Gene Expression and DNA Methylation Profiling Suggest Potential Biomarkers for Azacitidine Resistance in Myelodysplastic Syndrome.

Myelodysplastic syndrome/neoplasm (MDS) comprises a group of heterogeneous hematopoietic disorders that present with genetic mutations and/or cytogenetic changes and, in the advanced stage, exhibit wide-ranging gene hypermethylation. Patients with higher-risk MDS are typically treated with repeated cycles of hypomethylating agents, such as azacitidine. However, some patients fail to respond to this therapy, and fewer than 50% show hematologic improvement. In this context, we focused on the potential use of epigenetic data in clinical management to aid in diagnostic and therapeutic decision-making. First, we used the F-36P MDS cell line to establish an azacitidine-resistant F-36P cell line. We performed expression profiling of azacitidine-resistant and parental F-36P cells and used biological and bioinformatics approaches to analyze candidate azacitidine-resistance-related genes and pathways. Eighty candidate genes were identified and found to encode proteins previously linked to cancer, chronic myeloid leukemia, and transcriptional misregulation in cancer. Interestingly, 24 of the candidate genes had promoter methylation patterns that were inversely correlated with azacitidine resistance, suggesting that DNA methylation status may contribute to azacitidine resistance. In particular, the DNA methylation status and/or mRNA expression levels of the four genes (AMER1, HSPA2, NCX1, and TNFRSF10C) may contribute to the clinical effects of azacitidine in MDS. Our study provides information on azacitidine resistance diagnostic genes in MDS patients, which can be of great help in monitoring the effectiveness of treatment in progressing azacitidine treatment for newly diagnosed MDS patients.

Genetic risk factors for bortezomib-induced neuropathic pain in an Asian population: A genome-wide association study in South Korea.

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP development in Korean MM patients, while evaluating reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BINP. GWAS was performed on the discovery cohort (n=74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 SNPs). Relevant biological pathways were identified using pathway scoring algorithm (PASCAL). The top 20 SNPs were validated in the validation cohort (n=111). Previously reported SNPs were validated in the entire cohort (n=185). Pathway analysis of the GWAS results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among top 20 SNPs from discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long non-coding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, p=0.085). This study represents the first investigation of novel genetic loci and biological pathways associated with BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PERSPECTIVE: This article is the first to explore novel genetic loci and pathways linked to bortezomib-induced neuropathic pain (BINP) in Korean multiple myeloma patients, offering novel insights beyond the existing research focused on Caucasian populations, into personalized risk assessment and therapeutic strategies of BINP.

Pursuing dynamics of minimal residual leukemic subclones in relapsed and refractory acute myeloid leukemia during conventional therapy.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. METHOD: Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. RESULTS: Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. CONCLUSIONS: In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones.

Risk factors for resistant gram-positive bacteremia in febrile neutropenic patients with cancer.

BACKGROUND: Gram-positive bacteria are frequently resistant to empirical beta-lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer. METHODS: Episodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia. RESULTS: Of 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 6.794; 95% confidence interval [95% CI], 3.130-14.749; P < 0.001) and catheter-related infection (aOR 4.039, 95% CI 1.366-11.946; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.231, 95% CI 0.059-0.905; P = 0.035) and hypotension at bacteremia (aOR 0.454, 95% CI 0.218-0.945; P = 0.035) were inversely associated with resistant Gram-positive bacteremia. CONCLUSIONS: Resistant Gram-positive bacteria should be considered in breakthrough bacteremia and catheter-related infection in febrile neutropenic patients with cancer.

Treatment outcomes and prognostic factors of patients with lymphoblastic lymphoma in East Asia.

Lymphoblastic lymphoma (LBL) is a rare, aggressive non-Hodgkin lymphoma (NHL) that has no established therapeutic approaches. The aim of this study was to investigate optimal treatments and prognostic risk models for patients with LBL in East Asia. We retrospectively examined the clinical data and treatment courses of adult patients diagnosed as LBL by WHO 2017 classification system. Median overall survival (OS) of the 78 patients with LBL was 38.3 months. There was no significant difference in OS between the patients who were treated with acute lymphoblastic leukemia (ALL)-like protocols and with NHL-like protocols (72.4 months vs 37.5 months, respectively, P = .546). The patients treated with ALL-like protocols had significantly shorter progression-free survival (PFS) (median 11.7 months for ALL-like protocols vs 27.0 months for NHL-like protocols, P = .030). A multivariable analysis found that central nervous system (CNS) prophylaxis, relapse of CNS lesions, leukemic transformation, and response to initial treatment were risk factors for OS of patients with LBL. Hematopoietic stem cell transplantation had no survival benefit, compared with chemotherapy-only treatment. Less intensive chemotherapy may be more optimal for patients in East Asia. Prophylaxis and management of CNS lesions should be emphasized throughout the treatment of LBL.

Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma.

Osteolytic bone lesion is a major cause of decreased quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306 and 52 patients with MM, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in bone marrow-derived plasma and found to be significantly elevated in MM than in AML or ALL that rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling, and nuclear translocation of ß-catenin. These results collectively show that FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of osteolytic process in MM with hyperdiploidy.

Clinical characteristics and treatment outcomes of Asian patients with T-cell large granular lymphocytic Leukemia: a single-center analysis of 67 cases.

Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of LGLs derived from cytotoxic T lymphocytes or natural killer cells. However, the clinical features and treatment responses are still not fully understood because of the rarity of the disease. To describe and assess a cohort of patients with T-cell large granular lymphocytic leukemia (T-LGLL). Single-center, retrospective, observational study. We retrospectively collected the clinical data of patients diagnosed with T-LGLL at Seoul National University Hospital since 2006. We included 67 patients in this study. The median age at diagnosis was 60 years. Additionally, 37 patients (55%) were symptomatic, and 25 (37%) had splenomegaly; 54 patients (81%) required treatment. Cyclophosphamide (n = 35), methotrexate (n = 25), and cyclosporin A (n = 19) were used most frequently for treatment, and their overall response rates were similar: cyclophosphamide (77%), methotrexate (64%), and cyclosporin A (63%). Splenomegaly was associated with an increased response rate to first-line therapy and a decreased complete response rate. Thrombocytopenia was associated with decreased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. In contrast, a high LGL number (> 2000/µL) in the peripheral blood smear was associated with increased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. This study describes the clinical features and treatment outcomes of patients with T-LGLL, providing valuable information for clinical decision-making regarding T-LGLL treatment.

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

Effects of tertiary palliative care on the pattern of end-of-life care in patients with hematologic malignancies in Korea.

INTRODUCTION: Patients with hematologic malignancies (HMs) often face challenges in accessing palliative care (PC) and receiving quality end-of-life (EOL) care. We examined factors associated with referrals to tertiary PC and the effects of tertiary PC on EOL care in patients with HMs. METHOD: We included patients with HMs who were admitted to a university-affiliated hospital and died during hospitalization between January 2018 and December 2021. We investigated the receipt of PC consultations, patient characteristics, and EOL care indicators. RESULTS: Overall, 487 patients were included in the analysis, with 156 (32%) undergoing PC consultation. Sex, residence, disease status, and admission purpose were factors associated with the likelihood of PC consultation, and there has been an increasing trend in the frequency of consultations in recent cases. A higher proportion of patients who received PC completed advance statements and life-sustaining treatment documents. Patients who received PC had lower rates of aggressive EOL care, including chemotherapy and intensive care unit admission, than those who did not receive PC. Notably, PC reduced the number of blood transfusions. CONCLUSION: Tertiary PC aims to reduce aggressive EOL care through patient-centered goal-of-care discussions. Therefore, there is an imperative need for concerted efforts toward seamless integration of PC.

A Phase II Study of 131I-rituximab for Patients With Relapsed or Refractory Marginal Zone Lymphoma.

Background: Radioimmunotherapy (RIT) is a rare treatment option for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). We investigated the safety and efficacy of 131I-rituximab in patients with relapsed or refractory marginal zone lymphomas. Methods: Patients with pathologically confirmed marginal zone lymphoma who relapsed or were resistant to prior therapy were enrolled. The patients received 250 mg/m2 of unlabeled rituximab immediately before receiving a therapeutic 131I-rituximab dose. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were toxicity assessment, progression-free survival (PFS), and overall survival (OS). Results: Ten patients (median age = 57.5 years; range = 32-71) were included. Owing to poor enrollment, only 10 of the initially intended 25 patients were included in the study, rendering it unfeasible to perform the primary endpoint analysis. Before RIT, patients received chemotherapy, with 40% (n = 4) receiving rituximab therapy. Median PFS and OS were 18.9 months (95% confidence interval [CI]: 0.0-38.9) and 100.0 months (95% CI: 39.8-160.1), respectively. The ORR was 90%, and the duration of response was 29.7 months (95% CI: 0.0-61.3). Considering a median follow-up of 78.5 months (95% CI: 42.7-114.3), 4 patients (40%) were diagnosed with secondary malignancy. Hematological toxicities were common treatment-related adverse events, and 60% and 50% of the patients experienced grade 3 to 4 thrombocytopenia and neutropenia, respectively. Conclusions: 131I-rituximab showed marked efficacy in patients with relapsed or refractory marginal zone lymphoma, with a considerable risk of secondary malignancies during long-term follow-up. Radioimmunotherapy is not a recommended treatment option for relapsed or refractory marginal zone lymphoma but may be considered when other treatment options are not feasible.

A randomized phase II study of acyclovir for the prevention of chemotherapy-induced oral mucositis in patients undergoing autologous hematopoietic stem cell transplantation.

OBJECTIVES: To prove our hypothesis that acyclovir prophylaxis in autologous hematopoietic stem cell transplantation (AHSCT) recipients with hematologic malignancies (HM) reduces the incidence of chemotherapy-induced oral mucositis (CIOM) by inhibiting the intraoral HSV reactivation during the neutropenic period, we conducted a randomized phase II study of acyclovir for the prevention of CIOM in adult HSV sero-positive AHSCT recipients. METHODS: Patients were randomized to either the study group (acyclovir 400 mg PO bid until neutrophil engraftment) or the control group (no prophylaxis) and received AHSCT. Oral examination and sampling for HSV were performed at three timepoints of AHSCT. RESULTS: In 54 patients who were randomized (for intention-to-analysis), the incidence of CIOM was 16.0% (4/25 patients) and 58.6% (17/29 patients) in the study group and the control group, respectively (P = 0.001). In 49 patients who completed the study (for per-protocol analysis), the incidence of CIOM was 13.0% (3/23 patients) and 61.5% (16/26 patients) in the study group and the control group, respectively (P = 0.001). In addition, HSV-1 PCR positivity in the study group was significantly lower than that the control group (4.3% vs. 46.2%, P = 0.001). A strong association between the HSV-1 reactivation status and CIOM was reconfirmed. CONCLUSIONS: Prophylactic use of oral acyclovir effectively reduced the incidence of CIOM in patients with HM who were undergoing AHSCT. TRIAL REGISTRATIONS: This trial was registered at the Clinical Research Information Service in the Republic of Korea under the number KCT0003885 (registration date 03/05/2019).

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor.

Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design: This is a prospective, multicenter study. Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Conclusion: Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

Asymmetric anti-CLL-1×CD3 bispecific antibody, ABL602 2+1, with attenuated CD3 affinity endows potent antitumor activity but limited cytokine release.

BACKGROUND: Acute myeloid leukemia (AML) is a type of leukemia in adults with a high mortality rate and poor prognosis. Although targeted therapeutics, chemotherapy, and hematopoietic stem cell transplantation can improve the prognosis, the recurrence rate is still high, with a 5-year survival rate of approximately 40%. This study aimed to develop an IgG-based asymmetric bispecific antibody that targets CLL-1 and CD3 for treating AML. METHODS: ABL602 candidates were compared in terms of binding activity, T-cell activation, and tumor-killing activities. ABL602-mediated T-cell activation and tumor-killing activities were determined by measuring the expression of activation markers, cytokines, cytolytic proteins, and the proportion of dead cells. We evaluated in vivo tumor growth inhibitory activity in two mouse models bearing subcutaneously and orthotopically engrafted human AML. Direct tumor-killing activity and T-cell activation in patient-derived AML blasts were also evaluated. RESULTS: ABL602 2+1 showed a limited CD3 binding in the absence of CLL-1, suggesting that steric hindrance on the CD3 binding arm could reduce CLL-1 expression-independent CD3 binding. Although the CD3 binding activity was attenuated compared with that of 1+1, ABL602 2+1 exhibited much stronger T-cell activation and potent tumor-killing activities in AML cell lines. ABL602 2+1 efficiently inhibited tumor progression in subcutaneously and orthotopically engrafted AML mouse models. In the orthotopic mouse model, tumor growth inhibition was observed by gross measurement of luciferase activity, as well as a reduced proportion of AML blasts in the bone marrow, as determined by flow cytometry and immunohistochemistry (IHC) staining. ABL602 2+1 efficiently activated T cells and induced the lysis of AML blasts, even at very low effector:target (E:T) ratios (eg, 1:50). Compared with the reference 1+1 antibody, ABL602 did not induce the release of cytokines including interleukin-6 and tumor necrosis factor-α in the healthy donor-derived peripheral blood mononuclear cell. CONCLUSIONS: With its potent tumor-killing activity and reduced cytokine release, ABL602 2+1 is a promising candidate for treating patients with AML and warrants further study.

Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited.

INTRODUCTION: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein's DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML. CLINICAL IMPLICATIONS: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents. CONCLUSIONS: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.

Serum Erythropoietin level in anemia of elderly with unclear etiology.

Anemia is a common condition, but its causes are often unclear, especially in elderly adults. Erythropoietin (EPO) levels are known to be elevated in myelodysplastic syndrome and hematologic malignancies, but decreased in chronic benign anemia. This study aimed to investigate whether EPO levels could be used to identify underlying bone marrow diseases including malignancies, among elderly anemic patients with unclear etiology. This single centered retrospective study included patients presented with isolated anemia and had their EPO levels measured at their first visit. Patients were divided into two groups: bone marrow disease and benign etiologic anemia, based on observation and bone marrow test results. Out of 1180 patients reviewed, 81 patients with anemia of unclear etiology were identified, including 67 with benign anemia and 14 with bone marrow disease. Statistically significant difference in EPO levels between these two groups (P < 0.001) were observed. The receiver operating characteristic curve analysis showed that an EPO cut-off value of 36.4 mU/mL had a sensitivity and specificity of 92.8% and 94.0% for detecting underlying bone marrow disease, respectively. We suggest measuring serum EPO levels can aid in the early detection of benign anemia from bone marrow disease, including malignancies, with high sensitivity and specificity.

The Effect of the Mixed Extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai on the Improvement of Degenerative Osteoarthritis through Inflammation Inhibition in the Monosodium Iodoacetate-Induced Mouse Model.

Osteoarthritis is a chronic inflammatory disease, and, due to the lack of fundamental treatment, the main objective is to alleviate pain and prevent cartilage damage. Kalopanax pictus Nakai and Achyranthes japonica Nakai are herbal plants known for their excellent anti-inflammatory properties. The objective of this study is to confirm the potential of a mixture extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai as a functional raw material for improving osteoarthritis through anti-inflammatory effects in macrophages and MIA-induced arthritis experimental animals. In macrophages inflamed by lipopolysaccharide (LPS), treatment of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture inhibits NF-κB and mitogen-activated protein kinase (MAPK) activities, thereby inhibiting inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), inflammatory factors PGE2, MMP-2, and MMP-9, and nitric oxide (NO) was reduced. In addition, in an animal model of arthritis induced by MIA (monosodium iodoacetate), administration of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture reduced blood levels of inflammatory cytokines TNF-α and IL-6, inflammatory factors prostaglandin E2(PGE2), matrix metalloproteinase-2(MMP-2), and NO. Through these anti-inflammatory effects, MIA-induced pain reduction (recovery of clinical index, increase in weight bearing, and increase in area and width of the foot), recovery of meniscus damage, loss of cartilage tissue or inflammatory cells in tissue infiltration reduction, and recovery of the proteglycan layer were confirmed. Therefore, it is considered that Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture has the potential as a functional raw material that promotes joint health.

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis.

INTRODUCTION: This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. METHODS: This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). RESULTS: In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. CONCLUSION: The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.