for overall survival. CONCLUSIONS: A high level of serum LDH at the time of first relapse may be a predictor of poor survival in relapsed MM patients.

LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal progressive disease characterized by an increased blood pressure in the pulmonary arteries. RhoA/Rho-kinase (RhoA/ROCK) signaling activation is often associated with PAH. The purpose of this study is to investigate the role and mechanisms of long noncoding RNA (lncRNA) smooth muscle-induced lncRNA (SMILR) to activate the RhoA/ROCK pathway in PAH. SMILR, microRNA-141 (miR-141), and RhoA were identified by qRT-PCR in PAH patients' serum. 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), wound-healing assay, cell counting kit-8 (CCK-8) assay, and flow cytometry were performed to determine cell viability, migration, proliferation, and cell cycle in human pulmonary arterial smooth muscle cells (hPASMCs) and primary PASMCs from PAH patients. We also performed bioinformatical prediction, luciferase reporter assay, and RNA-binding protein immunoprecipitation (RIP) to assess the interaction among SMILR, miR-141, and RhoA. The RhoA/ROCK pathway and proliferation-related proteins were measured by Western blotting. Finally, we introduced the small hairpin (sh)SMILR to monocrotaline-induced PAH rat model and used the hemodynamic measurement, qRT-PCR, and immunohistochemistry to examine the therapeutic effects of shSMILR. SMILR and RhoA expression were upregulated, while miR-141 expression was downregulated in PAH patients. SMILR directly interacted with miR-141 and negatively regulated its expression. Knockdown of SMILR suppressed PASMC proliferation and migration induced by hypoxia. Furthermore, overexpression of miR-141 could inhibit the RhoA/ROCK pathway by binding to RhoA, thereby repressing cell proliferation-related signals. Knockdown of SMILR significantly inhibited the Rho/ROCK activation and vascular remodeling in monocrotaline-induced rats. Knockdown of SMILR effectively elevated miR-141 expression and in turn inhibited the RhoA/ROCK pathway to regulate vascular remodeling and reduce blood pressure in PAH.NEW & NOTEWORTHY Smooth muscle enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.

The Usage of Separating Gel Vacuum Tube with Different IgG Concentration.

BACKGROUND: Observing serum IgG concentration on the distribution of serum, blood cells, and separation gel after centrifugation in different separation gel vacuum tubes. METHODS: 3 mL venous blood was collected in each of two separation gel procoagulant vacuum tubes: BD Vacutainer SST II(3.5ml, 75×13 mm) and BD Vacutainer SST(5ml, 100×13 mm). After complete solidifaction, both tubes were centrifuged at 2000g for 10 minutes. The distribution of serum, blood cells, and separation gel in the vacuum tube was observed. The immunoglobulin concentration was detected using the special protein analyzer Siemens BNII. RESULTS: 1. In the group of BD Vacutainer SST II where the IgG concentration exceeded 50g/L but less than 122g/L: The serum was located below the separation gel and was distributed in three layers: separation gel, serum, and blood cells. 2. In the group of BD Vacutainer SST where the IgG concentration exceeded 50g/L but less than 122g/L: The serum was located above the separating gel, and was distributed in three layers: serum, separation gel, and blood cells. 3. Increases in IgA and IgM serum concentration did not cause the separation gel inversion. CONCLUSIONS: Increases in serum IgG were positively correlated with the concentration of total protein. The rising of serum IgG caused the floating of separation gel after centrifugation. The BD Vacutainer SST was more suitable for clinical blood sample collection.

Loss of miR-532-5p in vitro promotes cell proliferation and metastasis by influencing CXCL2 expression in HCC.

MicroRNAs (miRNAs) have been widely reported, which play important roles in cancer development. CXCL2 acts as an oncogene, however, its regulation by miRNAs is not clear in hepatocellular carcinoma (HCC). In our research, it is aimed to study the role of CXCL2 in HCC and the regulation of its expression by miRNAs. Firstly, we found that CXCL2 was up-regulated in the blood of patients with HCC and cell lines compared with the normal controls. CXCL2 could enhance HCC cell proliferation and metastasis. miR-532-5p was predicted as a regulatory miRNA of CXCL2 in HCC, and negatively associated with CXCL2 in HCC samples. It was also verified that miR-532-5p inhibited cell proliferation and metastasis of HCC cells by inhibition CXCL2. Collectively, our findings suggested that miR-532-5p may function as a tumor suppressor in HCC by targeting CXCL2.