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Background: Patients with hematological malignancies (HM) were at a high risk of developing severe disease from coronavirus disease 2019 (COVID-19). We aimed to assess the clinical outcome of COVID-19 in hospitalized patients with HM. Methods: Adult patients with HM who were hospitalized with a laboratory-confirmed COVID-19 between May, 2021 and November, 2022 were retrospectively identified. Primary outcome was respiratory failure requiring mechanical ventilation or mortality within 60 days after hospitalization. We also analyzed associated factors for de-isolation (defined as defervescence with a consecutive serial cycle threshold value > 30) within 28 days. Results: Of 152 eligible patients, 22 (14.5%) developed respiratory failure or mortality in 60 days. Factors associated with developing respiratory failure that required mechanical ventilation or mortality included receipt of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) (adjusted hazards ratio [aHR], 5.10; 95% confidence interval [CI], 1.64–15.85), type 2 diabetes mellitus (aHR, 2.47; 95% CI, 1.04–5.90), lymphopenia at admission (aHR, 6.85; 95% CI, 2.45–19.15), and receiving

Background: The prognosis for people living with HIV (PLWH) who develop lymphomas has been greatly improved by combination antiretroviral therapy (cART) and anti-CD20 monoclonal antibodies. However, real-world clinical data on this patient group in Asia are limited. Methods: Treatment outcomes were retrospectively examined for 104 PLWH with lymphomas between 2000 and 2019. The cohort comprised five PLWH with Hodgkin lymphoma (HL) and 99 with non-Hodgkin lymphomas, including 61 with diffuse large B-cell lymphoma (DLBCL), 19 with Burkitt lymphoma (BL), nine with primary central nervous system lymphoma (PCNSL) and ten with other subtypes. Results: The 5-year overall survival (OS) rates were as follows: HL (100%), PCNSL (76.2%), other subtypes (60.0%), BL (57.4%), and DLBCL (55.6%). Individuals who achieved complete response (CR) to front-line therapies had a significantly better 5-year OS rate than those without (96.2% vs. 17.8%, p

IntroductionSignal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM.Methods and resultsThis retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence.ConclusionIn our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.

Abstract Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) of the head‐and‐neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR‐DLBCL and those with SN‐DLBCL in the rituximab era remain unclear. Methods To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR‐DLBCL and SN‐DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN‐DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event‐free survival (EFS), and overall survival (OS) among the three subgroups. Results We analyzed 67, 15, and 106 patients with WR‐DLBCL, SN‐DLBCL, and LN‐DLBCL, respectively, between January 2000 and December 2019. All patients received front‐line rituximab‐based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone‐based regimens. More patients with SN‐DLBCL had revised International Prognostic Index (R‐IPI) score 3 (27%) when compared with those with WR‐DLBCL (7%) and those with LN‐DLBCL (10%, p = 0.181). Patients with WR‐DLBCL, LN‐DLBCL, and SN‐DLBCL had 5‐year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN‐DLBCL, those with WR‐DLBCL also had a significantly favorable 5‐year EFS rate (p = 0.021) and 5‐year OS rate (p = 0.023). Three of the 15 patients with SN‐DLBCL experienced lymphoma recurrence in the brain after front‐line treatment. In multivariate analyses, R‐IPI scores of 1–2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. Conclusions Compared to patients with LN‐DLBCL, patients with WR‐DLBCL receiving front‐line rituximab‐based treatments had favorable clinical outcomes; however, patients with SN‐DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN‐DLBCL are warranted.

IntroductionCatheter ablation is an effective and safe strategy for treating atrial fibrillation patients. Nevertheless, studies on the long-term outcomes of catheter ablation in patients with dilated cardiomyopathy are limited. This study aimed to assess the electrophysiological characteristics of atrial fibrillation patients with dilated cardiomyopathy and compare the long-term clinical outcomes between patients undergoing catheter ablation and medical therapy.MethodPatient baseline characteristics and electrophysiological parameters were examined to identify the predictors of atrial fibrillation recurrence following catheter ablation. The clinical outcomes of catheter ablation and medical therapy were compared using the propensity score matched method.ResultsA total of 343 patients were enrolled, with 46 in the catheter ablation group and 297 in the medical therapy group. Among the catheter ablation group, 58.7% (n = 27) had persistent atrial fibrillation. The recurrence rate of atrial arrhythmia was 30.4% (n = 14) after an average follow-up duration of 7.7 years following catheter ablation. The only predictive factor for atrial fibrillation recurrence after catheter ablation was the left atrial diameter. When compared to medical therapy, catheter ablation demonstrated significantly better outcomes in terms of overall survival, freedom from heart failure hospitalization, improvement in left ventricular ejection fraction, and a greater reduction in left ventricular diameter and left atrial diameter after propensity score matching.ConclusionsTherefore, catheter ablation proves to be effective in providing long-term control of atrial fibrillation in patients with dilated cardiomyopathy. In addition to standard heart failure care, catheter ablation significantly enhanced both morbidity and mortality outcomes and reversed structural remodeling when compared to heart failure medication alone.

BackgroundAtrial fibrillation (AF) and mitral regurgitation (MR) have a complex interplay. Catheter ablation (CA) of AF may be a potential method to improve the severity of MR in AF patients.MethodsPatients with symptomatic AF and moderate to severe MR who underwent catheter ablation from 2011 to 2021 were retrospectively included in the study. Patients' baseline characteristics and electrophysiological features were examined. These patients were classified as group 1 with improved MR and group 2 with refractory MR after CA.ResultsFifty patients (age 60.2 ± 11.6 years, 29 males) were included in the study (32 in group 1 and 18 in group 2). Group 1 patients had a lower CHA2DS2-VASc score (1.7 ± 1.5 vs. 2.7 ± 1.5, P = 0.005) and had a lower incidence of hypertension (28.1% vs. 66.7%, P = 0.007) and diabetes mellitus (3.1% vs. 22.2%, P = 0.031) as compared to group 2 patients. Electroanatomic three-dimensional (3D) mapping showed that group 1 patients demonstrated less scars on the posterior bottom of the left atrium compared to group 2 patients (12.5% vs. 66.7%, P

Previous studies have explored the use of engineered blinatumomab-secreting autologous αβ T cells for CD19-targeted cancer therapy. To create a more flexible allogeneic delivery system, we utilized γ9δ2 T cells rather than αβ T cells in a similar application. First, we showed that γ9δ2 T cells could serve as effector cells for blinatumomab, and these effector memory cells could survive for at least 7 days after infusion. The genetically modified blinatumomab-secreting γ9δ2 T cells induced significant cytotoxicity in CD19+ tumor cell lines and primary cells from chronic lymphocytic leukemia patients. Of note, blinatumomab-secreting γ9δ2 T cells might also exhibit dual-targeting of CD19 and isopentenyl pyrophosphate, a universal tumor-associated antigen. Furthermore, blinatumomab-secreting γ9δ2 T cells killed CD19-transfected adherent cells, suggesting that the γ9δ2 T cells might be effective for treating solid tumors with appropriate cancer antigens. Together, these results demonstrate the promise of blinatumomab-secreting γ9δ2 T cells as a cancer therapy.

Abstract Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468

Abstract Despite the advances in medical and device therapies for heart failure (HF), sudden cardiac death (SCD) remains a tremendous global burden in patients with HF. Among the risk factors for SCD, HF has the greatest impact. Previous studies focusing on patients with systolic dysfunction have found several predictive factors associated with SCD, leading to the subsequent development of strategies of primary prevention, like placement of implantable cardioverter-defibrillator (ICD) in high-risk patients. Although patients with HF with preserved ejection fraction (HFpEF) were less prone to SCD compared to patients with HF with reduced ejection fraction (HFrEF), patients with HFpEF did account for a significant proportion of all HF patients who encountered SCD. The cutoff value of left ventricular ejection fraction (LVEF) to define the subset of HF did not reach consensus until 2016 when the European Society of Cardiology proposed a new classification system by LVEF. There is a great unmet need in the field of SCD in HFpEF regarding risk stratification and appropriate device therapy with ICD implantation. In this article, we will approach SCD in HFpEF from HFrEF subsets. We also aim at clarifying the mechanisms, risk factors, and prevention of SCD in HFpEF.

Background/purpose: Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. Methods: We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. Results: Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN

Asian patientswith chronic lymphocytic leukemia (CLL) exhibit immunoglobulin heavy variable (IGHV) gene repertoires that are distinct from those observed in Western populations, and a higher proportion of Asian CLL patients carry heavy loads of somatic hypermutations (SHM) within the B-cell receptor immunoglobulins (BcR IG). Due to the low regional incidence of CLL in Asia, only a limited number of studies had attempted to probe the phenomenon of BcR IG stereotypy in Asian populations. In this study, we analyzed the IGHV-IGHD-IGHJ gene rearrangements from a series of 255 CLL patients recruited in a nationwide, multicenter study in Taiwan. Our analysis revealed that the IGHV gene repertoire was characterized by evident biases, with IGHV3-7, IGHV4-34, and IGHV3-23 being the most frequent rearranged IGHV genes, and a higher proportion of cases carrying mutated IGHV. In terms of BcR stereotypy, the incidence of major subsets was less frequent in this cohort, with subsets #77 and #28A being the most common, while the incidence of minor subsets was approximately equivalent to that reported in the Western cohorts. With this study, we provide evidence that CLL in Asia is indeed associated with distinct immunogenetic characteristics regarding IGHV gene usage, SHM status, and BcR IG stereotypy.

Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.

Abstract Background Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. Methods shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. Results Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P

Abstract Background Follicular lymphoma (FL) is less prevalent in Asians, but detailed epidemiological analyses were not available. This study aimed to characterize the epidemiologic features of FL in Taiwan to explore the factors relevant to disease development and prognosis. Methods We obtained epidemiological data for Taiwanese citizens during 1990‐2012 from Taiwan's National Cancer Registry Database, and the corresponding data for US Caucasians from the Surveillance, Epidemiology, and End Results Program. Changes in incidence rates were evaluated with age‐period‐cohort (APC) analyses. Patient outcomes were compared with 5‐year relative survival rates (RS) estimates. Results Incidence rates of FL in Taiwan increased continuously during the study period (0.34 to 0.91 per 100 000 person‐year from 1993‐1997 to 2008‐2012 in men, and from 0.29 [1993‐1997] to 0.81 [2008‐2012] in women), while rates in the US remained stable in both sexes, ranging between 3.73 and 3.96 in men and between 3.24 and 3.55 in women. Estimates of average annual percentage changes in incidence were significantly positive in Taiwan, but not in US Caucasians. Notably, the APC analysis identified a strong birth‐cohort effect in Taiwan, corresponding to environmental alterations present during the study period. The estimated 5‐year RS rates in both populations showed steady improvement, but the RS in Taiwanese patients was consistently 10% lower than in US Caucasians. Conclusion A distinct increasing trend of incidence with a strong birth‐cohort effect was identified in Taiwan, providing evidence of the association between environmental factors and disease development.

Background: Multicolor flow cytometry (MFC) analysis is widely used to identify minimal residual disease (MRD) after treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, current manual interpretation suffers from drawbacks of time consuming and interpreter idiosyncrasy. Artificial intelligence (AI), with the expertise in assisting repetitive or complex analysis, represents a potential solution for these drawbacks. Methods: From 2009 to 2016, 5333 MFC data from 1742 AML or MDS patients were collected. The 287 MFC data at post-induction were selected as the outcome set for clinical outcome validation. The rest were 4:1 randomized into the training set (n = 4039) and the validation set (n = 1007). AI algorithm learned a multi-dimensional MFC phenotype from the training set and input it to support vector machine (SVM) classifier after Gaussian mixture model (GMM) modeling, and the performance was evaluated in The validation set. Findings: Promising accuracies (84·6% to 92·4%) and AUCs (0·921–0·950) were achieved by the developed algorithms. Interestingly, the algorithm from even one testing tube achieved similar performance. The clinical significance was validated in the outcome set, and normal MFC interpreted by the AI predicted better progression-free survival (10·9 vs 4·9 months, p

Diffuse alveolar hemorrhage (DAH) secondary to anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is rare in clinical practice and may present as severe acute respiratory distress syndrome (ARDS) with high mortality. Extracorporeal membrane oxygenation (ECMO) has been reported to be a salvage treatment providing the time necessary for immunosuppressive treatment in cases accompanied by severe ARDS. Prone positioning (PP) has been proven to reduce the mortality in patients with severe ARDS. However, there is no consensus about choosing PP or ECMO in severe ARDS due to DAH secondary to ANCA-associated vasculitis. We reported a case of microscopic polyangiitis (MPA)-related DAH and severe ARDS treated with PP successfully providing the time necessary for early glucocorticoids and plasma exchange to control the underlying disease. Since anticoagulation therapy is not necessary in PP, it does not increase the risk of bleeding tendency unlike ECMO. PP has a life-saving role in the management of patients with severe ARDS due to ANCA-associated pulmonary vasculitis.

Abstract Background DNMT3A gene mutation has been associated with poor prognosis in acute myeloid leukemia, but its clinical implications in myelodysplastic syndrome (MDS) and dynamic changes during disease progression remain controversial. Results In this study, DNMT3A mutation was identified in 7.9% of 469 de novo MDS patients. DNMT3A-mutated patients had higher platelet counts at diagnosis, and patients with ring sideroblasts had the highest incidence of DNMT3A mutations, whereas those with multilineage dysplasia had the lowest incidence. Thirty-one (83.8%) of 37 DNMT3A-mutated patients had additional molecular abnormalities at diagnosis, and DNMT3A mutation was highly associated with mutations of IDH2 and SF3B1. Patients with DNMT3A mutations had a higher risk of leukemia transformation and shorter overall survival. Further, DNMT3A mutation was an independent poor prognostic factor irrespective of age, IPSS-R, and genetic alterations. The sequential study demonstrated that the original DNMT3A mutations were retained during follow-ups unless allogeneic hematopoietic stem cell transplantation was performed, while DNMT3A mutation was rarely acquired during disease progression. Conclusions DNMT3A mutation predicts unfavorable outcomes in MDS and was stable during disease evolutions. It may thus be a potential biomarker to predict prognosis and monitor the treatment response.

Differences in chronic lymphocytic leukemia between the Asian and the Western population are widely known. To further clarify these ethnic differences, we profiled the molecular genetics in a cohort of 83 newly diagnosed patients from Taiwan. In detail, we assessed: (i) the usage and the mutational status of the clonotypic immunoglobulin heavy-chain variable region (IgHV) genes, (ii) the presence of VH CDR3 stereotypes, and (iii) TP53, NOTCH1, SF3B1, BIRC3, and MYD88 mutations. The IgHV gene repertoire was biased and distinct from that observed in the West with the most common IgHV genes being IgHV3-23, IgHV3-7, and IgHV3-48. In terms of IgHV gene mutational status, 63.8% of patients carried mutated rearrangements, whereas 22.4% of patients were assigned to stereotyped subsets (6.9% to major subsets and 15.5% to minor ones). The frequencies of NOTCH1, SF3B1, BIRC3 and MYD88 mutations were 9.6%, 7.2%, 1.2%, and 2.4%, respectively; however, the frequency of TP53 mutations was significantly higher (20.5%). Patients with TP53 mutations or del(17p), SF3B1 mutations and unmutated IgHV had a worse outcome compared to the other patients. In conclusion, the differences observed in IgHV properties suggest different pathogenetic factors implicated in the development of chronic lymphocytic leukemia, while the high frequency of TP53 mutations could in part explain the dismal outcome of these patients in Taiwan