Effect of sustained measurable residue disease negativity and post-remission treatment selection on the prognosis of acute lymphoblastic leukemia in adults.

BACKGROUND: To explore the effects of monitoring measurable residual disease and post-remission treatment selection on the clinical outcomes of B-cell acute lymphoblastic leukemia (B-ALL) in adults. METHODS: Between September 2010 and January 2022, adult patients with B-ALL who received combination chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (allo-HSCT), were included in the retrospective study, which was approved by the Ethics Committee and the observation of Declaration of Helsinki conditions. RESULTS: One hundred and forty-three B-ALL patients achieved complete remission (CR) were included in the study, of whom 94 patients (65.7%) received allo-HSCT in first complete remission (CR1). Multivariate analysis showed that the most powerful factors affecting OS were transplantation (hazard ratio [HR] = 0.540, p = 0.037) and sustained measurable residue disease (MRD) negativity (HR = 0.508, p = 0.037). The subgroup analysis showed that the prognosis of the allo-HSCT group was better than that of the chemotherapy group, regardless of whether MRD was negative or positive after two courses of consolidation therapy. After consolidation therapy, the prognosis of patients with positive MRD remained significantly better in the allo-HSCT group than in the chemotherapy group. However, no significant difference was observed in the prognosis between the allo-HSCT and chemotherapy groups with negative MRD after consolidation therapy. CONCLUSIONS: B-ALL patients who achieve sustained MRD negativity during consolidation therapy have excellent long-term outcomes even without allo-HSCT. Allo-HSCT is associated with a significant benefit in terms of OS and DFS for patients who were with positive MRD during consolidation therapy.

More fear reduction, better posttraumatic stress symptoms resilience: 1 year longitudinal study based on the psychological trauma recover project-5-6.

OBJECTIVE: The outbreak of COVID-19 not only raised public health concerns but also caused tremendous psychological distress. Deficits in fear played a role in the development and maintenance of posttraumatic stress symptoms (PTSS). We aimed to investigate the relationship between fear and PTSS during COVID-19 at two points. METHOD: The questionnaire at the first time of investigation (T1) was conducted through WeChat or phone from January 30, 2020 to February 25, 2020 as part of the psychological trauma recover project-5-6 in China. And the questionnaire at the second time of investigation (T2) was collected from March 17, 2021 to June 17, 2021. After 12 months, data from 150 participants were included in the final analysis. Fear was measured by a self-reported question. Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) was designed to assess PTSS. Pearson correlation, multivariate regression analysis, and multiple mediator model were used as statistical analyses. RESULTS: Fear reduced significantly over time. Participants with higher fear presented worse PTSS in both T1 and T2. Positive correlations between fear and PTSS of participants were found over time. Occupation and change of fear are significant predictors in the severity of PTSS over time. Change of fear partially mediated the relationship between the PCL-5 total score in T1 and the development of PTSS. CONCLUSION: Fear reduction was beneficial to trauma resilience. Future interventions could be developed to reduce excessive fear in facing natural disasters or following epidemics. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

CEAC (oral semustine, etoposide, cytarabine and cyclophosphamide) vs BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen of autologous stem cell transplantation for diffuse large B-cell lymphoma: a post-hoc, propensity score-matched, cohort study in Chinese patients.

Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250 mg/m2 d-6, etoposide 300 mg/m2 d-5 ~ d-2, cytarabine 500 mg/m2 d-5 ~ d-2, and cyclophosphamide 1200 mg/m2 d-5 ~ d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95% vs 97%, P = 1.000) and complete response rate (66% vs 73%, P = 0.580) between the two cohorts. The 5-year progression-free survival (PFS), 5-year overall survival (OS), and 5-year cumulative incidence of relapse (CIR) for all patients were 72% (95% CI 62%-82%), 92% (95% CI 86%-97%), and 29% (95% CI 17%-38%), respectively. There was no significant difference in the 5-year PFS (80% vs 70%, P = 0.637), 5-year OS (95% vs 91%, P = 0.496), and 5-year CIR (20% vs 30%, P = 0.733) between cohorts. In terms of safety, the CEAC cohort had a lower incidence rate of grade 1-2 gastrointestinal hemorrhage (P = 0.023) and severe nausea (P = 0.007) compared with the BEAM cohort. In conclusion, the CEAC regimen seems to be a suitable alternative to the BEAM regimen for ASCT in DLBCL patients.

Comparison of Stem Cell Transplantation Using Unrelated, Haploidentical, and Sibling Donors for Patients with Acquired Severe Aplastic Anemia: A Single-Center Retrospective Cohort Study.

The preferred donor (haploidentical donor [HID] versus matched unrelated donor [URD]) choice in patients with acquired severe aplastic anemia (SAA) who lack an HLA-matched sibling donor (MSD) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n = 58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) and 5-year failure-free survival (FFS) were comparable among the URD (n = 8), HID (n = 25), and MSD (n = 25) cohorts (OS: mean, 87.5 ± 11.7% versus 98.0 ± 6.5% versus 83.3 ± 7.6% [P = .926]; FFS: mean, 60.0 ± 18.2% versus 87.0 ± 7.0% versus 78.3 ± 8.6% [P = .222]). Multivariate analysis revealed that primary engraftment failure independently predicted OS and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, but donor type and age were not predictive of these outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Our findings show that an alternative donor SCT is indicated for eligible SAA patients without an MSD even if age ≥40 years.

Sequential autologous and allogeneic stem cell transplantation for treatment of primary plasma cell leukemia: A case report.

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell disorder, which accounts for ~70% of all PCL. Survival of pPCL remains poor, and is related with early mortality. There is no standard therapy for patients with pPCL. In the present study, a 26-year-old man who was diagnosed with pPCL was reported. The patient achieved stringent complete remission to the successful treatment of intensive chemotherapy combined with sequential autologous and allogeneic stem cell transplantation (SCT) followed by maintenance therapy with oral administration of ixazomib, thalidomide and dexamethasone (IRD regimen). Development of complex treatment algorithms that combine novel agents, SCT and post-transplantation remission strategies may translate into survival in patients with pPCL.

New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

The clinical impact of IKZF1 mutation in acute myeloid leukemia.

Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

Ellagic acid induces apoptosis and autophagy in colon cancer through the AMPK/mTOR pathway.

Ellagic acid (EA), found in fruits and foods, has been shown to be effective in the treatment of breast, colon and bladder cancer. However, due to the complexity of colon cancer, the therapeutic mechanism of EA for colon cancer is still unclear. Cell Counting Kit-8 (CCK-8) assay were employed to investigate the cell proliferation. Western blotting and flow cytometry assays were utilized to investigate apoptosis and autophagy in CRC cells (HCT116), respectively. Moreover, western blotting and luciferase reporter assays were evaluated the effect of EA on AMPK/mTOR pathway. Through flow cytometry analysis, EA could promote the apoptosis of HCT116 cells. In addition, EA can reduce the phosphorylation of mTOR, promoted phosphorylation of AMPK, and induced autophagy in HCT116 cells. Also, Dorsomorphin pretreatment can reduce the expression of autophagy protein, which indicates that EA induces autophagy through AMPK/mTOR pathway. These results suggest that EA inhibits the growth of colon cancer through AMPK/mTOR pathway and induces apoptosis and protective autophagy.

Re-induction therapy in patients with acute myeloid leukemia not in complete remission after the first course of treatment.

A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.

Cytogenetic evolution predicts a poor prognosis in acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation.

Acute myeloid leukemia (AML) patients relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a poor prognosis. Cytogenetic evolution (CGE) has been investigated and found to have an important impact on the prognosis of relapsed leukemia, but its impact on AML patients relapsing after transplantation remains controversial. In this study, we analyzed 34 AML patients relapsing after allo-HSCT, among whom 14 developed additional abnormalities in chromosomal karyotype after leukemia recurrence (CGE group) and 20 patients did not (non-CGE group). We found that the cytogenetic characteristics were much more complex at relapse in the CGE group, and the acquisition of aberrations at relapse most commonly involved chromosome 11. The 6-month post-relapse overall survival (PROS) of the CGE group was significantly lower than that of the non-CGE group (21.4% versus 50.0%, P = 0.004). The CGE group also showed a trend of worse 2-year OS (7.1% versus 28.6%, P = 0.096). In the multivariate analyses, the occurrence of chronic graft-versus-host disease (HR 0.27 [95% CI, 0.11-0.68], P = 0.006) and a reduced-intensity FBA conditioning regimen (HR 0.42 [95% CI, 0.18-0.98], P = 0.045) were found to be two independent factors for a better PROS, whereas CGE (HR 3.16 [95% CI, 1.42-7.05], P = 0.005) was associated with a worse PROS. In conclusion, CGE was associated with a poor prognosis in AML patients who relapsed after allo-HSCT, and the importance of monitoring karyotype changes after transplantation should be noted.

A kinetic study of biotransformation from valencene to nootkatone in an oscillatory baffled reactor.

In this paper we report our kinetic study of an oxidation reaction from valencene to nootkatone using enzyme in an oscillatory baffled reactor. The aims of this work are to elucidate the reaction mechanism and evaluate reaction kinetics. Towards these objectives, a full kinetic model using the Langmuir-Hinshelwood method was established and applied to the experimental data, allowing reactor schemes and orders to be confirmed and reaction rate constants to be extracted. Our full kinetic analysis suggests that most of the reversible reaction steps can be treated as irreversible, simplifying the overall reaction schemes. The effect of mass transfer on the kinetics was also investigated. © 2023 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

The risk factors and early predictive model of hematotoxicity after CD19 chimeric antigen receptor T cell therapy.

Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.

Long Non-Coding RNA CKMT2-AS1 Reduces the Viability of Colorectal Cancer Cells by Targeting AKT/mTOR Signaling Pathway.

Background: Colorectal cancer (CRC) has not only seriously affected people's lives, but also burdened the government healthcare system. Long non-coding RNAs (lncRNA) have attracted more and more attention in the cancer study field. Methods: Experiments were completed in the Medical Research and Innovation Center of Shanghai Pudong Hospital, China from 2019 to 2020. Cell cycle was detected by western blot analyzing and flow cytometry. Apoptosis analysis were determined using flow cytometry or western blot analysis. LncRNA CKMT2-AS1 was knocked down by shRNA transfection. Results: We found CKMT2-AS1 was the most significant=0.0105 for SW480 and P=0.0071 for HCT116) difference lncRNA between colorectal cancer treated with autophagy inducer and colorectal cancer without any treatment. Effective shRNA-CKMT2-AS1 was also designed. Following, we found the treatment of autophagy inducer and autophagy inducer + shRNA-NC were able to suppress the proliferation of both SW480 and HCT116 cells. In addition, the treatment of autophagy inducer + shRNA-CKMT2-AS1 significantly reduced the apoptosis of SW480 and HCT116 cells induced by autophagy. Furthermore, we found the phosphorylation of mTOR, AKT was enhanced in SW480, and HCT116 cells treated with autophagy inducer + shRNA-CKMT2-AS1 compared to the cells treated with autophagy inducer of autophagy inducer + shRNA-NC. Conclusion: Enhancing the expression of CKMT2-AS1 will become a promising strategy to prevent the progress of colorectal cancer.

Prognostic differences of refractory/relapsed nodal and extranodal diffuse large B-cell lymphoma in the chimeric antigen receptor T cell therapy era.

BACKGROUND: Extranodal involvement is recognized as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, the prognostic differences of patients with refractory/relapsed (R/R) nodal and extranodal DLBCL in the chimeric antigen receptor T cell (CART) therapy era are still unclear. MATERIALS AND METHODS: In this study, 18 R/R nodal DLBCL (R/R N-DLBCL) and 19 R/R extranodal DLBCL (R/R EN-DLBCL) were enrolled to compare clinical outcomes. RESULTS: The median follow-up time was 13 (range, 1-47) months and one-year progression-free survival (PFS; 83.3% vs. 42.1%, P = 0.008) and one-year overall survival (OS; 94.4% vs. 63.2%, P = 0.020) were significantly different between nodal and extranodal patients. In the multivariable Cox regression analysis, R/R EN-DLBCL was associated with worse PFS (hazard ratio [HR] = 4.263, P = 0.018) and OS (HR = 9.589, P = 0.034) compared to R/R N-DLBCL. Additionally, autologous hematopoietic stem cell transplantation (ASCT) combined with CART therapy (ASCT + CART) was correlated with better PFS (HR = 0.164, P = 0.003) compared to CART treatment alone. CONCLUSIONS: The clinical outcomes of R/R EN-DLBCL were worse than R/R N-DLBCL in patients receiving CART therapy and ASCT + CART therapy is a promising alternative treatment for patients with R/R EN-DLBCL.

Cytogenetic abnormalities in NPM1-mutated acute myeloid leukemia.

NPM1mut acute myeloid leukemia (AML) has been identified as a distinct entity of myeloid neoplasms according to the 2017 European LeukemiaNet (ELN) guidelines. It confers a favorable prognosis regardless of cytogenetic abnormalities. We evaluated 418 newly diagnosed AML patients to test the validity of this hypothesis. Seventy-four patients with NPM1mut AML showed a good response to induction and a relatively favorable prognosis. Abnormal karyotypes were observed in 15 patients. Chromosomal abnormalities were significantly associated with a worse prognosis in NPM1mut AML patients (5-year overall survival (OS): 38.9 ± 12.9%, p = .037; event-free survival (EFS): 33.3 ± 12.2%, p = .043, respectively). Four patients with abnormal karyotypes who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) during CR1 had longer survival than those who received chemotherapy only. Multivariable analysis revealed abnormal karyotypes independently predicted OS and EFS among NPM1mut AML patients. In summary, cytogenetic abnormalities are strong prognostic indicators in NPM1mut AML. Therefore, they should be classified accordingly, and alloHSCT should be performed on selected patients during CR1.

B2M mutation paves the way for immune tolerance in pathogenesis of Epstein-Barr virus positive diffuse large B-cell lymphomas.

This study focused genetic pathogenesis and tumor microenvironment of Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCL) in patients without immunodeficiency. DNA samples from these cases were sequenced by next generation sequencing (NGS) using a selected gene panel. Results revealed that most gene mutations were not specific for EBV positive DLBCL. However, B2M (ß2-microglobulin) mutations were significantly increased and HLA-I or HLA-II expression was decreased in these cases, which was related to patient's poor outcome. B2M mutations and deregulation of B2M expression were further confirmed by Sanger sequencing and immunohistochemistry. Reducing the infiltration of CD8+ T lymphocytes, related to decreased expression of HLA-I or HLA-II was found in these patients. These results suggest that the mutations of B2M could cause the disruption of the expression and functions of this important subunit of HLA, leading to decreased expression of HLA-I or HLA-II and subsequently to reduce T lymphocyte infiltration in tumor tissues. The consequence of this event lessens the recognition and elimination of EBV+ tumor cells by host immunity and paves the way for the host immune tolerance to EBV+ tumor cells by evading immune recognition and escaping the T lymphocyte killing.

A clinical prediction model identifies a subgroup with inferior survival within intermediate risk acute myeloid leukemia.

Intermediate risk acute myeloid leukemia (AML) comprises around 50% of AML patients and is featured with heterogeneous clinical outcomes. The study aimed to generate a prediction model to identify intermediate risk AML patients with an inferior survival. We performed targeted next generation sequencing analysis for 121 patients with 2017 European LeukemiaNet-defined intermediate risk AML, revealing 122 mutated genes, with 24 genes mutated in > 10% of patients. A prognostic nomogram characterized by white blood cell count ≥10×109/L at diagnosis, mutated DNMT3A and genes involved in signaling pathways was developed for 110 patients who were with clinical outcomes. Two subgroups were identified: intermediate low risk (ILR; 43.6%, 48/110) and intermediate high risk (IHR; 56.4%, 62/110). The model was prognostic of overall survival (OS) and relapse-free survival (RFS) (OS: Concordance index [C-index]: 0.703, 95%CI: 0.643-0.763; RFS: C-index: 0.681, 95%CI 0.620-0.741), and was successfully validated with two independent cohorts. Allogeneic hematopoietic stem cell transplantation (alloHSCT) reduced the relapse risk of IHR patients (3-year RFS: alloHSCT: 40.0±12.8% vs. chemotherapy: 8.6±5.8%, P= 0.010). The prediction model can help identify patients with an unfavorable prognosis and refine risk-adapted therapy for intermediate risk AML patients.

Is Higher Subjective Fear Predictive of Post-Traumatic Stress Symptoms in a Sample of the Chinese General Public?

Background: COVID-19 has taken a huge toll on medical resources and the economy and will inevitably have an impact on public mental health. Post-traumatic stress disorder (PTSD), as the most common mental illness after an epidemic, must be seriously addressed. This study aimed to investigate the subjective fear of the Chinese general public during COVID-19 and to explore how it affected the development of PTSD. Methods: An online questionnaire survey was conducted among 1,009 people from January 30 to February 14, 2020 (about 1 month after the COVID-19 outbreak). The subjective fear was measured by a self-reported single-choice question. Four items from the Pittsburgh Sleep Quality Index (PSQI) were selected to measure the subjects' sleep quality. Their post-traumatic stress symptoms (PTSS) were measured by the PTSD Checklist for DSM-5 (PCL-5). Pearson correlation, hierarchical multivariate regression analysis, multiple mediator model, and bootstrapping were used in statistical analyses. Results: Different people showed different levels of subjective fear in response to the outbreak. There was a significant positive correlation between subjective fear and the total score of PCL-5 (R = 0.513, P < 0.01), meaning that the higher the degree of subjective fear, the more severe the symptoms of post-traumatic stress are. Subjective fear was an important predictor of PTSS, accounting for 24.3% of the variance. The total effect of subjective fear on PCL-5 scores was significant (total effect = 7.426, SE = 0.405, 95% CI = 6.631-8.221). The total indirect effect of subjective fear on PCL-5 scores through sleep quality was also significant (total indirect effect = 1.945, SE = 0.258, 95% CI = 1.436-2.470). Conclusions: Subjective fear has an important predictive effect on PTSS. In addition to the direct effect, our findings firstly demonstrate the mediating role of sleep quality in the relationship between subjective fear and PTSS.