Lysosomal-targeted doxorubicin delivery using RBC-derived vesicles to overcome drug-resistant cancer through mitochondrial-dependent cell death.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.

Bone marrow plasma level of decorin may be associated with improved treatment outcomes in a subset of multiple myeloma patients.

BACKGROUND/PURPOSE: Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. METHODS: We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. RESULTS: Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN <9.76 ng/mL) groups. Patients in the H-DCN group had more advanced-stage disease, including more osteolysis terms of higher levels of C-terminal telopeptides of type I collagen (0.69 ± 0.55 vs. 0.49 ± 0.36 ng/mL; P = 0.028), than those in the L-DCN group. Decorin levels correlated positively with hepatocyte growth factor (HGF) levels in BM plasma samples from NDMM patients (Pearson correlation coefficient, 0.226; P < 0.001). Patients with low HGF (<0.79 ng/mL) but high decorin levels (≥12.95 ng/mL) had a higher treatment response rate (90.5% vs. 54.5%, respectively; P = 0.015) and improved overall survival (not reached vs. 53 months; P = 0.0148) than those with lower decorin levels (<12.95 ng/mL). Multivariate analysis confirmed that a high decorin level was an independent predictive factor for treatment response and survival in patients with low HGF levels. CONCLUSION: Our findings suggest that decorin may exert protective effects in this subset of MM patients.

CD9 Upregulation-Decreased CCL21 Secretion in Mesenchymal Stem Cells Reduces Cancer Cell Migration.

Tetraspanin CD9 is widely expressed on various cell types, such as cancer cells and mesenchymal stem cells (MSCs), and/or cell-released exosomes. It has been reported that exosomal CD9 plays an important role in intercellular communications involved in cancer cell migration and metastasis. However, reports on the effect of the CD9 of MSCs or MSC-derived exosomes on cancer cell migration are still lacking. In this study, using a transwell migration assay, we found that both dextran-coated iron oxide nanoparticles (dex-IO NPs) and ionomycin stimulated exosomal CD9 expression in human MSCs (hMSCs); however, hMSCs could not deliver them to melanoma cells to affect cell migration. Interestingly, a reduced migration of melanoma cell line was observed when the ionomycin-incubated hMSC-conditioned media but not dex-IO NP-labeled hMSC-conditioned media were in the bottom chamber. In addition, we found that dex-IO NPs decreased cellular CD9 expression in hMSCs but ionomycin increased this. Simultaneously, we found that ionomycin suppressed the expression and secretion of the chemokine CCL21 in hMSCs. The silencing of CD9 demonstrated an inhibitory role of cellular CD9 in CCL21 expression in hMSCs, suggesting that ionomycin could upregulate cellular CD9 to decrease CCL21 expression and secretion of hMSCs, which would reduce the migration of B16F10, A549 and U87MG cancer cell lines due to chemoattraction reduction of CCL21. The present study not only highlights the important role of bone marrow-derived hMSCs' CD9-mediated CCL21 regulation in cancer bone metastasis but also suggests a new distinct pharmaceutical strategy for prevention or/and therapy of cancer metastasis.

Long non-coding RNA HOXB-AS3 promotes myeloid cell proliferation and its higher expression is an adverse prognostic marker in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. METHODS: shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. RESULTS: Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P <  0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group. CONCLUSIONS: This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.

Hyperleukocytosis is associated with distinct genetic alterations and is an independent poor-risk factor in de novo acute myeloid leukemia patients.

OBJECTIVES: Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the genetic landscape and clinical outcome in this group of patients are limited. METHODS: A total of 693 newly diagnosed de novo non-M3 AML patients were consecutively enrolled. We compared relevant mutations in 20 genes between AML patients with or without HL and exposed their prognostic implications. RESULTS: Hyperleukocytosis, defined as initial white blood cell counts above 50 000/µL, occurred in 28.9% of AML patients. HL patients had higher incidences of FLT3-ITD, NPM1, DNMT3A, CEBPA, and TET2 mutations. Multivariate analysis demonstrated that HL was an independent poor prognostic factor for overall survival and disease-free survival in total patients, those with intermediate-risk cytogenetics and normal karyotype irrespective of genetic alterations. Intriguingly, HL predicted poor survival in CEBPA double mutated, NPM1 + /FLT3-ITD- and NPM1-/FLT3-ITD- patients. Further, HL patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR) had a significantly longer overall survival and disease-free survival than those without allo-HSCT. CONCLUSIONS: Hyperleukocytosis is an independent poor prognostic factor irrespective of cytogenetics and mutation status. Allo-HSCT in first CR seems to ameliorate the poor prognostic impact of HL.

GATA2 mutations in patients with acute myeloid leukemia-paired samples analyses show that the mutation is unstable during disease evolution.

Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA (double-mut)), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA (double-mut), CEBPA (single-mut), and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.

A study of 65 patients with acquired hemophilia A in Taiwan.

BACKGROUND/PURPOSE: Acquired hemophilia A (AHA) is a rare disorder that has not been comprehensively reported in the Chinese population. Treatment-related fatal sepsis (TRS), other than hemorrhage, is the leading cause of death in patients with AHA. However, researchers have not systematically evaluated salient parameters, to determine their association with the risk of TRS in this rare disorder. This study reports the salient features of AHA in Chinese patients and presents possible factors associated with TRS. METHODS: Sixty-five Chinese patients with AHA, including 42 men and 23 women, were studied retrospectively. RESULTS: The median age was 64 years (range = 18-94 years). The features, laboratory findings, and outcomes of various therapies designed to arrest acute bleeding and eliminate autoantibodies against the factor VIII coagulant protein (VIIIi) were comparable to those previously reported. The complete response (CR) rate was 60%, and the median time to CR was 16 weeks. Ten patients (15%) died of bleeding related to FVIIIi by the end of the median follow-up period of 115 months. The estimated 1- and 5-year hemorrhage-related mortality rates were 15% and 22%, respectively. The absence of CR to therapy was the only independent factor associated with shorter survival. The rate of TRS was 20%, and the use of a rituximab-based (Rb) regimen (odds ratio = 8.0, 95% CI, 1.1-68.2) and platelet < 1.5 × 10(11)/L at diagnosis (odds ratio = 38.5, 95% CI, 1.3-1107.6) were the two significantly independent factors associated with TRS. CONCLUSION: The salient features of AHA and treatment outcomes of the patients in this study are similar to those of other patients. Two independent factors (the use of a Rb regimen and platelet < 1.5 × 10(11)/L) were significantly associated with TRS.

DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications.

DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.

IPSS-R in 555 Taiwanese patients with primary MDS: Integration of monosomal karyotype can better risk-stratify the patients.

The revised International Prognostic Scoring System (IPSS-R) was recently developed to better assess the clinical outcome of adult patients with myelodysplastic syndrome (MDS). In this study, we aimed to investigate the prognostic impact of this new risk model on 555 MDS patients in Taiwan. Generally, the IPSS-R could discriminate MDS patients regarding risk of leukemia evolution and overall survival in our cohort and it further refined prognostic stratification in all IPSS risk categories. However, we could not find the inter-group difference between IPSS-R very low and low risk subgroups in both leukemia-free survival (LFS) and overall survival (OS). IPSS-R couldn't distinguish the prognosis between very good and good and between good and intermediate risk cytogenetic categories in OS, and between very good and good and between intermediate and poor cytogenetic-risk categories in LFS, either. On the other hand, incorporation of monosomal karyotype (MK) into IPSS-R could further stratify MDS patients with higher-risk IPSS-R (intermediate, high and very high risk) into four groups, rather than three groups, with different OS (P < 0.001). Intriguingly, patients receiving allogeneic hematopoietic stem cell transplantation had longer survival than those without in the IPSS-R high and very high, but not other risk groups. Similarly, patients treated with hypomethylating agents had better survival than those not in the IPSS-R very high risk group. In conclusion, IPSS-R can risk-stratify MDS patients in Taiwan but with some limitations, especially in very low risk category, and MK has additional prognostic value in discriminating MDS patients with higher-risk IPSS-R.

SF3B1 mutations in patients with myelodysplastic syndromes: the mutation is stable during disease evolution.

The SF3B1 mutation can be detected in patients with myelodysplastic syndrome (MDS), but the report regarding the association of this mutation with other genetic alterations and its stability during disease progression is limited. In this study, SF3B1 mutations were identified in 10% of total cohort of 479 MDS patients and 61.8% of 34 patients with refractory anemia with ring sideroblasts (RARS). SF3B1 mutations were closely associated with older age, higher platelet counts, lower lactate dehydrogenase levels, good-risk cytogenetics, and mutations of DNMT3A, but inversely related to ASXL1 mutations. Most SF3B1-mutated patients had concurrent other genetic alterations, including DNMT3A and RUNX1 mutations. There was no prognostic difference between patients with SF3B1 mutations and those without. Sequential studies in 417 samples from 142 patients demonstrated that all SF3B1-mutated patients retained the same mutations during disease evolution with the exception of two patients who lost the mutation after allogeneic hematopoietic stem cell transplantation, whereas none of the SF3B1-wild patients acquired a novel mutation during clinical follow-ups. In conclusion, the patients with SF3B1 mutations had distinct clinic-biologic features. SF3B1 mutations, accompanied with other genetic alterations, especially DNMT3A mutations, may play a role in the development of MDS, but have little role in disease progression.

TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics.

The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1(+)/FLT3-ITD(-) or CEBPA(+)). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution.

Lineage switch of KMT2A-rearranged adult B-lineage acute lymphoblastic leukemia following bispecific T-cell engager and monoclonal antibody therapy.

Adult B-lineage acute lymphoblastic leukemia (B-ALL) with t(4;11)(q21;q23) is very rare. It is characterized by mixed-lineage leukemia and has the potential for lineage switching during the treatment course. We report the disease course of a patient with B-ALL with t(4;11)(q21;q23) to demonstrate that close monitoring of cell morphology and immunophenotyping is necessary to capture the lineage switch at an early stage. Cell morphology, immunophenotyping, and cytogenetics were used to evaluate the patient's disease status. A 36-year-old woman was diagnosed with B-ALL with t(4;11)(q21;q23), which encodes the KMT2A::AFF1 fusion. After the initial induction chemotherapy, her disease remained refractory, and the patient received salvage immunotherapy with blinatumomab and inotuzumab ozogamicin. However, the ALL did not respond. Repeated bone marrow examinations unexpectedly revealed the emergence of a major population of monoblasts, in addition to a minor population of the original B lymphoblasts. The patient was diagnosed with disease evolution from B-ALL to mixed-phenotype acute leukemia (MPAL, B/myeloid). We present this case to highlight the potential of KMT2A-rearranged B-ALL to undergo lineage switch following B-cell targeted therapy. Patients with this kind of B-ALL should therefore be closely monitored to capture potential changes in the nature of the disease and prompt appropriate treatment.

Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations.

Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen-DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3-internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.

Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation.

Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.

WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system.

The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P < .001), French-American-British M6 subtype (P = .006), and t(7;11)(p15;p15) (P = .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P < .001). Sequential analyses were performed on 133 patients. WT1 mutations disappeared at complete remission in all WT1-mutated patients studied. At relapse, 3 of the 16 WT1-mutated patients who had paired samples lost the mutation and 2 acquired additional mutations, whereas 3 of 110 WT1-wild patients acquired novel mutations. In conclusion, WT1 mutations are correlated with poor prognosis in AML patients. The mutation status may be changed in some patients during AML progression.

Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

Soluble triggering receptor expressed on myeloid cells-1 as an infection marker for patients with neutropenic fever.

OBJECTIVE: To assess the value of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of infection in patients with neutropenic fever comparing with procalcitonin and C-reactive protein. DESIGN: Prospective, comparative, single-center study. SETTING: Hematology ward at a university hospital. SUBJECTS: Seventy-five patients with neutropenic fever after chemotherapy for their hematologic malignancies. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 137 episodes of neutropenic fever in 75 patients were classified into 75 episodes of documented infections and 62 low likelihood of infection. The level of soluble triggering receptor expressed on myeloid cells-1 was significantly elevated in the group of documented infection. The area under the receiver operating characteristic curve for the diagnosis of infection was 0.719 (95% confidence interval, 0.632-0.806; p < .0001) for soluble triggering receptor expressed on myeloid cells-1, which was larger than the values of 0.501 for procalcitonin (0.465-0.657; p = .218) and 0.491 for C-reactive protein (0.394-0.589, p = .858). The fitted marginal logistic regression model of all episodes contained two statistically significant predictors of infection: soluble triggering receptor expressed on myeloid cells-1 (per 1-pg/mL increase; odds ratio [OR], 1.0002; 95% CI, 1.0001-1.0003; p < .0001) and procalcitonin (per 1-ng/mL increase; OR, 1.0094; 95% CI, 1.0005-1.0184; p = .0002). In a diagnostic panel with soluble triggering receptor expressed on myeloid cells-1 and procalcitonin, the sensitivity and specificity were 88% and 48%, respectively. CONCLUSIONS: Soluble triggering receptor expressed on myeloid cells-1 is better than procalcitonin in the prediction of infection at the onset of neutropenic fever. By applying soluble triggering receptor expressed on myeloid cells-1 and procalcitonin together, low or high risk for infection can be defined at the onset of neutropenic fever.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations.

Somatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival.

Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.