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.

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.

Appropriateness of the anxiety subscale of the Hospital Anxiety and Depression Scale for Koreans to measure preoperative anxiety and the effect of preoperative anxiety on postoperative quality of recovery.

BACKGROUND: The reliability and validity of the anxiety subscale of the Hospital Anxiety and Depression Scale for Koreans (K-HADS-A) has not been studied in Korean surgical patients. This study aimed to validate the usefulness of K-HADS-A for measuring preoperative anxiety in Korean surgical patients. Additionally, the effect of preoperative anxiety on postoperative quality of recovery was evaluated. METHODS: Preoperative anxiety in 126 inpatients with planned elective surgery was measured using the K-HADS-A. The postoperative quality of recovery was measured using the Korean version of the Quality of Recovery-15. The validity and reliability of the K-HADS-A were evaluated. The differences in quality of recovery on the first and seventh day postoperatively were then compared between the anxious and non-anxious groups. RESULTS: There was a statistical correlation between the K-HADS-A and Anxiety Likert Scale. The goodness-of-fit indices of the structural equation model showed how well the data from the K-HADS-A match their concept. The Kaiser-Meyer-Olkin value was 0.848, and the P value of Bartlett's test of sphericity was < 0.001. Cronbach's alpha was high at 0.872. The K-HADS-A had an acceptable level of validity and reliability. Postoperative quality of recovery was significantly lower in the anxious group (postoperative day 1: t = 2.058, P = 0.042; postoperative day 7: t = 3.430, P = 0.002). CONCLUSIONS: The K-HADS-A is an acceptable tool for appropriately assessing preoperative anxiety in Korean surgical patients. Assessing preoperative anxiety is valuable, because preoperative anxiety affects the postoperative quality of mental and physical recovery.

Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in acute myeloid leukemia.

Vitamin C has been demonstrated to regulate hematopoietic stem cell frequencies and leukemogenesis by augmenting and restoring Ten-Eleven Translocation-2 (TET2) function, potentially acting as a promising adjunctive therapeutic agent for leukemia. However, glucose transporter 3 (GLUT3) deficiency in acute myeloid leukemia (AML) impedes vitamin C uptake and abolishes the clinical benefit of vitamin C. In this study, we aimed to investigate the therapeutic value of GLUT3 restoration in AML. In vitro GLUT3 restoration was conducted with the transduction of GLUT3-overexpressing lentivirus or the pharmacological salvage with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) treatment to OCI-AML3, a naturally GLUT3-deficient AML cell line. The effects of GLUT3 salvage were further confirmed in patient-derived primary AML cells. Upregulation of GLUT3 expression made AML cells successfully augment TET2 activity and enhanced the vitamin C-induced anti-leukemic effect. Pharmacological GLUT3 salvage has the potential to overcome GLUT3 deficiency in AML and improves the antileukemic effect of vitamin C treatments.

The effects of the administration sequence and the type of hypnotics on the development of remifentanil-induced chest wall rigidity: a randomized controlled trial.

BACKGROUND: Research on remifentanil-induced chest wall rigidity is limited. Furthermore, its incidence is unknown, and the clinical factors influencing its development remain unclear. This prospective, double-blind, randomized controlled trial aimed to investigate the effects of the administration sequence of hypnotics and remifentanil as well as the type of hypnotic administered on the development of remifentanil-induced chest wall rigidity. METHODS: A total of 125 older patients aged [Formula: see text] 65 years, who were scheduled to undergo elective surgery under general anesthesia, were enrolled in this study. Participants were randomly assigned to one of four groups; Thio-Remi, Pro-Remi, Remi-Thio, or Remi-Pro. After confirming the loss of consciousness and achieving a target effect-site concentration of 3 ng/mL remifentanil, the development of remifentanil-induced chest wall rigidity was evaluated. RESULTS: The incidence of chest wall rigidity was significantly higher in the remifentanil-hypnotic group than in the hypnotic-remifentanil (opposite sequence) group (55.0% vs. 21.7%, P < 0.001). Logistic regression analysis revealed that remifentanil-hypnotic administration was a significant predictor of the development of chest wall rigidity (crude odds ratio 4.42, 95% confidence interval 1.99; 9.81, P < 0.001). CONCLUSIONS: Pretreatment with hypnotics potentially reduces the development of chest wall rigidity during the induction of balanced anesthesia with remifentanil in older patients. TRIAL REGISTRATION: This article was registered at WHO International Clinical Trials Registry Platform (Trial number: KCT0006542).

Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation.

BACKGROUND: Although most patients with diffuse large B-cell lymphoma (DLBCL) achieve complete remission after first-line rituximab-containing immunochemotherapy, up to 40% of patients relapse and require salvage therapy. Among those patients, a substantial proportion remain refractory to salvage therapy due to insufficient efficacy or intolerance of toxicities. A hypomethylating agent, 5-azacytidine, showed a chemosensitizing effect when primed before chemotherapy in lymphoma cell lines and newly diagnosed DLBCL patients. However, its potential to improve outcomes of salvage chemotherapy in DLBCL has not been investigated. RESULTS: In this study, we demonstrated the mechanism of 5-azacytidine priming as a chemosensitizer in a platinum-based salvage regimen. This chemosensitizing effect was associated with endogenous retrovirus (ERV)-induced viral mimicry responses via the cGAS-STING axis. We found deficiency of cGAS impaired the chemosensitizing effect of 5-azacytidine. Furthermore, combining vitamin C and 5-azacytidine to synergistically activate STING could be a potential remedy for insufficient priming induced by 5-azacytidine alone. CONCLUSIONS: Taken together, the chemosensitizing effect of 5-azacytidine could be exploited to overcome the limitations of the current platinum-containing salvage chemotherapy in DLBCL and the status of cGAS-STING has the potential to predict the efficacy of 5-azacytidine priming.

Rapid MRI Abdomen for Assessment of Clinically Suspected Acute Appendicitis in the General Adult Population: a Systematic Review.

OBJECTIVES: To perform a systematic review on the use of magnetic resonance imaging (MRI) of the abdomen to evaluate clinically suspected appendicitis in the general adult population. We examined the diagnostic accuracy, the reported trends of MRI use, and the factors that affect the utility of MRI abdomen, including study duration and cost-benefits. METHODS: We conducted a systematic literature search on PubMed, MEDLINE, Embase, Web of Science, and Cochrane Library databases. We enrolled primary studies investigating the use of MRI in diagnosing appendicitis in the general adult population, excluding studies that predominantly reported on populations not representative of typical adult appendicitis presentations, such as those focusing on paediatric or pregnant populations. RESULTS: Twenty-seven eligible primary studies and 6 secondary studies were included, totaling 2,044 patients from eight countries. The sensitivity and specificity of MRI for diagnosing appendicitis were 96% (95% CI: 93-97%) and 93% (95% CI: 80-98%), respectively. MRI can identify complicated appendicitis and accurately propose alternative diagnoses. The duration of MRI protocols in each primary study ranged between 2.26 and 30 minutes, and only one study used intravenous contrast agents in addition to the non-contrast sequences. Decision analysis suggests significant benefits for replacing computed tomography (CT) with MRI and a potential for cost reduction. Reported trends in MRI usage showed minimal utilisation in diagnostic settings even when MRI was available. CONCLUSIONS: MRI accurately diagnoses appendicitis in the general adult population and improves the identification of complicated appendicitis or alternative diagnoses compared to other modalities using a single, rapid investigation.

Prognostic circulating proteomic biomarkers in colorectal liver metastases.

The liver is the most common site of metastasis in colorectal cancer. Multimodal treatment, including liver resection, is potentially curative and prolongs survival for selected patients with colorectal liver metastases (CRLM). However, the treatment of CRLM remains challenging because recurrence is common, and prognosis varies widely between patients despite curative-intent treatment. Clinicopathological features and tissue-based molecular biomarkers, either alone or in combination, are insufficient for accurate prognostication. As most of the functional information in cells resides in the proteome, circulating proteomic biomarkers may be useful for rationalising the molecular complexities of CRLM and identifying potentially prognostic molecular subtypes. High-throughput proteomics has accelerated a range of applications including protein profiling of liquid biopsies for biomarker discovery. Moreover, these proteomic biomarkers may provide non-invasive prognostic information even before CRLM resection. This review evaluates recently discovered circulating proteomic biomarkers in CRLM. We also highlight some of the challenges and opportunities with translating these discoveries into clinical applications.

Identification of Fusobacterium Species Using Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry by Updating ASTA CoreDB.

PURPOSE: Fusobacterium species can cause infections, and associations with cancer are being increasingly reported. As their clinical significance differs, accurate identification of individual species is important. However, matrix-assisted laser desorption/ionization-time of flight mass spectrometry has not been found to be effective in identifying Fusobacterium species in previous studies. In this study, we aimed to improve the accuracy and efficacy of identifying Fusobacterium species in clinical laboratories. MATERIALS AND METHODS: In total, 229 Fusobacterium isolates were included in this study. All isolates were identified at the species level based on nucleotide sequences of the 16S ribosomal RNA gene and/or DNA-dependent RNA polymerase ß-subunit gene (rpoB). Where necessary, isolates were identified based on whole genome sequences. Among them, 47 isolates were used for updating the ASTA database, and 182 isolates were used for the validation of Fusobacterium spp. identification. RESULTS: Fusobacterium isolates used for validation (182/182) were correctly identified at the genus level, and most (180/182) were correctly identified at the species level using the ASTA MicroIDSys system. Most of the F. nucleatum isolates (74/75) were correctly identified at the subspecies level. CONCLUSION: The updated ASTA MicroIDSys system can identify nine species of Fusobacterium and four subspecies of F. nucleatum in good agreement. This tool can be routinely used in clinical microbiology laboratories to identify Fusobacterium species and serve as a springboard for future research.

Expansion of Human Megakaryocyte-Lineage Progeny via Aryl Hydrocarbon Receptor Antagonism with CH223191.

Aryl hydrocarbon receptor (AhR) antagonism is known to expand human hematopoietic stem cells (HSCs). However, its regulatory effect on the lineage-skewed differentiation of HSCs has not been sufficiently studied. Here, we investigate the effect of the AhR-selective antagonist CH223191 on the regulation of HSC differentiation. Consistent with the well-known effects of AhR antagonists, CH223191 treatment increase phenotypic HSCs (Lin-CD34 + CD38-CD90 + CD45RA-) and preserves their functionality. On the other hand, CH223191 leads to an overall expansion of megakaryocyte (MK)-lineage populations, such as MK progenitors (MKps, CD34 + CD41 +), immature MKs (CD41 + CD42b-), and mature MKs (CD41 + CD42b +), and it also activates MK/platelet-associated signaling pathways. Furthermore, CH223191 expands MKps, mature MKs, and p-selectin (CD62p)-positive platelet-like particles in immune thrombocytopenia (ITP) patient bone marrow (BM). These results highlight the numerical expansion of human MK-lineage progeny through AhR antagonism with CH223191. This approach using CH2231291 may be applicable in the development of auxiliary treatment regimens for patients with abnormal thrombopoiesis.

A case report of malignant hyperthermia in a patient with myotonic dystrophy type I: A CARE-compliant article.

RATIONALE: Several hereditary myopathies that can predispose to malignant hyperthermia (MH) are reported. However, the risk of MH in myotonic dystrophy type I (DM1) has been suggested equal to general population, although the evidence is limited to only a few case reports. PATIENT CONCERNS: We encountered a rare case of MH during anesthesia induction with sevoflurane in a male adolescent with previously undiagnosed DM1. DIAGNOSES: After the event, genetic testing revealed the presence of a previously unknown heterozygous missense mutation in ryanodine receptor 1 (RYR1) associated with MH (c.6898T > C; p.ser2300Pro). Concomitantly, the patient was diagnosed with DM1 with abnormal cytosine-thymine-guanine triplet expansion in the DMPK gene. INTERVENTIONS: Dantrolene was administered to treat the hypermetabolic manifestations in 20 minutes after the identification of MH. OUTCOMES: The patient was successfully treated and discharged without any complications. Laboratory abnormalities were recovered to baseline at postoperative 4 days. LESSONS: The authors suggest that possible MH susceptibility in DM1 patients may be refocused. Genetic testing can be a screening tool for MH susceptibility in these population, prior to receiving general anesthesia.

Validity and reliability of the Korean version of the Quality of Recovery-15 questionnaire.

BACKGROUND: The quality of recovery-40 questionnaire (QoR-40) has been widely used to assess quality of recovery after surgery, but it is too lengthy for clinical use. The short form of QoR-40, QoR-15, has been validated in many languages; however, an official Korean version of the QoR-15 (QoR-15K) has not yet been established. This study aimed to develop and validate QoR-15K. METHODS: Based on the previously-validated Korean QoR-40, we selected 15 items; the QoR-15K was patterned on the original QoR-15. We analyzed 210 subjects who had been scheduled for elective surgery under general anesthesia. The patients completed the questionnaire before surgery and on postoperative days one and two. The validity, reliability, and responsiveness of the QoR-15K were evaluated. RESULTS: We obtained excellent convergent validity on visual analog scale for recovery (ρ = 0.882, P < 0.001). The duration of anesthesia, post-anesthesia care unit, and overall hospital stay with the QoR-15K showed a significant negative correlation (ρ = -0.183, -0.151, and -0.185, respectively). Cronbach's α was 0.909. Cohen's effect size and standardized response mean were 0.819 and 0.721. The recruitment and completion rate were 92.9% and 100%, respectively. We based the above calculations on the results obtained on the first day following surgery. CONCLUSIONS: The validity and reliability of the QoR-15K are comparable to those of the English version. The QoR-15K would be a good instrument to assess the quality of recovery in Korean patients after surgery.

Potential of MALDI-TOF-based serum N-glycan analysis for the diagnosis and surveillance of breast cancer.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based serum N-glycan analysis has gained acknowledgment for the diagnosis of breast cancer in recent years. In this study, the possibilities of expanding its application for breast cancer management and surveillance were discovered and evaluated. First, a novel MALDI-TOF platform, IDsys RT, was confirmed to be effective for breast cancer analysis, showing a maximum area under the curve of 0.91. Multiple N-glycan markers were identified and validated using this process, and they were found to be applicable for differentiating recurring breast cancer samples from healthy control or ordinary breast cancer samples. Recurrence samples were especially distinct from non-recurrence samples when N-glycan signatures were sampled in multiple time points and monitored via MALDI-TOF, throughout the therapy. These results suggested the feasibility of MALDI-TOF-based N-glycan analysis for tracking the molecular signatures of breast cancer and predicting recurrence.

Single-cell analysis of AIMP2 splice variants informs on drug sensitivity and prognosis in hematologic cancer.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a non-enzymatic component required for the multi-tRNA synthetase complex. While exon 2 skipping alternatively spliced variant of AIMP2 (AIMP2-DX2) compromises AIMP2 activity and is associated with carcinogenesis, its clinical potential awaits further validation. Here, we found that AIMP2-DX2/AIMP2 expression ratio is strongly correlated with major cancer signaling pathways and poor prognosis, particularly in acute myeloid leukemia (AML). Analysis of a clinical patient cohort revealed that AIMP2-DX2 positive AML patients show decreased overall survival and progression-free survival. We also developed targeted RNA-sequencing and single-molecule RNA-FISH tools to quantitatively analyze AIMP2-DX2/AIMP2 ratios at the single-cell level. By subclassifying hematologic cancer cells based on their AIMP2-DX2/AIMP2 ratios, we found that downregulating AIMP2-DX2 sensitizes cells to anticancer drugs only for a subgroup of cells while it has adverse effects on others. Collectively, our study establishes AIMP2-DX2 as a potential biomarker and a therapeutic target for hematologic cancer.

Induction of leukemic stem cell differentiation by aryl hydrocarbon receptor agonist and synergy with gilteritinib in FLT3-ITD + acute myeloid leukemia.

Leukemic stem cells (LSCs) are a major cause of treatment failure and recurrence of acute myeloid leukemia (AML). Targeting LSC is essential to developing a potential cure for patients with relapsed/refractory AML. Here we investigated the effect of aryl hydrocarbon receptor (AhR) signaling on AML stem/progenitor proportion and examined the combined effect of AhR agonist and tyrosine kinase inhibitor. The AhR agonist, 6-formylindolo[3,2-b]carbazole (FICZ), significantly decreased the LSC proportion and clonogenicity and increased differentiation markers in AML primary cells. Synergistic/additive effects of FICZ and gilteritinib, FMS-like tyrosine kinase 3 (FLT3) inhibitor, were confirmed in AML cells with FLT3-ITD. We present evidence that combination of both agents inhibits FLT3 downstream molecules and degrades clonogenicity. Collectively, our results suggest that FICZ not only compels LSC differentiation, but also enhances the efficacy of gilteritinib when combined. Clinical application of this combined approach may pave a new therapeutic strategy for patients with FLT3 mutated AML.

Breast cancer diagnosis by analysis of serum N-glycans using MALDI-TOF mass spectroscopy.

Blood and serum N-glycans can be used as markers for cancer diagnosis, as alterations in protein glycosylation are associated with cancer pathogenesis and progression. We aimed to develop a platform for breast cancer (BrC) diagnosis based on serum N-glycan profiles using MALDI-TOF mass spectroscopy. Serum N-glycans from BrC patients and healthy volunteers were evaluated using NosQuest's software "NosIDsys." BrC-associated "NosID" N-glycan biomarkers were selected based on abundance and NosIDsys analysis, and their diagnostic potential was determined using NosIDsys and receiver operating characteristic curves. Results showed an efficient pattern recognition of invasive ductal carcinoma patients, with very high diagnostic performance [area under the curve (AUC): 0.93 and 95% confidence interval (CI): 0.917-0.947]. We achieved effective stage-specific differentiation of BrC patients from healthy controls with 82.3% specificity, 84.1% sensitivity, and 82.8% accuracy for stage 1 BrC and recognized hormone receptor-2 and lymph node invasion subtypes based on N-glycan profiles. Our novel technique supplements conventional diagnostic strategies for BrC detection and can be developed as an independent platform for BrC screening.