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Clinical Case Reports May 2024In a patient with de novo AML, co-existing isoform and rearrangement is accompanied by a very poor prognosis including limited response to treatment and no molecular...
KEY CLINICAL MESSAGE
In a patient with de novo AML, co-existing isoform and rearrangement is accompanied by a very poor prognosis including limited response to treatment and no molecular remission. It is essential to develop a consensus on the therapeutic modalities different from the current regimen.
ABSTRACT
Acquisition of fusion as a primary or secondary event and fusion independently is reported in de novo and therapy-related MDS/AML, albeit with low frequency (<0.5%). Coexistence of and translocation is known to cause leukemogenesis in animal models and progression towards blast crisis CML but not AML. Here we report a unique case of pediatric AML with concomitant BCR::ABL1 and RUNX1::MECOM fusion.Routine diagnostic work-up included WBC manual differential, immunophenotype, morphology, qPCR, FISH, and NGS-based CNV analyses. The patient presented with history of fever, dizziness, fatigue, gingival bleeding, and epistaxis associated with ecchymosis in right hand and heavy, prolonged menstrual period. At presentation, her hemoglobin was 5.3 g/dL, WBC 52.1(10*9/L), PLT 10(10*9/L), ESR 5 mm/h and LDH 2658 U/L. Bone marrow was hypercellular with 71% blasts, and flow cytometry showed myeloid markers including CD11c, CD33, CD34, and CD45 among others indicating AML with monocytic differentiation. FISH analyses showed variant t(9;22) (q34.1;q11.1), one additional copy each of chromosome 8 and gene, while NGS-based CNV analyses revealed a terminal and proximal pathogenic gain within 9q34.12q34.3 and 22q11.1q11.23, respectively, and gain of entire chromosome 8 and 12 in mosaic state. qPCR confirmed the presence of and also revealed fusion. Patient received ADE (cytarabine, daunorubicin, and etoposide) induction regimen but required multiple ICU admissions due to sepsis, cardiac shock, acute myocarditis, and thyroiditis. Coexisting and fusion is suggestive of poor prognosis, and a need for consensus on the treatment modalities other than the current regimen is warranted.
PubMed: 38751957
DOI: 10.1002/ccr3.8917 -
BMC Molecular and Cell Biology May 2024Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in...
BACKGROUND
Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure.
MATERIALS AND METHODS
AC16 cells were treated with 2 µmol/L of doxorubicin (DOX) for 12, 24, and 48 h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry.
RESULTS
Increased DUOX1 expression levels were observed after DOX treatment for 24 h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1β, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1β, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors.
CONCLUSION
These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.
Topics: Pyroptosis; Heart Failure; Oxidative Stress; Dual Oxidases; Reactive Oxygen Species; Humans; Doxorubicin; Caspase 1; Up-Regulation; Cell Line; Interleukin-18; Interleukin-1beta
PubMed: 38750444
DOI: 10.1186/s12860-024-00506-8 -
International Heart Journal May 2024Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the...
Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.
Topics: Doxorubicin; Animals; Fibrosis; Mice; Single-Cell Analysis; Cardiotoxicity; Myocardium; Antibiotics, Antineoplastic; Disease Models, Animal; Fibroblasts; Gene Expression Profiling; Transcriptome; Male; Myofibroblasts; Mice, Inbred C57BL
PubMed: 38749755
DOI: 10.1536/ihj.23-302 -
Journal of Investigative Medicine High... 2024Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease...
Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease has non-specific clinical manifestations, making early diagnosis crucial. However, DLBCL diagnosis is commonly delayed, and its prognosis is typically poor. Herein, we report the case of a 51-year-old male patient with DLBCL who presented with recurrent chest tightness for 4 months as the primary clinical symptom. The patient was admitted to the hospital and diagnosed with acute myocardial infarction and left ventricular hypertrophy with heart failure. Echocardiography revealed a progression from left ventricular thickening to local pericardial thickening and adhesion in the inferior and lateral walls of the left ventricle. Finally, pathological analysis of myocardial biopsy confirmed the diagnosis of DLBCL. After treatment with the R-CHOP chemotherapy regimen, the patient's chest tightness improved, and he was discharged. After 2 months, the patient succumbed to death owing to sudden ventricular tachycardia, ventricular fibrillation, and decreased blood pressure despite rescue efforts. Transthoracic echocardiography is inevitable for the early diagnosis of DLBCL, as it can narrow the differential and guide further investigations and interventions, thereby improving the survival of these patients.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Heart Neoplasms; Myocardial Infarction; Echocardiography; Fatal Outcome; Antineoplastic Combined Chemotherapy Protocols; Hypertrophy, Left Ventricular; Vincristine; Doxorubicin; Rituximab; Cyclophosphamide; Prednisone
PubMed: 38747509
DOI: 10.1177/23247096241253334 -
Acta Oncologica (Stockholm, Sweden) May 2024Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients.
METHODS
Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications.
RESULTS
Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low.
INTERPRETATION
Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.
Topics: Humans; Male; Adenocarcinoma; Esophageal Neoplasms; Female; Middle Aged; Aged; Oxaliplatin; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Docetaxel; Stomach Neoplasms; Fluorouracil; Leucovorin; Epirubicin; Adult; Cisplatin; Aged, 80 and over; Perioperative Care; Esophagogastric Junction
PubMed: 38745482
DOI: 10.2340/1651-226X.2024.35431 -
Blood Science (Baltimore, Md.) Apr 2024An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we...
An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.
PubMed: 38742239
DOI: 10.1097/BS9.0000000000000189 -
The Journal of Medical Investigation :... 2024The Common Terminology Criteria for Adverse Events (CTCAE) is used as a tool to evaluate the adverse events (AE) of chemotherapy in cancer patients. Since CTCAE by...
BACKGROUND
The Common Terminology Criteria for Adverse Events (CTCAE) is used as a tool to evaluate the adverse events (AE) of chemotherapy in cancer patients. Since CTCAE by medical providers underestimates AE more than patient-reported outcomes (PRO), the National Cancer Institute developed PRO-CTCAE. The present study investigated differences between symptoms detected using CTCAE by medical providers and PRO-CTCAE by breast cancer patients.
METHODS
Patients received chemotherapy comprising epirubicin and cyclophosphamide pre- or postoperatively. AE were evaluated using 4 questionnaires:PRO-CTCAE, CTCAE, the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ-30), and Hospital Anxiety and Depression Scale (HADS) after 1, 2, and 3 courses of chemotherapy.
RESULTS
Forty-two patients were registered. Regarding the recognition of psychological symptoms, such as fatigue, anxiety, and discouragement, and subjective symptoms, including heart palpitations and shortness of breath, PRO using PRO-CTCAE was significantly higher than medical provider-recognized outcomes using CTCAE. Concerning the recognition of regimen-specific symptoms, such as vomiting, nausea, and decreased appetite, medical provider- recognized outcomes were the same or higher than PRO. In QLQ-C30, the physical and role functions, fatigue and dyspnea significantly worsened after 2 and 3 courses of chemotherapy. J. Med. Invest. 71 : 82-91, February, 2024.
Topics: Humans; Breast Neoplasms; Female; Middle Aged; Quality of Life; Adult; Aged; Surveys and Questionnaires; Epirubicin; Patient Reported Outcome Measures; Cyclophosphamide; Antineoplastic Agents
PubMed: 38735729
DOI: 10.2152/jmi.71.82 -
Cell Death & Disease May 2024We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily...
We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34 hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.
Topics: Animals; Humans; Liposomes; Mice; Xenograft Model Antitumor Assays; Cell Death; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Cell Line, Tumor; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38734740
DOI: 10.1038/s41419-024-06715-5 -
BMC Complementary Medicine and Therapies May 2024Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of...
Cepharanthine synergistically promotes methylprednisolone pharmacodynamics against human peripheral blood mononuclear cells possibly via regulation of P-glycoprotein/glucocorticoid receptor translocation.
BACKGROUND
Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of the main active components of Cepharanthin. The purpose of this study was to investigate the effects of CEP on GC pharmacodynamics on immune cells and analyse the possible action mechanism of their interactions.
METHODS
Peripheral blood mononuclear cells (PBMCs), T lymphocytic leukemia MOLT-4 cells and daunorubicin resistant MOLT-4 cells (MOLT-4/DNR) were used to evaluate the pharmacodynamics and molecular mechanisms. Drug pharmacodynamics was evaluated by WST-8 assay. P-glycoprotein function was examined by rhodamine 123 assay. CD4CD25Foxp3 regulatory T cells and Th1/Th2/Th17 cytokines were detected by flow cytometry. P-glycoprotein expression and GC receptor translocation were examined by Western blot.
RESULTS
CEP synergistically increased methylprednisolone (MP) efficacy with the suppressive effect on the cell viability of PBMCs. 0.3 and 1 μM of CEP significantly inhibited P-glycoprotein efflux function of CD4 cells, CD8 cells, and lymphocytes (P<0.05). 0.03~3 μM of CEP also inhibited the P-glycoprotein efflux function in MOLT-4/DNR cells in a concentration-dependent manner (P<0.001). However, 0.03~3 μM of CEP did not influence P-glycoprotein expression. 0.03~0.3 μM of CEP significantly increased the GC receptor distribution from the cytoplasm to the nucleus in a concentration-dependent manner in MOLT-4/DNR cells. The combination did not influence the frequency of CD4, CD4CD25 and CD4CD25Foxp3 T cells or the secretion of Th1/Th2/Th17 cytokines from PBMCs. In contrast, CEP alone at 1 μM decreased the percentage of CD4 T cell significantly (P<0.01). It also inhibited the secretion of IL-6, IL-10, IL-17, TNF-α, and IFN-γ.
CONCLUSIONS
CEP synergistically promoted MP pharmacodynamics to decrease the cell viability of the mitogen-activated PBMCs, possibly via inhibiting P-glycoprotein function and potentiating GC receptor translocation. The present study provides new evidence of the therapeutic effect of Cepharanthin alone or in combination with GC for the management of chronic ITP.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Benzylisoquinolines; Drug Synergism; Leukocytes, Mononuclear; Methylprednisolone; Receptors, Glucocorticoid
PubMed: 38734604
DOI: 10.1186/s12906-024-04489-z -
International Journal of Molecular... May 2024Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly...
Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.
Topics: Animals; Chemokine CCL2; Podocytes; Doxorubicin; Angiotensin II; Mice; Mice, Knockout; Male; Renal Insufficiency, Chronic; Gene Deletion; Disease Models, Animal
PubMed: 38732210
DOI: 10.3390/ijms25094987