To investigate the clinical characteristics and prognosis of acute B-cell lymphoblastic leukemia (B-ALL) patients with MEF2D fusions. We retrospectively analyzed 15 newly diagnosed MEF2D-positive B-ALL patients admitted to The First Affiliated Hospital of Soochow University between January 2021 and December 2024, confirmed via targeted RNA sequencing (RNA-seq) or reverse transcription multiplex PCR. Immunophenotypic, cytogenetic, and molecular mutation profiles were assessed, along with treatment responses. Among the 228 patients initially diagnosed with high-risk B-ALL, 15 patients (6.58

Implantable cardiovascular biomaterials face critical clinical challenges, such as thrombosis, bacterial infection, and insufficient endothelial regeneration. In this study, aligned chitosan/silk fibroin (CS/SF) electrospun scaffolds were fabricated by heparin functionalization via parameter optimization, polydopamine-mediated surface modification, and controlled heparin grafting. A comprehensive characterization confirmed that the optimized scaffolds possessed well-aligned uniform nanofibers, desirable mechanical performance, adjustable hydrophilicity, and programmable degradation behavior. Immobilized heparin displayed a typical release profile consisting of an initial burst phase followed by sustained long-term delivery. In vitro biological evaluations demonstrated that the heparin-modified scaffolds inhibited platelet adhesion and activation and prolonged activated partial thromboplastin time (APTT), yielding favorable anticoagulant efficacy. Benefiting from the synergistic interaction between cationic CS and anionic heparin, the scaffolds exhibited prominent bactericidal effects against Escherichia coli and Staphylococcus aureus. Furthermore, the scaffolds suppressed the expression of pro-inflammatory Interleukin-6 (IL-6) to mitigate inflammatory reactions, facilitated the proliferation, migration and oriented arrangement of endothelial cells, and activated the Hypoxia-Inducible Factor 1-alpha/Vascular Endothelial Growth Factor‌‌ (HIF-1α/VEGF) signaling cascade. The elevated Platelet Endothelial Cell Adhesion Molecule-1 (CD31) expression further validated the endothelial maturation and angiogenic capacity of the scaffolds. Collectively, these multifunctional heparin-grafted CS/SF composite scaffolds integrated anticoagulant, antibacterial, anti-inflammatory, and pro-endothelial bioactivities, making them promising candidates for cardiovascular interventional implants. This study offers a facile and versatile strategy for designing multifunctional bioactive biomaterials for vascular tissue engineering applications.

Therapy-related myeloid neoplasms (t-MN) are an aggressive and heterogeneous group of myeloid disorders with no established guidelines for frontline treatment. This retrospective study of 53 consecutive t-MN patients at our institution evaluated the influence of clinical features, treatment approaches, and prognostic indicators on clinical outcomes of t-MN. The 1-year, 3-year, and 5-year overall survival (OS) rates were 61.0

Objective:To evaluate the predictive value of preoperative platelet-to-white blood cell ratio (PWR) for postoperative outcomes in patients with acute type A aortic dissection (ATAAD). Methods:In this single-center retrospective cohort study, 363 ATAAD patients undergoing emergency type II hybrid aortic arch repair between January 2021 and February 2024 were stratified by median PWR into low PWR (<13.259) and high PWR (≥13.259) groups. Clinical variables, operative details, and outcomes were collected. Primary outcome was in-hospital postoperative adverse events (PAEs) incidence; secondary outcomes included short- and mid-term mortality. Associations were analyzed using multivariable logistic regression and Cox proportional hazards models. Results:A considerably higher incidence of PAEs was observed in the low PWR (<13.259) relative to the high PWR (41.99% vs. 21.43%, p < 0.001) groups. Moreover, patients with low PWR showed increased in-hospital (13.81% vs. 3.30%, p = 0.001), 90-day (14.36% vs. 4.40%, p < 0.001), and 1-year (16.38% vs. 5.56%, p = 0.001) mortalities. Multivariable logistic regression detected low preoperative PWR as a distinct marker of PAEs. The areas under the curve for PWR in estimating PAEs was 0.705 (95% CI, 0.649-0.760). Cox regression analysis confirmed a significant association between low PWR and elevated short- and mid-term mortality. Conclusion:Preoperative low PWR independently predicts postoperative complications and mortality in ATAAD patients, serving as an accessible and cost-effective biomarker for risk stratification and clinical decision-making.

Anxiety and depression are common psychological disorders in patients with coronary heart disease (CHD). These changes might affect postoperative treatment and cardiac rehabilitation in patients with CHD. The purpose of this study was to evaluate the curative effects of the Shexiang Baoxin Pill (SBP) on anxiety and depression and prognoses in patients with CHD after percutaneous coronary intervention. A total of 236 patients with CHD and anxiety and/or depression who were admitted to our hospital from March 2021 to April 2023 were selected and non-randomly divided into a control group and a treatment group. Both groups were given medications (antiplatelets, statins, and vasodilators) and intervention therapy for CHD. The treatment group received additional treatment involving SBP administered orally (2 capsules/time, twice a day). All patients were followed up for 3 months. The basic data, laboratory examinations, symptom self-rating scale, anxiety scale (SAS)/depression scale (SDS) scores, and the incidence of cardiovascular adverse events were compared between 2 groups. Two groups of patients remained synchronous in their baseline data, laboratory data, and left ventricular systolic function. Through comparisons of the mental status of patients, we found that the SAS and SDS scores of patients in the SBP treatment group were significantly lower than those in the control group after 1 month and 3 months of treatment. The decreased value of the SAS and SDS scores in the SBP treatment group was significantly higher than the variation in the control group. The proportion of patients with anxiety or depression in the treatment group was significantly lower than the proportion before the SBP treatments. Furthermore, there was no statistically significant difference in the levels of examination data in the follow-up between the 2 groups of patients. The incidence of discomfort symptoms and adverse cardiovascular events in the treatment group was lower than in the control group. The combination of SBP with conventional treatments could not only effectively alleviate anxiety and depression and myocardial ischemia symptoms, but also safely and effectively reduce the occurrence of adverse cardiovascular events in patients with CHD. These findings provide strong clinical evidence for the treatment of dual heart disease with SBP in clinics.

BACKGROUND:The relapse after chimeric antigen receptor (CAR) T-cell therapy remains a critical challenge, and the optimal timing and treatment strategies for CAR T urgently need to be explored. Autologous hematopoietic stem cell transplantation (auto-HSCT) demonstrates comparable leukemia-free survival (LFS) and overall survival (OS) in patients who rapidly achieve MRD-negative complete remission (CR) compared with allogeneic HSCT (allo-HSCT). Thus, combining CAR T cells with auto-HSCT may represent a promising treatment strategy. The trial registration is ClinicalTrials.gov identifier NCT05470777. METHODS:This phase 2 trial evaluated the safety and efficacy of sequential CD22/CD19 CAR T cells combined with an auto-HSCT "sandwich" strategy in patients with Philadelphia chromosome-negative (Ph-negative) B-cell acute lymphoblastic leukemia (B-ALL), including adolescents and young adults (AYA) as well as adults who were unable or declined to allo-HSCT. The primary and secondary end points were OS and LFS, respectively. The trial registration is ClinicalTrials.gov identifier NCT05470777. RESULTS:At a median follow-up of 28 months, the median OS and LFS were not reached. The 2-year OS and LFS rates were 97% (95% confidence interval [CI], 90%-100%) and 72% (95% CI, 58%-90%), respectively. All 35 patients who completed the sandwich strategy survived. Continuous MRD-negative CR rates after the second CAR T-cell infusion were 80% by multiparameter flow cytometry and 70% by next-generation sequencing of immunoglobulin H rearrangements. OS and LFS did not differ between poor and standard genetic risk groups. Compared with the allo-HSCT external control group, the sandwich strategy showed improved OS and comparable LFS. No cases of immune effector cell-associated neurotoxicity syndrome or severe cytokine release syndrome were observed. The trial registration is ClinicalTrials.gov identifier NCT05470777. CONCLUSION:The CD22/CD19 CAR T-cell and auto-HSCT sandwich strategy represents a promising approach for the treatment of Ph-negative B-ALL in AYA and adult patients, offering high efficacy and a favorable safety profile. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Introduction Patients with immune thrombocytopenic purpura (ITP) usually express thyroid antigen-specific antibodies. The purpose of this study was to explore the causal relationship between Hashimoto's thyroiditis (HT) and ITP.Methods A two-sample Mendelian randomization (TSMR) analysis was applied to investigate the potential causal relationship between HT and ITP in European population. Five complementary methods including inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), weighted median, and weighted mode were performed in our study. Risk genes of HT and ITP were selected through Mendelian randomization (MR), and the common risk genes were further analysed by bioinformatics methods to explore the common pathogenesis of the two diseases.Results The MR analysis revealed a potential causal relationship between HT and risk of ITP [odds ratio (OR) = 1.22; 95% confidence interval (CI) 1.01, 1.49; P = 0.046]. Gene eQTL data were obtained from the IEU database. HT and ITP were respectively treated as outcome variables for MR analysis, and a total of 32 common risk genes were selected, including 12 high-risk genes and 20 low-risk genes. Functional analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis revealed that risk genes were closely related to antigen processing and presentation, and played a crucial role in the process of various viral and bacterial infections.Conclusion Our study demonstrated that HT may increase the risk of ITP, and revealed the role of their common risk genes in the development of the two diseases.

Abstract Introduction: Relapse or refractory acute myeloid leukemia (R/R AML) is a highly heterogeneous disease with poor prognosis. Current conventional reinduction regimens, such as FLAG-ida and MEC, yield remission rates of 30%–50% and a two-year survival rate of only 27%. Venetoclax, a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine, achieving a reinduction rate of approximately 40%. Additionally, cladribine-based regimens have demonstrated synergistic effects with cytarabine, with remission rates exceeding 50%. To explore more effective treatment options for R/R AML, we designed a multicenter, randomized controlled trial comparing the reinduction efficacy of MEC versus a novel combination of venetoclax, cladribine, and low-dose cytarabine (CAV). Here, we present the interim analysis of this ongoing clinical trial (NCT05657639). Methods: This randomized, controlled, multicenter study evaluated the efficacy and safety of CAV compared to MEC. Eligible patients were randomized 1:1 to receive either CAV (cladribine 5 mg/m2/day, cytarabine 20mg q12h, venetoclax 100mg d1, 200 d2, 400 mg/day from day 3 to day 21) or MEC (mitoxantrone 8mg/m2 d1-5, etoposide 100mg/m2 d1-5, cytarabine 1g/m2 d1-5). The primary endpoint of the study was overall response rate (ORR), the secondary endpoints of the study were adverse events (AEs), overall survival (OS) and event free survival (EFS). Bone marrow evaluation was performed after the blood cell count recovery or within 14 days after treatment completion. Results: From October 2022 to July 2025, a total of 55 R/R AML patients were enrolled and randomly assigned, 30 to the CAV group and 25 to the MEC group. Baseline characteristics were relatively balanced between groups. 28 (50.9%) of 55 patients were male and 27 (49.1%) were female. The median age was 49.5 years (range 15-66) and 51 years (range 30-68) in the CAV group and MEC group, respectively. Overall, 10 (22%) of patients had a high-risk stratification, including 43.3% in the CAV and 20% in MEC group. ORR (CR/CRh/CRi/MLFS) was 53.3% (16/30) in the CAV group and 32.0% (8/25) in the MEC group (P=0.11). CR was achieved in 30% and 4%, respectively. Notably, in the venetoclax-naïve subgroup, CAV achieved a significantly superior ORR of 66.7% (10/15) versus 32% (8/25) with MEC (P=0.03). While the 1-year overall survival rate was 67.1% in the MEC group, it was not yet reached in the CAV group. Following treatment, 34.5% (19/55) patients underwent allogeneic hematopoietic stem cell transplantation. Seven patients died because of disease progression, four patients died of infection. Grade ≥3 hematologic toxicities were similar in both treatment groups, with neutropenia reported in 100% in both groups. The commonest grade≥3 nonhematologic toxicities in the CAV and MEC groups were pneumonia (10% vs 20%), sepsis (3% vs 28%). Conclusion: Our findings demonstrate that the CAV regimen represents an effective and well-tolerated salvage therapy for R/R AML, particularly in venetoclax-naïve patients who achieved significantly superior response rates. These promising results warrant further validation in larger prospective studies to confirm the regimen's efficacy.

OBJECTIVE:To identify risk factors for heart failure (HF) within one year after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and to develop a predictive nomogram model. METHODS:A retrospective analysis was performed on 492 patients with ACS treated at Suzhou Municipal Hospital between January 2020 and October 2023. Patients were divided into the HF group and the non-HF group according to the occurrence of HF within one year after PCI. 70% of the cases were randomly assigned to the training set and 30% to the validation set. Univariate and multivariate logistic regression analyses were conducted to screen independent predictors, and a nomogram model was subsequently established. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS:Among the 492 patients, the incidence of HF within one year after PCI was 26.42% (n = 130). Logistic regression identified type 2 diabetes mellitus (T2DM), left ventricular ejection fraction (LVEF), lipoprotein(a) [LP(a)], B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (Hs-CRP) as independent predictors of HF, with odds ratios of 5.756, 0.904, 1.427, 1.012, and 1.666, respectively (all P < 0.05). The model demonstrated excellent discrimination, with areas under the ROC curve of 0.946 in the training set and 0.958 in the validation set. DCA indicated that the model provided greater net clinical benefit than the "treat-all" or "treat-none" strategies, and its predictive performance surpassed that of each individual factor (P < 0.05). CONCLUSION:The nomogram model incorporating T2DM, LVEF, LP(a), BNP and Hs-CRP provides an effective tool for predicting HF risk within one year after PCI in patients with ACS, offering valuable guidance for early clinical identification and risk stratification of high-risk individuals.

OBJECTIVE:To evaluate the efficacy and safety of personalized conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of relapsed/ refractory acute myeloid leukemia (R/R AML). METHODS:A retrospective analysis of the clinical data of 14 R/R AML patients who underwent allo-HSCT with a personalized conditioning regimen was conducted. RESULTS:Among the 14 patients, there were 8 males and 6 females with a median age of 34.5 years (range 14-56). One patient received a transplant from a fully matched related donor, 2 from unrelated donors, and 12 from haploidentical donors. Prior to transplantation, all patients had a myeloblast percentage greater than 5% before transplantation, with a median myeloblast of 8.5 (6-88)%. Thirteen patients (92.86%) achieved morphologic leukemia-free state (MLFS) after conditioning. All patients achieved successful engraftment and hematopoietic recovery. The median time to neutrophil engraftment was 12 days (range 10-14), and the median time to platelet engraftment was 21.5 days (range 17-29). There was no obvious hepatorenal toxicity during the conditioning, and no mucositis more than grade 2 according to CTCAE 5.0 [1]. Bone marrow biopsies at +30 days post-transplant indicated remission in all cases. Two patients relapsed at 2 and 3 months post-transplant, with 2 dying after relapse. Additionally, 2 patients had CMV infections; 1 became negative after treatment, while the other remained positive and later died due to severe infection. As of the last follow-up, 11 out of 14 patients were alive (with marrow morphology and MRD Continuously negative). CONCLUSION:Allo-HSCT with a personalized conditioning regimen can be considered a treatment option for patients with R/R AML.

There is no consensus on the most efficient ablation strategy for patients with persistent atrial fibrillation (PerAF). This study aimed to conduct a systematic review and network meta-analysis (NMA) to evaluate the effectiveness of different ablation strategies for PerAF. The primary efficacy outcome was the recurrence of any atrial arrhythmia after a single ablation procedure during the follow-up period. The primary safety outcome of interest was any reported complication related to the procedure. The secondary outcome was the procedure time. Fifty-two studies with 9048 patients were included in this NMA. The studies were conducted between 2004 and 2024, and 22 different ablation strategies were identified. Pulmonary vein isolation + posterior wall box isolation + extra-pulmonary vein isolation was the most effective ablation therapy for PerAF. Most additional substrate modification ablation strategies do not show significant additional benefits. There were no significant differences in the incidence of procedure-related complications between the different ablation strategies. Pulmonary vein isolation combined with additional ablation sites increases the duration of the procedure.

Objective:To investigate the clinical characteristics and prognostic of venetoclax(VEN)combined targeted therapy in acute leukemia(AL)patients with PICALM∷MLLT10 fusion gene positivity.Methods:A retrospective analysis was conducted on 16 PICALM∷MLLT10-positive AL patients treated at the First Affiliated Hospital of Soochow University from January 2021 to August 2024.These patients were diagnosed by targeted RNA sequencing(RNA-seq)or reverse transcription multiplex PCR,including newly diagnosed and relapsed/refractory(R/R)cases.The immunophenotypes,genetic features,gene mutations,and the efficacy of VEN combination targeted therapy of patients were evaluated.Results:Among the 16 cases,3 were confirmed by reverse transcription multiplex PCR,and 13 were detected through targeted RNA-seq among 528 AL patients,with a detection rate of 2.46％.The averge age of patients was(28.0±8.58)years.Patients exhibited diverse immunophenotypes,including 7 cases of acute myeloid leukemia,5 of acute T-lymphoblastic leukemia,1 of acute B-lymphoblastic leukemia,1 of acute undifferentiated leukemia,and 2 of mixed-phenotype acute leukemia.Among them,11 had extramedullary disease(EMD),14 expressed CD7,and 12 expressed CD33.Major co-occurring mutations included PHF6(6 cases),NOTCH1(5 cases),and 7 cases with complex karyotypes.Of the 12 patients who received standard induction therapy,7 did not achieve remission(PR+NR).All 4 patients treated with VEN combination therapy achieved complete remission(CR).Among the 7 induction failure cases,4 achieved CR upon re-induction with VEN,while the remaining 3 re-induced with standard therapy,did not achieve CR.Thirteen patients received allogeneic hematopoietic stem cell transplantation,including 6 who received maintenance therapy with hypomethylating agents(HMA)alone or in combination with VEN,and seven were followed up.Survival analysis showed that the overall survival was better in the maintenance therapy group(P=0.044).Conclusion:PIC ALM∷MLLT10-positive AL involves multiple lineages and demonstrates poor response to conventional chemotherapy.VEN combination therapy shows promising efficacy in both newly diagnosed and R/R patients.Post-transplant maintenance therapy with HMA alone or combined with VEN may extend survival;however,further clinical validation is required.

Background: Acute myocardial infarction (AMI) is a critical condition requiring effective postoperative recovery management. Hospital noise, often exceeding recommended levels, can heighten stress and disrupt healing post-AMI. This study investigated the effects of acoustic design in hospital wards on postoperative recovery for patients with AMI. Methods: A retrospective analysis was conducted on 192 patients with AMI hospitalized between June 2021 and July 2023. Patients were allocated into two groups on the basis of ward design: an acoustically optimized ward (AOW, n = 91) and a conventional ward (CW, n = 101). Outcomes, including vital signs, sleep quality, patient perceptions, and recovery metrics, were assessed. Noise levels were monitored continually, and sleep quality was gauged using sleep diaries. Results: The AOW group exhibited significantly lower systolic (P = 0.011) and diastolic (P = 0.016) blood pressures and improved postoperative left ventricular ejection fraction (LVEF, P = 0.002) than the CW group, but LVEF was not reassessed at discharge. The AOW group further demonstrated reduced noise levels both day (P = 0.004) and night (P = 0.021), fostering better sleep outcomes such as fewer awakenings (P = 0.024). Additionally, the AOW group experienced shorter hospital stays (13.21 ± 3.57 days) than the CW group (14.34 ± 3.19 days, P = 0.022) and improved patient satisfaction at discharge (P = 0.029). Perceived pain was significantly reduced in the AOW group (P = 0.026). Anxiety levels displayed no significant differences. Conclusion: The acoustic optimization of hospital wards was associated with improvements in postoperative recovery outcomes, such as lower blood pressure, enhanced sleep quality, reduced perceived pain, and shorter hospital stays, for patients with AMI, suggesting that a good sound environment may play a positive role in postoperative recovery.

Background: Acute Leukaemias of Ambiguous Lineage(ALAL) accounts for less than 4% of AL. It represents a rare type of leukaemia and is reported to have a poor prognosis. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. However, Both treatment showed limited effect for ALAL, so management of ALAL patients is still challenging. The efficacy and safety of venetoclax with azacitidine or chemotherapy has been reported in refractory/relapse ALAL but not in newly diagnosed population. Here, we designed a multicenter, phase 2 study utilizing the venetoclax and azacitidine (VA) regimen for the treatment of ALAL (NCT05901974). Methods: The VA regimen consisted of azacitidine 75 mg/m2 subcutaneously once daily from day 1 to day 7 and venetoclax 100mg d1, 200 mg d2, 400 mg/day from day 3 to day 28. ALAL patients with Philadelphia chromosome(Ph)-positive received a concomitant BCR::ABL1 tyrosine kinase inhibitor (TKI). Bone aspiration evaluation was performed at 14-28 days after the completion of VA regimen. ALAL was diagnosed according to 2022 WHO classification. Treatment responses were evaluated according to the 2022 NCCN guidelines. Measurable Residual Disease(MRD) was assessed by multicolor flow cytometry (MFC). MRD negative remission in Ph-negative ALAL was defined as <0.01%, and in Ph-positive ALAL was defined as <0.01% by MFC and the absence of quantifiable BCR::ABL1 transcripts by PCR <0.01% on the international scale. Patients were considered non-responders if the criteria for overall response were not achieved after two induction cycles. Results: Since Janary 2022, a total of 10 patients with ALAL were enrolled in this study. The median age was 45 years (range, 22-61years)，with 4 (60%) female and 6 (60%) male patients. Among them, 3 patients were diagnosed with acute undifferentiated leukaemia (AUL). 3 patients were diagnosed with T/myeloid mixed phenotype acute leukemia (MPAL), 2 were B/myeloid MPAL, 2 were Ph+ B/myeloid MPAL. Among them, seven patients were biphenotypic and one was bilineal with the coexistence of B lineage and myeloid lineage . Eight patients responded to VA regimen after one cycle of regimen, with 7/10 (70%) with complete remission (CR), 1/10 (10%) with complete remissioni with incomplete hematologic recovery(CRi). Two patients with no remission(NR) are currently receiving re-induction therapy, and for the rest having completing two cycles of regimen, 6/8(75%) achieved CR, 2/8(25%) achieved CRi. Among patients who achieved treatment response, 5/8 (62.5%) patients attained MRD negativity. Four patients (40%) received an allogeneic haematopoetic stem cell transplantation (HSCT). During the treatment with the VA regimen, the most frequent grade 3 or higher adverse events were hematologic toxicity, including neutropenia (100%), thrombocytopenia (50%) and anemia (50%). One patient had temporary discontinuation due to grade 4 infections. Grade 2 infections and Grade 1 to 2 liver dysfunction were observed in 1/10(10%) and 2/10(20%) patients. Disease relapse occurred in 2 (20%) patients. One patient revceived salvage chemotherapy whereas one died of disease progression. With a median follow-up of 8.3 months (range, 1.4-31.2 months), the estimated 1-year overall survival rate was 50% and 1-year event-free survival rate was 68.6% when data were censored for HSCT. The median OS and EFS were not reached. The 2-year cumulative relapse rate was 31.4%. Conclusion: Our results demonstrated that VA regimen had encouraging efficacy and would possibly be an successful bridge to transplant in ALAL patients.

Heart failure (HF) is still a leading cause of mortality and morbidity despite considerable advances in therapy. This study aimed to evaluate the efficacy of cardiac contractility modulation (CCM) for treating Chinese patients with HF. This retrospective study included six HF patients who had New York Heart Association (NYHA) class II or III and received CCM implantation at the First Affiliated Hospital of Soochow University from May 2022 to May 2023. Assessments were conducted before and after 12 months of CCM treatment to evaluate the left ventricular ejection fraction (LVEF), the left ventricular end-diastolic dimension (LVEDD), the left atrium diameter (LAD), and cardiac function. After the 12-month follow-up, all outcome measures showed improvement: the LVEF increased from (27 ± 4.73)

Efficacy and safety of cladribine, low-dose cytarabine

Chemotherapy-induced cardiotoxicity with subsequent heart failure (HF) is a major cause of morbidity and mortality in cancer survivors worldwide. Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation. To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF, we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive (MISA) that could be delivered locally through an endoscope-guided intrapericardial injection. To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients, we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections. In vitro, we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability, but also inhibited their apoptosis. In vivo, we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation, angiogenesis, and mitochondrial respiration. Additionally, we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system. In general, our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.

Introduction: Chronic graft-versus-host disease (cGVHD) is a fatal late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studied demonstrate that the interaction between T follicular helper (Tfh) cells and B cells promotes pathogenicity of cGVHD. The glucocorticoids are still the first-line standard treatment of cGVHD, which are effective in only 50-60% of cases. Chidamide, is an oral innovative subtype-selective histone deacetylase (HDAC) inhibitor, independently developed in China. It could induce chromatin remodeling, epigenetic changes, inhibiting cell cycle and thereby inducing tumor cell apoptosis. It is primarily approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (R/R-PTCL) and has superior response in Tfh-PTCL. Therefore, we conduct a prospective clinical study (NCT05140616), to investigate the efficacy and safety of chidamide in steroid-dependent and steroid-refractory cGVHD (SR-cGVHD). Methods: Patients who undergoing allo-HSCT with modified myeloablative BU/CY conditioning regimen and developing SR-cGVHD at the First Affiliated Hospital of Soochow University were enrolled. The diagnosis and grade of SR-cGVHD were based on the NIH criteria. All patients received oral chidamide 15mg twice a week and a total of two cycles was recommended. The primary study endpoint was overall response rate (ORR) at 3 months. The secondary endpoints were the safety of chidamide, overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of enrolled patients. Survival outcomes were conducted with the Kaplan-Meier method. Results: 11 enrolled patients included 8 (72.7%) males and 3 (27.3%) females. The median age of patients was 34 years (range 16-50 years). The patients consisted of 4 (36.4%) acute myeloid leukemia, 4 (36.4%) acute lymphoblastic leukemia, 2 (18.2%) myelodysplastic syndrome and 1 (9.1%) lymphoblastic lymphoma. Of 11 patients. 6 (54.5%) were HLA-matched sibling donor transplantation and 5 (45.5%) were haplo-identical donor transplantation. Patients were assessed and divided into moderate group (4, 36.4%) and severe group (7, 63.6%) according to the NIH criteria. By analyzing the targeted organs, there were 9/11 (81.9%) patients with skin involvement. The pulmonary cGVHD occurred in 7 (63.6%) patients and 5 (45.5%) patients had liver-cGVHD. For enrolled patients, the ORR to chidamide therapy was 45.5%, including 1 (9.1%) patient with CR and 4 (36.4%) with PR. In addition, 4 (36.4%) patients were in stable condition during treatment. The median following-up time was 31 months (range 1-41 months) after the initiation of chidamide. The 2-year OS was 81.8%, 2-year PFS was 71.6%, 2-year CIR was 12.5% and 2-year NRM was 18.2%, respectively. 1 (9.1%) patient died due to relapse of leukemia and 2 (18.2%) died due to pulmonary cGVHD progression. The adverse events (AEs) were observed in 3 (27.3%) patients, 1(9.1%) thrombocytopenia, 1 (9.1%) gastrointestinal tract reaction and 1 (9.1%) cough were included. AEs were obviously improved by symptomatic treatment. Conclusion: Collectively, our results primarily suggested selective HDAC inhibitor chidamide could serve as potential therapeutic choice for SR-cGVHD.

Introduction Venetoclax plus hypomethylating agents (VEN+HMA) has shown remarkable efficacy in elderly and unfit AML patients. However, prospective studies comparing VEN+HMA to standard intensive chemotherapy in young and fit AML patients are lacking. We conducted a phase 2 study to compare the efficacy and safety of VEN+HMA versus the standard 7+3 regimen in newly diagnosed AML patients eligible for intensive chemotherapy. Preliminary results were reported at ASH 2023 (#970). The study, now complete with increased sample size and extended follow-up, presents the final analysis. Methods In this multicenter, randomized, open-label, controlled phase 2 trial, newly diagnosed Chinese AML patients aged 18-59 years and eligible for intensive chemotherapy were randomly assigned, in a 1:1 ratio to receive either venetoclax plus decitabine (VEN-DEC) or the idarubicin plus cytarabine (IA-12) as induction therapy. Patients in the VEN-DEC arm received venetoclax (orally, once daily, for 28 days, target dose 400 mg) and decitabine (20 mg/m² intravenously on days 1-5). Patients in the IA-12 arm received intravenous idarubicin (12 mg/m² on days 1-3) and cytarabine (100 mg/m² on days 1-7). The primary endpoint was composite complete remission (CRc), including complete remission and complete remission with incomplete hematologic recovery, aiming to demonstrate the non-inferiority of VEN-DEC as induction therapy compared to IA-12 with a non-inferiority margin of 5% and a one-sided type 1 error of 2.5%. Secondary endpoints included the incidence of grade 3 or worse infections during induction treatment, duration of severe myelosuppression, event-free survival (EFS), overall survival (OS), and the measurable residual disease (MRD) negativity rates post-induction therapy. The exploratory endpoint was the efficacy of the two treatment regimens in cytogenetic subgroups. The study was registered on ClinicalTrials.gov (NCT05177731), and the data cut-off date was 30 April, 2024. Results The intention-to-treat population comprised 188 patients (94 in each group). The median age was 45 years in the VEN-DEC group and 40 years in the IA-12 group. Composite complete remission was observed in 84 (89%) of 94 patients in the VEN-DEC group versus 74 (79%) of 94 patients in the IA-12 group (test for non-inferiority, p=0.0021). VEN-DEC demonstrated non-inferiority to IA-12 at the 2.5% significance level. The difference in CRc between VEN-DEC and IA-12 was estimated to be 10.6% (95% CI 0.2 to 21.3). The rate of MRD negativity in CRc patients after induction therapy was 80% in both the VEN-DEC (67/84) and the IA-12 groups (59/74). Subgroup analysis of CRc rates showed that compared to IA-12, patients aged ≥40 years (91% vs 75%), with ELN-2022 adverse risk factors (91% vs 42%), and with epigenetic modifier mutations (91% vs 67%) benefited more from VEN-DEC, whereas the RUNX1::RUNX1T1subgroup responded better to IA-12 (44% vs 88%). Fewer patients in the VEN-DEC group experienced grade 3 or worse infections compared to the IA-12 group (30 [32%] vs 63 [67%], χ² test, p<0.001). Key grade 3 or worse infections included pneumonia (16% in the VEN-DEC group vs 32% in the IA-12 group), sepsis (7% vs 25%), and septic shock (1% vs 6%). 82% of patients in the VEN-DEC group and 93% in the IA-12 group experienced grade 3-4 hematologic adverse events. The median duration of severe neutropenia (<0.5×109/L) was longer in the VEN-DEC group (23 days, IQR 17-28) compared to the IA-12 group (19 days, IQR 16-23) (p=0.001). Conversely, the median duration of severe thrombocytopenia (<25×109/L) was shorter in the VEN-DEC group (13 days, IQR 0-20) compared to the IA-12 group (19 days, IQR 14-26) (p<0.001). At a median follow-up of 12.1 months (range, 0.33 to 26.5), the median survival time was not reached in either group, with no significant difference in EFS (hazard ratio, HR=0.91, p=0.714) or OS (HR=1.15, p=0.705). However, in the VEN-DEC group, patients with CEBPAbZIP had a 1-year RFS rate of 52.5% (95% CI 33.2 to 83.0), significantly lower than 85.1% (95% CI 68.0 to 100) in the IA-12 group (HR for relapse or death, 5.43; 95% CI 1.14 to 25.75; p=0.017). Conclusions In newly diagnosed adult patients under 60 years old who are eligible for intensive chemotherapy, VEN+DEC showed comparable efficacy but improved safety compared to the standard 7+3 regimen. However, caution is warranted when using VEN+DEC in AML patients with RUNX1::RUNX1T1 or CEBPAbZIP mutations.