Effects of goal-directed analgesia using the analgesia nociception index in children undergoing surgery for moyamoya disease: A randomised controlled trial.

BACKGROUND: The potential benefits of Analgesia Nociception Index guided intra-operative analgesia on intra-operative opioid consumption remains to be demonstrated in paediatric anaesthesia. OBJECTIVES: This study aimed to explore the effects of Analgesia Nociception Index guided analgesia on sufentanil consumption during anaesthesia and postoperative pain scores in paediatric patients with moyamoya disease. DESIGN: A prospective randomised controlled study. SETTING: Seoul National University Children's Hospital, Seoul, Republic of Korea. PATIENTS: A total of 40 children scheduled for encephaloduroarteriosynangiosis. MAIN OUTCOME MEASURES: The primary outcome was total intra-operative sufentanil consumption, and the secondary outcomes included postoperative pain scores and incidence of opioid-related adverse events. RESULTS: The Analgesia Nociception Index group showed lower intra-operative sufentanil consumption (in µg kg-1 h-1) compared with the Standard group (0.30 ±â€Š0.12 and 0.39 ±â€Š0.17, respectively; mean difference, -0.09; 95% confidence interval, -0.19 to 0.00; P = 0.049). Postoperatively, compared with the Standard group, the Analgesia Nociception Index group reported lower median pain scores at 18 and 24 h and maximum pain within 24 h (1 [0 to 2] vs. 3 [2 to 5]; P = 0.004, 1 [0 to 2] vs. 3 [1 to 4]; P = 0.041, and 4 [3 to 5] vs. 5 [4 to 7]; P = 0.045, respectively), with fewer patients experiencing nausea (3 [15%] vs. 10 [50%], P = 0.043). CONCLUSION: The Analgesia Nociception Index guided analgesic protocol can reduce intra-operative sufentanil consumption and postoperative pain within 24 h with fewer nausea symptoms in paediatric patients with moyamoya disease who undergo encephaloduroarteriosynangiosis. TRIAL REGISTRATION NUMBER: NCT05672212 (registered at clinicaltrials, principal investigator: K.E.H., registration date: 2 January 2023).

Surface Crystal and Degradability of Shape Memory Scaffold Essentialize Osteochondral Regeneration.

The minimally invasive deployment of scaffolds is a key safety factor for the regeneration of cartilage and bone defects. Osteogenesis relies primarily on cell-matrix interactions, whereas chondrogenesis relies on cell-cell aggregation. Bone matrix expansion requires osteoconductive scaffold degradation. However, chondrogenic cell aggregation is promoted on the repellent scaffold surface, and minimal scaffold degradation supports the avascular nature of cartilage regeneration. Here, a material satisfying these requirements for osteochondral regeneration is developed by integrating osteoconductive hydroxyapatite (HAp) with a chondroconductive shape memory polymer (SMP). The shape memory function-derived fixity and recovery of the scaffold enabled minimally invasive deployment and expansion to fill irregular defects. The crystalline phases on the SMP surface inhibited cell aggregation by suppressing water penetration and subsequent protein adsorption. However, HAp conjugation SMP (H-SMP) enhanced surface roughness and consequent cell-matrix interactions by limiting cell aggregation using crystal peaks. After mouse subcutaneous implantation, hydrolytic H-SMP accelerated scaffold degradation compared to that by the minimal degradation observed for SMP alone for two months. H-SMP and SMP are found to promote osteogenesis and chondrogenesis, respectively, in vitro and in vivo, including the regeneration of rat osteochondral defects using the binary scaffold form, suggesting that this material is promising for osteochondral regeneration.

Comparing the Impacts of Strain Types on Oxygen-Vacancy Formation in a Perovskite Oxide via Nanometer-Scale Strain Fields.

The utilization of an in-plane lattice misfit in an oxide epitaxially grown on another oxide with a different lattice parameter is a well-known approach to induce strains in oxide materials. However, achieving a sufficiently large misfit strain in this heteroepitaxial configuration is usually challenging, unless the thickness of the grown oxide is kept well below a critical value to prevent the formation of misfit dislocations at the interface for relaxation. Instead of adhering to this conventional approach, here, we employ nanometer-scale large strain fields built around misfit dislocations to examine the effects of two distinct types of strains─tension and compression─on the generation of oxygen vacancies in heteroepitaxial LaCoO3 films. Our atomic-level observations, coupled with local electron-beam irradiation, clarify that the in-plane compression notably suppresses the creation of oxygen vacancies, whereas the formation of vacancies is facilitated under tensile strain. Demonstrating that the defect generation can considerably vary with the type of strain, our study highlights that the experimental approach adopted in this work is applicable to other oxide systems when investigating the strain effects on vacancy formation.

Microbial production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate), from lab to the shelf: A review.

Polyhydroxyalkanoates (PHAs) are natural biopolyesters produced by microorganisms that represent one of the most promising candidates for the replacement of conventional plastics due to their complete biodegradability and advantageous material properties which can be modulated by varying their monomer composition. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)] has received particular research attention because it can be synthesized based on the same microbial platform developed for poly(3-hydroxybutyrate) [P(3HB)] without much modification, with as high productivity as P(3HB). It also offers more useful mechanical and thermal properties than P(3HB), which broaden its application as a biocompatible and biodegradable polyester. However, a significant commercial disadvantage of P(3HB-co-3HV) is its rather high production cost, thus many studies have investigated the economical synthesis of P(3HB-co-3HV) from structurally related and unrelated carbon sources in both wild-type and recombinant microbial strains. A large number of metabolic engineering strategies have also been proposed to tune the monomer composition of P(3HB-co-3HV) and thus its material properties. In this review, recent metabolic engineering strategies designed to for enhanced production of P(3HB-co-3HV) are discussed, along with their current status, limitations, and future perspectives.

Comprehensive multiomics analysis reveals distinct differences between pediatric choroid plexus papilloma and carcinoma.

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.

Red2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice.

Image-based lineage tracing enables tissue turnover kinetics and lineage potentials of different adult cell populations to be investigated. Previously, we reported a genetic mouse model system, Red2Onco, which ectopically expressed mutated oncogenes together with red fluorescent proteins (RFP). This system enabled the expansion kinetics and neighboring effects of oncogenic clones to be dissected. We now report Red2Flpe-SCON: a mosaic knockout system that uses multicolor reporters to label both mutant and wild-type cells. We develop the Red2Flpe mouse line for red clone-specific Flpe expression, as well as the FRT-based SCON (Short Conditional IntrON) method to facilitate tunable conditional mosaic knockouts in mice. We use the Red2Flpe-SCON method to study Sox2 mutant clonal analysis in the esophageal epithelium of adult mice which reveal that the stem cell gene, Sox2, is less essential for adult stem cell maintenance itself, but rather for stem cell proliferation and differentiation.

Genetic polymorphisms linked to extreme postorthodontic external apical root resorption in Koreans.

BACKGROUND: External apical root resorption (EARR) is a common undesirable outcome of orthodontic treatment, this study aimed to identify genetic polymorphisms associated with the susceptibility to extreme orthodontic-induced EARR in a Korean population using extreme phenotype analysis sampling. METHODS: Genomic DNA was isolated from the saliva of 77 patients who underwent orthodontic treatment involving two maxillary premolar extractions. The patients were divided into two groups based on EARR values measured on periapical radiographs: The significant resorption group (SG, EARR ≥ 4 mm) and the normal group (NG, EARR < 2 mm). In the NG group, patients with EARR < 1 mm were named the non-resorption group (NonG). Targeted next-generation sequencing was performed using the screened single nucleotide polymorphisms (SNPs), and firth logistic regression analysis was used to determine genetic associations with EARR. Haplotype-based association analysis was performed for specific SNPs. RESULTS: SNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 were found to be significantly associated with severe EARR (p < 0.05, pre-Bonferroni correction p-values). Additionally, the haplotype CCA of rs17525809, rs208294, and rs1718119 P2RX7 had a higher frequency in the SG group. CONCLUSION: Extreme phenotype analysis has identified eleven SNPs related to genes TNFSF11, TNFRSF11B, WNT3A, SFRP2, LRP6, P2RX7, and LRP1 that are associated with severe root resorption in the Korean population. These findings will contribute to the development of predictive diagnostic tools for identifying severe root resorption that may occur during orthodontic treatment.

Novel Hemodynamic, Vascular Lesion and Cytokine/Chemokine Differences Regarding Sex in a PAH Model.

Sex differences are recognized in pulmonary hypertension, however the progression of disease with regards to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics and alterations in circulating chemokines/cytokines differ between male and female. We used a progressive model of PAH, SU/Hx and analyzed cohorts of male and female rats at timepoints suggested to indicate worsening disease. Our analysis included echocardiograpy for hemodynamics, morphometry, immunofluoresecence and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index compared to females at each time point as well as increased medial artery thickening at 8-weeks PAH. Further, females exhibit fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, GM-CSF, IL-10, and MIP-1 that are not observed in females, while females have increased RANTES and CXCL-10 not found in males. Males also have increased infiltrating macrophages in vascular lesions as compared to females. We found that development of progressive PAH in hemodynamics, morphology and chemokine/cytokine circulation differ significantly between males and females. These data suggest a macrophage driven pathology in males, while there may be T-cell protection from vascular damage in female PAH.

How does the consecutive use of intraoral scanners affect musculoskeletal health? A preliminary clinical study.

BACKGROUND: Minimizing muscle strain and reducing the risk of musculoskeletal disorders associated with intraoral scanner (IOS) usage require ergonomic awareness, device selection, and workplace adjustments in dental practice. This preliminary clinical study aimed to simulate intraoral scanning tasks using wired and wireless IOSs and assess muscle activation and fatigue for both types. MATERIALS AND METHODS: Fourteen participants performed intraoral scanning tasks using wired and wireless IOSs (i700; MEDIT), with weights of 280 g and 328 g, respectively. The same computer system and software conditions were maintained for both groups (N = 14 per IOS group). Electrodes were placed on arm, neck, and shoulder muscles, and maximal voluntary contraction (MVC) was measured. Surface electromyography (EMG) was performed during the simulation, and EMG values were normalized using MVC. The root mean square EMG (%MVC) and muscle fatigue (%) values were calculated. Statistical comparisons were performed using the Mann-Whitney U and Friedman tests, with the Bonferroni adjustment for multiple comparisons (α = 0.05). RESULTS: Arm (flexor digitorum superficialis) and neck muscles (left sternocleidomastoid and left splenius capitis) showed significantly higher EMG values with wireless IOS (P < 0.05). The neck (left sternocleidomastoid and right levator scapulae) and shoulder muscles (right trapezius descendens) demonstrated significantly higher muscle fatigue with wireless IOS (P < 0.05). CONCLUSIONS: The consecutive use of heavier wireless IOS may increase the risk of muscle activation and fatigue in certain muscles, which may have clinical implications for dentists in terms of ergonomics and musculoskeletal health.

Chip collection of hepatocellular carcinoma based on O2 heterogeneity from patient tissue.

Hepatocellular carcinoma frequently recurs after surgery, necessitating personalized clinical approaches based on tumor avatar models. However, location-dependent oxygen concentrations resulting from the dual hepatic vascular supply drive the inherent heterogeneity of the tumor microenvironment, which presents challenges in developing an avatar model. In this study, tissue samples from 12 patients with hepatocellular carcinoma are cultured directly on a chip and separated based on preference of oxygen concentration. Establishing a dual gradient system with drug perfusion perpendicular to the oxygen gradient enables the simultaneous separation of cells and evaluation of drug responsiveness. The results are further cross-validated by implanting the chips into mice at various oxygen levels using a patient-derived xenograft model. Hepatocellular carcinoma cells exposed to hypoxia exhibit invasive and recurrent characteristics that mirror clinical outcomes. This chip provides valuable insights into treatment prognosis by identifying the dominant hepatocellular carcinoma type in each patient, potentially guiding personalized therapeutic interventions.

Usefulness of the heart rate variability test in predicting intradialytic hypotension in patients undergoing chronic haemodialysis.

Background: Intradialytic hypotension (IDH) is the primary complication of haemodialysis (HD); however, its diverse pathophysiology and inconsistent definitions complicate its prediction. Despite attempts using the heart rate variability (HRV) test for IDH prediction, studies on its usefulness for predicting IDH diagnosed per the nadir 90 criterion are lacking. We aimed to evaluate HRV test efficacy and reproducibility in predicting IDH based on the nadir 90 criterion. Methods: Seventy patients undergoing HD participated in this multicentre prospective observational study. The HRV test was performed during non-HD periods and IDH was monitored during 12 HD sessions. IDH was diagnosed according to the nadir 90 criterion, defined as a decrease in systolic blood pressure of ≤90 mmHg during HD. After monitoring, the HRV test was repeated. An HRV-IDH index was developed using multivariate logistic regression analysis employing HRV test parameters. The predictive power of the HRV-IDH index was analysed using the area under the receiver operating characteristics curve (AUROC). Reproducibility was evaluated using correlation analysis of two HRV tests on the same patient. Results: There were 37 and 33 patients in the IDH and non-IDH groups, respectively. The HRV-IDH index predicted IDH occurrence with AUROCs of 0.776 and 0.803 for patients who had experienced at least one or repeated IDH episodes, respectively. Spearman's correlation coefficient for HRV-IDH indices was 0.859 for the first and second HRV tests. Conclusions: The HRV test holds promise for predicting IDH, particularly for patients with recurring IDH diagnosed based on the nadir 90 criterion.

Bioelectrical impedance parameters add incremental value to waist-to-hip ratio for prediction of metabolic dysfunction associated steatotic liver disease in youth with overweight and obesity.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing health concern in pediatric populations due to its association with obesity and metabolic syndrome. Bioelectrical impedance analysis (BIA) offers a non-invasive and potentially effective alternative for identifying MASLD risk in youth with overweight or obesity. Therefore, this study aimed to assess the utility of BIA for screening for MASLD in the youth. Method: This retrospective, cross-sectional study included 206 children and adolescents aged <20 years who were overweight and obese. The correlations between anthropometric measurements and BIA parameters and alanine aminotransferase (ALT) levels were assessed using Pearson's correlation analysis. Logistic regression analysis was performed to examine the associations between these parameters and ALT level elevation and MASLD score. Receiver operating characteristic (ROC) curves were generated to assess the predictive ability of the parameters for MASLD. Results: Pearson's correlation analysis revealed that waist-to-hip ratio (WHR), percentage body fat (PBF), and BIA parameters combined with anthropometric measurements were correlated with ALT level. Logistic regression revealed that WHR, skeletal muscle mass/WHR, PBF-WHR, fat-free mass/WHR, and appendicular skeletal muscle mass/WHR were correlated with ALT level elevation after adjusting for age, sex, and puberty. WHR, PBF-WHR, and visceral fat area (VFA)-WHR were positively correlated with the MASLD score in the total population after adjusting for age, sex, and puberty. PBF-WHR and VFA-WHR were correlated with the MASLD score even in youth with a normal ALT level. The cutoff points and area under the ROC curves were 34.6 and 0.69 for PBF-WHR, respectively, and 86.6 and 0.79 for VFA-WHR, respectively. Discussion: This study highlights the utility of combining BIA parameters and WHR in identifying the risk of MASLD in overweight and obese youth, even in those with a normal ALT level. BIA-based screening offers a less burdensome and more efficient alternative to conventional MASLD screening methods, facilitating early detection and intervention in youth at risk of MASLD.

Atmospheric particulate matter and hypoxaemia in Korean children receiving general anaesthesia: A retrospective analysis.

BACKGROUND: The association between the concentration of atmospheric particulate matter on the day of surgery and the occurrence of intra-operative hypoxaemia in children receiving general anaesthesia is unclear. OBJECTIVE: To investigate the association between the exposure to of particulate matter on the day of surgery and the occurrence of intra-operative hypoxaemia, defined as a pulse oximetry oxygen saturation of less than 90% for more than 1 min, in children. DESIGN: Retrospective study. SETTING: Single-centre. PARTICIPANTS: Children aged 18 years or younger who received general anaesthesia between January 2019 and October 2020. INTERVENTION: Information on daily levels of particulate matter with a diameter 10 µm or less and 2.5 µm or less measured within a neighbourhood corresponding to the area defined by the hospital's zip code was obtained from publicly available air-quality data. MAIN OUTCOME MEASURES: The primary outcome was intra-operative hypoxaemia, defined as a pulse oximetry oxygen saturation of less than 90% lasting for more than 1 min, manually verified by anaesthesiologists using vital sign registry data extracted at 2 s intervals. RESULTS: Of the patients finally analysed, 3.85% (489/13 175) experienced intra-operative hypoxaemia. Higher levels of particulate matter 10 µm or less in diameter (≥81 µg m-3, 472/12 900, 3.7%) were associated with an increased occurrence of intra-operative hypoxaemia compared with lower particulate matter concentrations [<81 µg m-3, 17/275, 6.2%; adjusted odds ratio, 1.71; 95% confidence interval (CI), 1.04 to 2.83; P = 0.035]. CONCLUSION: The level of particulate matter on the day of surgery pose a risk of intra-operative hypoxaemia in children receiving general anaesthesia. If the concentrations of particulate matter 10 µm or less in diameter on the day of surgery are high, children receiving general anaesthesia should be managed with increased caution.

Development and Validation of a Mortality Risk Score for Repaired Tetralogy of Fallot.

BACKGROUND: Robust risk assessment is crucial for the growing repaired tetralogy of Fallot population at risk of major adverse clinical outcomes; however, current tools are hindered by lack of validation. This study aims to develop and validate a risk prediction model for death in the repaired tetralogy of Fallot population. METHODS AND RESULTS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR (International Multicenter Tetralogy of Fallot Registry) cohort with clinical, arrhythmia, cardiac magnetic resonance, and outcome data were included. Patients from London, Amsterdam, and Boston sites were placed in the development cohort; patients from the Toronto site were used for external validation. Multivariable Cox regression was used to evaluate factors associated with time from cardiac magnetic resonance until the primary outcome: all-cause death. Of 1552 eligible patients (n=1221 in development, n=331 in validation; median age at cardiac magnetic resonance 23.4 [interquartile range, 15.6-35.6] years; median follow up 9.5 years), 102 (6.6%) experienced the primary outcome. The multivariable Cox model performed similarly during development (concordance index, 0.83 [95% CI, 0.78-0.88]) and external validation (concordance index, 0.80 [95% CI, 0.71-0.90]) and identified older age at cardiac magnetic resonance, obesity, type of tetralogy of Fallot repair, higher right ventricular end-systolic volume index, and lower biventricular global function index as independent predictors of death. A risk-scoring algorithm dividing patients into low-risk (score ≤4) versus high-risk (score >4) groups was validated to effectively discriminate risk of death (15-year survival of 95% versus 74%, respectively; P<0.001). CONCLUSIONS: This externally validated mortality risk prediction algorithm can help identify vulnerable patients with repaired tetralogy of Fallot who may benefit from targeted interventions.

Enhanced toxicity-free astaxanthin extraction from Haematococcus pluvialis via concurrent cell disruption and demulsification.

The extraction of astaxanthin from Haematococcus pluvialis involves the utilization of petroleum-derived organic solvents or supercritical CO2, beset by safety concerns, high costs, and environmental sustainability limitations. This study, in contrast, employed a method involving the adjustment of salt concentration, propylene glycol, and vegetable oil fraction to disrupt emulsion in aqueous cell lysates for facilitating the separation of astaxanthin. Under optimized conditions, an astaxanthin-containing oil with a content of 1.88% was obtained even with the use of wet biomass, and four rounds of consecutive extraction resulted in a cumulative recovery yield of 66.41%. This process produced astaxanthin-enriched soybean oil with 9.49 times improved antioxidant capacity that satisfies a requirement for health functional application. Omitting the solvent removal and drying processes, which consume tremendous energy, can reduce the production cost by 2.98 times compared to conventional methods. Consequently, this study suggests an effective technique for producing edible oil containing H. pluvialis-derived astaxanthin.

ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers.

The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.

Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway.

The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.

A phase ib clinical trial of oral ciprofloxacin and etoposide in subjects with resistant acute myeloid leukemia.

A phase 1b study was conducted to evaluate the safety and feasibility of ciprofloxacin and etoposide combination treatment in subjects with relapsed and refractory acute myeloid leukemia. Eleven subjects were enrolled in the study. Utilizing the standard '3 + 3' design, escalating ciprofloxacin doses (750 mg, 1000 mg) twice daily on D1-D10 in combination with a fixed dose (200 mg) of etoposide on D2-D8 were administered. Maximum tolerated dose was determined to be 1000 mg of ciprofloxacin in combination with 200 mg of etoposide. Serious adverse events occurred in 54.5% (n = 6) subjects and 91% (n = 10) subjects reported ≥ grade 3 toxicities. Nine subjects completed treatment, one had a dose-limiting toxicity, and one withdrew. One subject achieved complete remission with a duration of 111 days and one subject achieved morphologic leukemia-free state after cycle 1. While the combination demonstrated safety and an acceptable toxicity profile, only modest hematologic and clinical benefits were observed.This trial was registered at www.clinicaltrials.gov as #NCT02773732.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.