Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA.

PURPOSE: Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. EXPERIMENTAL DESIGN: A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). CONCLUSIONS: Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.

[Safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia]. / 贝林妥欧单抗治疗儿童复发/éš¾æ²»æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— çš„å®‰å ¨æ€§åŠè¿‘æœŸç–—æ•ˆåˆ†æž.

OBJECTIVES: To study the safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia (R/R-ALL). METHODS: Six children with R/R-ALL who received blinatumomab treatment from August 2021 to August 2022 were included as subjects, and a retrospective analysis was performed for their clinical data. RESULTS: Among the six children, there were three boys and three girls, with a median age of 10.5 (5.0-13.0) years at the time of inclusion. Of all six children, one had refractory ALL and did not achieve remission after several times of chemotherapy, and 5 relapsed for the first time, with a median time of 30 (9-60) months from diagnosis to relapse. Minimal residual disease (MRD) before treatment was 15.50% (0.08%-78.30%). Three children achieved complete remission after treatment, among whom two had negative conversion of MRD. Five children had cytokine release syndrome (CRS), among whom 3 had grade 1 CRS and 2 had grade 2 CRS. Four children were bridged to allogeneic hematopoietic stem cell transplantation, with a median interval of 50 (40-70) days from blinatumomab treatment to transplantation. The six children were followed up for a median time of 170 days, and the results showed an overall survival rate of 41.7% (95%CI: 5.6%-76.7%) and a median survival time of 126 (95%CI: 53-199) days. CONCLUSIONS: Blinatumomab has good short-term safety and effectiveness in the treatment of childhood R/R-ALL, and its long-term effectiveness needs to be confirmed by studies with a larger sample size.

[Clinical features and prognosis of juvenile myelomonocytic leukemia: an analysis of 63 cases]. / 63ä¾‹å¹¼å¹´åž‹ç²’å•æ ¸ç»†èƒžç™½è¡€ç— çš„ä¸´åºŠç‰¹å¾ä¸Žé¢„åŽåˆ†æž.

OBJECTIVES: To investigate the clinical features of juvenile myelomonocytic leukemia (JMML) and their association with prognosis. METHODS: Clinical and prognosis data were collected from the children with JMML who were admitted from January 2008 to December 2016, and the influencing factors for prognosis were analyzed. RESULTS: A total of 63 children with JMML were included, with a median age of onset of 25 months and a male/female ratio of 3.2∶1. JMML genetic testing was performed for 54 children, and PTPN11 mutation was the most common mutation and was observed in 23 children (43%), among whom 19 had PTPN11 mutation alone and 4 had compound PTPN11 mutation, followed by NRAS mutation observed in 14 children (26%), among whom 12 had NRAS mutation alone and 2 had compound NRAS mutation. The 5-year overall survival (OS) rate was only 22%±10% in these children with JMML. Of the 63 children, 13 (21%) underwent hematopoietic stem cell transplantation (HSCT). The HSCT group had a significantly higher 5-year OS rate than the non-HSCT group (46%±14% vs 29%±7%, P<0.05). There was no significant difference in the 5-year OS rate between the children without PTPN11 gene mutation and those with PTPN11 gene mutation (30%±14% vs 27%±10%, P>0.05). The Cox proportional-hazards regression model analysis showed that platelet count <40×109/L at diagnosis was an influencing factor for 5-year OS rate in children with JMML (P<0.05). CONCLUSIONS: The PTPN11 gene was the most common mutant gene in JMML. Platelet count at diagnosis is associated with the prognosis in children with JMML. HSCT can improve the prognosis of children with JMML.

Clinical Impact of Drug Adherence of Tyrosine Kinase Inhibitors in Children with Ph-Positive Acute Lymphoblastic Leukemia.

PURPOSE: This study aimed to explore the impact of ABL1-tyrosine kinase inhibitors (TKIs) adherence on the survival of chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) children and clarify the potential predictors of patients' prognosis from TKIs intake practices. Materials and Methods: Ninety newly diagnosed Ph+ ALL patients who received TKIs were enrolled. We collected the baseline characteristics and adverse events in all children; moreover, TKIs adherence was measured by an eight-item Morisky medication adherence scale (MMAS-8). Progression-free survival (PFS) and overall survival (OS) analysis were performed, and risk factors for PFS and OS were evaluated. RESULTS: Among all patients, 69 cases were regarded as adherers, while 21 were non-adherers. The median duration of TKIs interruption was significantly prolonged in the non-adherence group than in the adherence group (13 [0-101] vs. 56 [11-128], p < 0.001). Additionally, dose reduction occurred in 55.2% of non-adherers versus 23.0% of adherers (p=0.002). The PFS and OS in adherers were significantly higher versus non-adherers (p=0.020 and p=0.039). MMAS-8 score was an independent risk factor for PFS (p=0.010) and OS (p=0.031). Among non-adherers, the median OS was only 23.1% (4.2%-42%) in patients aged ≤ 10 years versus 54.4% (38.8%-70%) in adolescents. Most of the patients who experienced TKIs non-adherence suffered pancytopenia. CONCLUSION: TKIs adherence during treatment significantly influenced the survival of pediatric Ph+ ALL patients, and non-adherers with age ≤ 10 years were more vulnerable to TKIs disruption. The cumulative TKIs dose should be especially emphasized to patients with age ≤ 10 years, which may result in an inferior achievement of relevant treatment milestones.

A digital workflow to predict facial aesthetics in patients with maxillofacial trauma with implant retained prostheses.

Purpose To introduce a digital workflow for the prediction of facial aesthetics, especially in patients with dentation deformity caused by maxillofacial trauma.Methods Cone-beam computed tomography (CBCT) and three-dimensional facial scans of patients with radiographic prostheses were collected. The aforementioned data were uploaded to ProPlan CMF software and merged to generate a virtual patient with craniofacial hard tissue, realistic facial soft tissue, and remaining dentition. The radiographic prostheses were scanned to form a digital cast, which was fitted with its CBCT image to create the virtual prostheses. Postoperative facial soft tissue was simulated according to the movement of the virtual prostheses. An appropriate virtual diagnostic prosthesis plan was selected by the patient and dentist. Subsequently, prosthetically driven implant guide and restoration were designed and fabricated.Conclusions A virtual patient was successfully constructed. A 4-mm protrusion of the virtual prosthesis was chosen. Subsequently, implant surgery was performed, and dental prostheses were fabricated based on this location. The fusion of the postoperative facial scan and preoperative facial prediction was found to be coincident. This technique can effectively predict facial aesthetic features of patients with maxillofacial trauma, facilitate communication with patients, reduce chairside time, and guide the multidisciplinary design of implant placement and restoration fabrication.

Use of a digitally guided triple technique for bone reduction, implant placement, and immediate interim prostheses in complete-arch implant surgery.

A digitally guided triple technique for bone reduction, implant placement, and immediate interim prostheses in complete-arch implant surgery is presented. This technique integrates bone reduction and implant placement information into a dual-function surgical template and introduces a digital approach to fabricating immediate interim implant-supported fixed dental prostheses with the same occlusal relationship as the one evaluated with diagnostic removable prostheses.

Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy.

BACKGROUND: The preferred salvage treatment for children with relapsed/refractory acute myeloid leukemia (R/R-AML) remains unclear. The combination of cladribine/Ara-C/granulocyte-colony stimulating factor and mitoxantrone (CLAG-M) shown promising results in adult R/R-AML. We aim to investigate the efficacy and safety of CLAG-M versus mitoxantrone/etoposide/cytarabine (MEC) or idarubicin/etoposide/cytarabine (IEC) in R/R-AML children. METHODS: Fifty-five R/R-AML children were analyzed. The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) at 3-year were documented. Karyotype or mutations status were summarized as different risk groups. RESULTS: The ORR was achieved in 80% (16/20) and 51% (18/35) of patients after one-cycle of CLAG-M and MEC/IEC treatment (p < 0.001). The CLAG-M group's OS (66.8% ± 16.2% vs. 40.4% ± 10.9%, p = 0.019) and PFS (52.6% ± 13.7% vs. 34.9% ± 9.1%, p = 0.036) at 3-year was significantly higher than the MEC/IEC group. In high-risk patients, 33.3% experienced progression of disease (PD) and 22.2% dead in CLAG-M group, while 50% experienced PD and 43.8% dead in MEC/IEC. When it comes to low-risk group, none of them in CLAG-M experienced PD or death, while up to 50% of patients received MEC/IEC suffered PD, and all of them died eventually. Similar results were also found in the intermediate-risk group. Surprisingly, the presence of FLT3-ITD was associated with poor outcome in both groups. The most common adverse events were hematologic toxicities, and the incidence was similar in both group. CONCLUSIONS: CLAG-M group demonstrated effective palliation along with acceptable toxicity in R/R-AML patients. However, patients with FLT3-ITD may benefit less from CLAG-M, owing to higher PD rate and all-cause mortality than other patients.

[Efficacy and prognostic factors in children with non-core binding factor acute myeloid leukemia].

OBJECTIVE: To compare the efficacy of the CAMS-2005 and CAMS-2009 regimens in treating children with non-core binding factor acute myeloid leukemia (non-CBF AML) and to study the prognosis factors. METHODS: A total of 161 children who were initially diagnosed with non-CBF AML from April 2005 to December 2015 were enrolled as study subjects, and were divided into a CAMS-2005 regimen group (n=52) and a CAMS-2009 regimen group (n=109) according to the chemotherapy regimen provided. The efficacy was retrospectively compared between the two groups. RESULTS: The complete remission (CR) rate at the first course of treatment was higher in the CAMS-2009 regimen group than that in the CMAS-2005 regimen group (63.3% vs 46.2%; P<0.05). There were no significant differences between the two groups in treatment-related mortality rate (11.9% vs 17.3%), recurrence rate (27.5% vs 28.8%), and three-year overall survival (OS) rate (44%±5% vs 28%±6%) (P>0.05). Children who achieved CR at the first course of treatment had significantly higher OS and event-free survival rates than those who did not achieved CR (P<0.01). CONCLUSIONS: The CAMS-2009 regimen is superior to the CAMS-2005 regimen in improving the CR rate in children with non-CBF AML after induction treatment. Whether CR is achieved at the first course of treatment can affect the OS rate of children with non-CBF AML.

[Association of cerebrospinal fluid status with prognosis in children with acute lymphoblastic leukemia].

OBJECTIVE: To study the clinical features of central nervous system infiltration-positive (CNSI+) children with acute lymphoblastic leukemia (ALL) based on flow cytometry, as well as the association of such clinical features with prognosis. METHODS: A retrospective analysis was performed for the clinical data of 66 CNSI+ children with ALL treated from April 2008 to June 2013. Clinical features, laboratory examination results and prognosis were compared between the children in different chemotherapy stages (induction stage and consolidation/maintenance stage). RESULTS: Among the 66 CNSI+ children, 50 were in the induction stage and 16 in the consolidation/maintenance stage. Compared with the CNSI+ children in the induction stage, the CNSI+ children in the consolidation/maintenance stage had a significantly higher proportion of children with the genes associated with good prognosis based on the results of molecular biology (P<0.05), as well as a significantly higher recurrence rate (P<0.05). Recurrence was observed in 21 CNSI+ ALL children, among whom 10 were in the induction stage and 11 were in the consolidation/maintenance stage. Compared with the children experiencing recurrence in the induction stage, the children experiencing recurrence in the consolidation/maintenance stage had a significantly higher proportion of children with recurrence of the central nervous system and bone marrow (P<0.05), as well as significantly higher proportion of biochemical positive rate of cerebrospinal fluid (P<0.05). The children in the induction stage had a significantly higher recurrence-free survival rate than those in the consolidation/maintenance stage (P<0.001), while there was no significant difference in overall survival rate between the two groups (P>0.05). CONCLUSIONS: In children with ALL, CNSI+ has a marked effect on recurrence-free survival rate in different chemotherapy stages, but has no obvious effect on overall survival rate. CNSI+ patients in the consolidation/maintenance stage have a higher recurrence.

Prognostic stratification of molecularly and clinically distinct subgroup in children with acute monocytic leukemia.

BACKGROUND: The prognosis of children with acute monocytic leukemia (AML-M5) remains unsatisfactory and the risk profile is still controversial. We aim to investigate the prognostic value of clinical and cytogenetic features and propose a new risk stratification in AML-M5 children. METHODS: We included 132 children with AML-M5. Overall survival (OS) and progression-free survival (PFS) were documented. Cox regression was performed to evaluate the potential risk factors of prognosis. RESULTS: The 5-year-OS was 46.0% (95% confidence intervals, 41.6%-50.4%) in all patients. There was significantly lower OS in the age ≤ 3 years old (P = .009) and hyperleukocytosis (P < .001). The FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) and MLL-rearrangement carriers were associated with fewer survivors in all patients (37.1% and 36.7%) and chemotherapy-only group (19.0% and 35.0%). Notably, the number of survivor with MLL-rearrangement did not increase in hematopoietic stem cell transplant (HSCT) group. According to the Cox regression analysis, HSCT was a significantly favorable factor (P = .001), while hyperleukocytosis, age ≤ 3 years old, and BM blast ≥ 70% adversely affected the OS in all patients (all P < .05). Additionally, FLT3-ITD was a risk factor for OS in the chemotherapy-only group (P = .023), while hyperleukocytosis and age ≤ 3 years independently contributed to poor PFS (both P < .05). In comparison to the standard-risk group, significant poorer outcome was found in the high-risk group (both P < .005). CONCLUSIONS: We propose that AML-M5 children with any of MLL-rearrangement, FLT3-ITD, hyperleukocytosis, BM blast ≥ 70%, or age ≤ 3 years old are classified into the high-risk group, and HSCT is beneficial especially in patients with FLT3-ITD mutation, hyperleukocytosis, and age ≤ 3 years old. Importantly, the choice of HSCT should be made more carefully in children with MLL-rearrangement for its suboptimal performance.

A New Method for Ultra-sensitive P24 Antigen Assay Based on Near-infrared Fluorescent Microsphere Immunochromatography.

OBJECTIVE: To develop a rapid, highly sensitive quantitative method for detecting P24 antigen based on near-infrared fluorescent microsphere immunochromatography. METHODS: First, we prepared a lateral flow assay test strip, and labeled the detection antibody using a fluorescent microsphere. Second, we optimized the antibody labeling conditions. Third, we optimized the detection conditions. Fourth, we created a working curve. Fifth, we conducted a methodological assessment of the established fluorescent microsphere immunochromatography method. Sixty-six clinical samples were tested, and we compared the established fluorescent microsphere immunochromatography with the quantitative ELISA method. RESULTS: According to the working curve, the detection limit of the method is 3.4 pg/mL, and the detection range is 3.4 pg/mL to 10 ng/mL. The average intra-assay recovery was 99.6%, and the Coefficient of Variation (CV) was 5.4%-8.6%; the average inter-assay recovery was 97.3%, and the CV was 8.5%-11%. The detection rate of fluorescent microsphere immunochromatography was higher than ELISA method, and had a good correlation with ELISA. CONCLUSION: The P24 antigen quantitative detection method based on near-infrared fluorescent microsphere immunochromatography has the advantages of rapid detection, high sensitivity, and wide detection range; thus, it is suitable for early clinical diagnosis and continuous monitoring of AIDS.

Diagnostic performance of diffusion-weighted magnetic resonance imaging in pulmonary malignant lesions: a meta-analysis.

BACKGROUND: Overuse or misuse of positron emission tomography/computed tomography (PET/CT) should be avoided for its ionizing-radiation. Diffusion-weighted magnetic resonance imaging (DW-MRI), characterized by no radiation, may be regarded as an alternative in differentiating pulmonary nodules. We aim to estimate the diagnostic accuracy of DW-MRI in diagnosing of pulmonary lesions. METHODS: Relevant studies were searched through PubMed and Embase with no language restriction from inception to March 8, 2019. We selected studies reporting sensitivity and specificity of DW-MRI for differentiating pulmonary nodules. A summary estimates of sensitivity, specificity and area under curve (AUC) of receiver operating characteristic (ROC) of DW-MRI were analyzed with a random effects model. RESULTS: We included data from 37 studies, which altogether included 2,311 pulmonary lesions. The pooled sensitivity and specificity were 0.86 (95% CI, 0.82-0.89) and 0.79 (95% CI, 0.72-0.85), and AUC was 0.90 (95% CI, 0.87-0.92). Subsequent subgroup analysis showed the higher sensitivity of DW-MRI in pulmonary lesion >2 cm in comparison to lesions ≤2 cm, however, higher specificity was observed in smaller lesions. CONCLUSIONS: Radiation-free DW-MRI showed a favorable balance between sensitivity and specificity in diagnosing pulmonary malignancies especially in lesion size ≤2 cm. Existing evidence indicated that DW-MRI may be considered as an independent substitute in diagnosis of lung lesions, which might help to prevent long-term side-effects from radiographic diagnosing and evaluating procedures.

Preliminary comparison of diffusion-weighted MRI and PET/CT in predicting histological type and malignancy of lung cancer.

INTRODUCTION: Emerging evidence shows that diffusion-weighted magnetic resonance imaging (DW MRI) and fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) might be useful in predicting histological type and malignancy of lung cancer, and even in specifically detecting the types of gene mutation. OBJECTIVE: We assessed whether DW MRI is equivalent to PET/CT in lung cancer diagnosis and evaluation. METHODS: The institutional review board approved this study, and written informed consent was obtained from all patients. DW MRI and FDG PET/CT were performed before therapy in 15 lung cancer patients diagnosed by pathological examination. Apparent diffusion coefficient (ADC), ratio of ADC (rADC = ADC in tumor/ADC in spinal cord) and maximal standardized uptake value (SUVmax ) were assessed. RESULTS: ADC, rADC and SUVmax did not reveal significant differences among different types of lung cancer. Sensitivity, specificity and accuracy of ADC, rADC and SUVmax proved to be not significantly different in the detection of adenocarcinoma and squamous cell carcinoma. Difference in the abilities of the sensitivity, specificity and accuracy of ADC, rADC and SUVmax to detect adenocarcinoma and squamous cell carcinoma proved to be insignificant. Although Ki-67 score did not show correlation with ADC, rADC and SUVmax , significant positive correlation was found between ADC and rADC, and ADC and SUVmax . CONCLUSIONS: Both DW MRI and FDG PET/CT had similar limited diagnostic capability of predicting different histological types and malignancy of lung cancer. This study may help provide a novel insight into diagnostic and therapeutic strategies of lung cancer based on DW MRI.

Diagnostic Performance of Diffusion-weighted Magnetic Resonance Imaging in Bone Malignancy: Evidence From a Meta-Analysis.

Current state-of-the-art nuclear medicine imaging methods (such as PET/CT or bone scintigraphy) may have insufficient sensitivity for predicting bone tumor, and substantial exposure to ionizing radiation is associated with the risk of secondary cancer development. Diffusion-weighted MRI (DW-MRI) is radiation free and requires no intravenous contrast media, and hence is more suitable for population groups that are vulnerable to ionizing radiation and/or impaired renal functions. This meta-analysis was conducted to investigate whether whole-body DW-MRI is a viable means in differentiating bone malignancy. Medline and Embase databases were searched from their inception to May 2015 without language restriction for studies evaluating DW-MRI for detection of bone lesions. Methodological quality was assessed by the quality assessment of diagnostic studies (QUADAS-2) instrument. Sensitivities, specificities, diagnostic odds ratio (DOR), and areas under the curve (AUC) were used as measures of the diagnostic accuracy. We combined the effects by using the random-effects mode. Potential threshold effects and publication bias were investigated. We included data from 32 studies with 1507 patients. The pooled sensitivity, specificity, and AUC were 0.95 (95% CI, 0.90-0.97), 0.92 (95% CI, 0.88-0.95), and 0.98 on a per-patient basis, and they were 0.91 (95% CI, 0.87-0.94), 0.94 (95% CI, 0.90-0.96), and 0.97 on a per-lesion basis. In subgroup analysis, there is no statistical significance found in the sensitivity and specificity of using DWI only and DWI combined with other morphological or functional imaging sequence in both basis (P > 0.05). A b value of 750 to 1000 s/mm enables higher AUC and DOR for whole-body imaging purpose when compared with other values in both basis either (P < 0.01). The ROC space did not show a curvilinear trend of points and a threshold effect was not observed. According to the Deek's plots, there was no publication bias on both basis. Our results support the use of DWI as an effective means for distinguishing malignant bone lesions; however, various imaging parameters need to be standardized prior to its broad use in clinical practice.