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1.
Medicine (Baltimore). 2018 Sep;97(39):e12102. doi: 10.1097/MD.0000000000012102.

Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: A retrospective cohort study.

Author information

1
Department of Hematology, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.

Abstract

To assess treatment response and overall survival (OS) in refractory or relapsed acute myeloid leukemia (R/R AML) patients treated by different common salvage chemotherapy regimens.Medical records data from 142 R/R AML patients were reviewed in this retrospective study. Patients were treated with regimens based on the following drugs: cytarabine, granulocyte colony-stimulating factor (G-CSF), and fludarabine (FLAG) (n = 46); cytarabine and G-CSF in addition to aclarubicin or daunorubicin (CAG/DAG) (n = 30); cytarabine, G-CSF, and cladribine (CLAG) (n = 27); cytarabine, etoposide, and mitoxantrone (MEA) (n = 17); cytarabine plus idarubicin, daunorubicin, or mitoxantrone (IA/DA/MA) (n = 12); and homoharringtonine, cytarabine, and aclarubicin or daunorubicin (HAA/HAD) (n = 10).A total of 43 (35.2%) patients achieved complete remission (CR), 60 (49.2%) patients achieved overall remission rate (ORR), and 18 (14.8%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR. Median OS was 8.0 (95% CI 6.6-9.4) months with a 1-year OS rate of (29.9 ± 3.9)% and 3-year OS rate of (11.1 ± 3.6)%. No difference of CR (P = .621), ORR (P = .385), and allo-HSCT (P = .537) achievement was observed among different chemotherapy regimens. Interestingly, we observed that the CLAG-based regimen did not affect CR (P = .165), while it achieved a numerically higher ORR (P = .093) and was an independent factor for prolonged OS (P = .016). No other regimens were determined to be correlated with CR, ORR, or OS.FLAG-, CAG/DAG-, CLAG-, MEA-, IA/DA/MA- and HAA/HAD-based regimens were found to achieve similar CR rates, while the CLAG-based regimen achieved numerically higher ORR rates and significant favorable OS. Therefore, CLAG-based regimens should be a prioritized treatment option for R/R AML patients.

PMID:
30278488
PMCID:
PMC6181529
DOI:
10.1097/MD.0000000000012102
[Indexed for MEDLINE]
Free PMC Article
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2.
3.
N Engl J Med. 2018 Sep 20;379(12):1186. doi: 10.1056/NEJMc1809507.

Ivosidenib in IDH1-Mutated Acute Myeloid Leukemia.

Author information

1
Warren Alpert Medical School of Brown University, Providence, RI ilyas_sahin@brown.edu
PMID:
30260154
DOI:
10.1056/NEJMc1809507
[Indexed for MEDLINE]
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4.
BMC Ophthalmol. 2018 Sep 14;18(Suppl 1):225. doi: 10.1186/s12886-018-0855-6.

Rare retinal complications of bone marrow transplantation (BMT): a case report.

Author information

1
Leeds Teaching Hospital, Beckett St, Leeds, LS9 7TF, England. farhatbutt@nhs.net.
2
Leeds Teaching Hospital, Beckett St, Leeds, LS9 7TF, England.

Abstract

BACKGROUND:

Bone marrow transplantation retinopathy is a rare condition affecting the posterior pole. The purpose of this case report is to highlight the possible risk factors and clinical features.

CASE PRESENTATION:

A 19y old male with relapsed and refractory acute lymphoblastic leukaemia was admitted under haematology with pyrexia of unknown origin. At the time of his admission, he reported bilateral and sequential visual impairment for 2 days. On examination, there was bilateral profound retinopathy across the posterior poles. This was symmetrical and with associated macular oedema. Infective aetiology was excluded and cyclosporine was stopped. Although no definitive treatment was initiated the visual acuity improved whilst macular oedema fluctuated.

CONCLUSION:

BMT and chemotherapy can cause ocular complications but these are usually confined to the anterior segment. Posterior segment complications in the form of retinopathy is very rare. We report this case to highlight some of the clinical features and course of disease.

KEYWORDS:

Bone marrow transplant; Ciclosporin; Retinal toxicity; Retinopathy

PMID:
30255790
PMCID:
PMC6157125
DOI:
10.1186/s12886-018-0855-6
[Indexed for MEDLINE]
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6.
Medicine (Baltimore). 2018 Sep;97(38):e12429. doi: 10.1097/MD.0000000000012429.

Unusual expansion of CD3+CD56+ natural killer T-like cells in peripheral blood after anticytokine treatment for graft-versus-host disease: A case report.

Author information

1
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou.
2
Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang Province, China.

Abstract

RATIONALE:

Basiliximab and etanercept have achieved promising responses in steroid-refractory graft versus host disease (SR-GVHD). However, the in vivo immune changes following the treatment have not been elucidated.

PATIENT CONCERNS:

A 14-year-old boy presented with skin rash and diarrhea 20 days after haploidentical hemotopoietic stem cell transplantation.

DIAGNOSES:

We made the diagnose of grade 3 acute GVHD with skin and gastrointestinal involvement.

INTERVENTIONS:

After the failure of the first-line treatment with methylprednisolone, combined anti-cytokine therapies with basiliximab and etanercept were prescibed.

OUTCOMES:

He achieved complete remission by basiliximab and etanercept. Furthermore, we detected that donor CD3CD56 Natural killer T(NKT)-like cells expanded gradually after the period of lymphocytopenia caused by GVHD and anti-cytokine therapy. The expansion of NKT-like cells was in association with high serum IFN-γ. NKT-like cells showed preferred proliferation in response to IFN-γ and potent cytotoxicity against leukemia cells. The expansion persisted > 2 years and the patient had a leukemia-free survival of 66 months.

LESSONS:

Our case indicated that combined anti-cytokine treatment may reset the immune system and cause NKT-like cells to exhibit a predilection for expansion.

PMID:
30235723
PMCID:
PMC6160206
DOI:
10.1097/MD.0000000000012429
[Indexed for MEDLINE]
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7.
Medicine (Baltimore). 2018 Sep;97(38):e12410. doi: 10.1097/MD.0000000000012410.

Concomitant T-cell prolymphocytic leukemia and visceral leishmaniasis: A case report.

Author information

1
Department of Laboratory Medicine, West China Hospital, Sichuan University, China.

Abstract

RATIONALE:

T-cell prolymphocytic leukaemia (T-PLL) is a rare aggressive lymphoid disease featured by a significant increased lymphocyte count and obvious hepatosplenomegaly with poor prognosis. The concomitant presentation of T-PLL and visceral leishmaniasis (VL) has not previously been reported.

PATIENT CONCERNS:

The patient initially suffered from anorexia, skin pigmentation, fever and hepatosplenomegaly. Bone marrow smear described leishmania and antibody test was positive. VL was diagnosed and he was given antimony gluconate therapy. His symptoms recurred.

DIAGNOSIS:

A combination of serological rk39 test, morphologic evaluation and immunophenotyping by flow cytometry finally supported the diagnosis of concomitant VL and T-PLL.

OUTCOMES:

Amphotericin B was used for the treatment of VL first and a referral for treating T-PLL after recovery from VL was suggested. Unfortunately, the patient requested to be discharged. Telephone follow-up indicated that he died a few days after leaving the hospital.

LESSONS:

Due to the rarity of the disease combination, the pathogenesis association of T-PLL and VL is unclear. However, a duly diagnosis is crucial for treatment. In immunosuppressed patients due to malignancies and treatment, VL should be considered as an opportunistic infection. In VL infections, the clinical manifestations mimicking hematological malignancies may cover up the underlying disease. Under such conditions, a complete work-up based on laboratory test is necessary to achieve a correct diagnosis.

PMID:
30235714
PMCID:
PMC6160114
DOI:
10.1097/MD.0000000000012410
[Indexed for MEDLINE]
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8.
Medicine (Baltimore). 2018 Sep;97(38):e12308. doi: 10.1097/MD.0000000000012308.

Dasatinib monotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia with pulmonary infection in induction remission: A case report and review of the literature.

Author information

1
Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China.

Abstract

RATIONALE:

There is currently no clinical standard for induction therapy in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Chemotherapy in combination with tyrosine kinase inhibitors (TKIs) recognized as the first line of therapy to induce remission in Ph ALL patients; however, both the infectious and non-infectious toxicities remain high and lead to early excessive treatment-related mortality (TRM). Single-agent TKI "monotherapy" may reduce toxicity and TRM; however, TKI induction monotherapy and its effectiveness in the induction of remission in newly diagnosed Ph ALL has yet to be investigated.

PATIENT CONCERNS:

A 59-year-old man who was newly diagnosed Ph ALL with 93% blast cells and a t (9, 22) karyotype. But the patient also suffered from pulmonary infection, including fever and dyspnea.

DIAGNOSES:

The patient was newly diagnosed with Ph ALL with pulmonary infection.

INTERVENTIONS:

The patient received oral dasatinib monotherapy (100 mg qd) for 28 days as induction therapy.

OUTCOMES:

The patient reached complete remission with negative minimal residual disease detected by real-time quantitative polymerase chain reaction after induction therapy for 28 days.

LESSONS:

This is the first report on the use of dasatinib monotherapy in the absence of other drugs, such as steroids, for induction therapy in a newly diagnosed Ph ALL patient with pulmonary infection.

PMID:
30235679
PMCID:
PMC6160254
DOI:
10.1097/MD.0000000000012308
[Indexed for MEDLINE]
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9.
N Engl J Med. 2018 Sep 20;379(12):1186. doi: 10.1056/NEJMc1809507.

Ivosidenib in IDH1-Mutated Acute Myeloid Leukemia.

Author information

1
University of Texas M.D. Anderson Cancer Center, Houston, TX cdinardo@mdanderson.org
PMID:
30231226
DOI:
10.1056/NEJMc1809507
[Indexed for MEDLINE]
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10.
BMC Bioinformatics. 2018 Sep 17;19(1):327. doi: 10.1186/s12859-018-2338-4.

Data-driven human transcriptomic modules determined by independent component analysis.

Author information

1
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
2
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. russ.altman@stanford.edu.
3
Department of Genetics, Stanford University, Stanford, CA, 94305, USA. russ.altman@stanford.edu.

Abstract

BACKGROUND:

Analyzing the human transcriptome is crucial in advancing precision medicine, and the plethora of over half a million human microarray samples in the Gene Expression Omnibus (GEO) has enabled us to better characterize biological processes at the molecular level. However, transcriptomic analysis is challenging because the data is inherently noisy and high-dimensional. Gene set analysis is currently widely used to alleviate the issue of high dimensionality, but the user-defined choice of gene sets can introduce biasness in results. In this paper, we advocate the use of a fixed set of transcriptomic modules for such analysis. We apply independent component analysis to the large collection of microarray data in GEO in order to discover reproducible transcriptomic modules that can be used as features for machine learning. We evaluate the usability of these modules across six studies, and demonstrate (1) their usage as features for sample classification, and also their robustness in dealing with small training sets, (2) their regularization of data when clustering samples and (3) the biological relevancy of differentially expressed features.

RESULTS:

We identified 139 reproducible transcriptomic modules, which we term fundamental components (FCs). In studies with less than 50 samples, FC-space classification model outperformed their gene-space counterparts, with higher sensitivity (p < 0.01). The models also had higher accuracy and negative predictive value (p < 0.01) for small data sets (less than 30 samples). Additionally, we observed a reduction in batch effects when data is clustered in the FC-space. Finally, we found that differentially expressed FCs mapped to GO terms that were also identified via traditional gene-based approaches.

CONCLUSIONS:

The 139 FCs provide biologically-relevant summarization of transcriptomic data, and their performance in low sample settings suggest that they should be employed in such studies in order to harness the data efficiently.

KEYWORDS:

Functional modules; Gene expression; Independent component analysis; Transcriptome

PMID:
30223787
PMCID:
PMC6142401
DOI:
10.1186/s12859-018-2338-4
[Indexed for MEDLINE]
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11.
Cell Physiol Biochem. 2018;49(4):1589-1599. doi: 10.1159/000493494. Epub 2018 Sep 17.

A Bayesian Network Meta-Analysis Comparing the Efficacies of Eleven Novel Therapies with the Common Salvage Regimen for Relapsed or Refractory Acute Myeloid Leukemia.

Author information

1
Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
2
Department of Hematology, North Sichuan Medical College, Nanchong, China.
3
Department of Obstetrics and Gynecology, Chengdu Integrated TCM and Western Medical Hospital, Chengdu, China.

Abstract

BACKGROUND/AIMS:

Acute myeloid leukemia (AML) is a relapsed and refractory hematological malignancy with a lower morbidity but higher mortality. In addition to hematopoietic stem cell transplantation, chemotherapy is used as the front-line treatment. However, the diversity of available agents and the inconsistency of outcomes of relevant trials render treatment decision-making tough. Network meta-analysis (NMA) is an efficient statistical framework that makes a comprehensive comparison and provides a valuable clinical reference.

METHODS:

All the potential trials were retrieved from the medical database and screened according to the inclusion and exclusion criteria. The main characteristics of each trial as well as the primary outcomes, including complete remission (CR), overall response rate (ORR), overall survival (OS), and event-free survival (EFS), were extracted. In addition, the network graph was plotted to illustrate the connections among the trials involved. Comparison results in the network were exhibited in a forest plot. Furthermore, the surface under the cumulative ranking curve (SUCRA) was introduced to rank the treatments for each endpoint.

RESULTS:

A total of 11 trials were selected from 1,625 identifications. No significant difference in the common treatment was observed for the endpoints CR and ORR. In terms of OS, CPX-351 (HR: 0.77, 95% CrI: 0.63, 0.94) and HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.68, 0.93) showed a superiority over the common salvage regimen in the short term, while HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.70, 0.93) and Ara-C plus vosaroxin (HR: 0.86, 95% CrI: 0.74, 0.99) outperformed the common salvage regimen for the 3-year OS. In addition, clofarabine plus Ara-C (HR: 0.61, 95% CrI: 0.53, 0.69) and CPX-351 (HR: 0.71, 95% CrI: 0.60, 0.83) were confirmed to be efficacious in enhancing the rate of EFS.

CONCLUSION:

Referring to the network outcome and SUCRA value, clofarabine plus Ara-C (CR: 79.05%, ORR: 80.02%) and Ara-C plus vosaroxin (CR: 75.42%, ORR: 73.43%) were potentially the top two choices for both CR and ORR. CPX-351 (1-year OS: 91.36%), HiDAC plus MK-8776 (3-year OS: 94.23%) and clofarabine plus Ara-C (1-year EFS: 97.34%) yielded the highest probabilities to be the optimal choices for 1-year OS, 3-year OS and 1-year EFS, respectively.

KEYWORDS:

Acute myeloid leukemia; Chemotherapy; Complete remission; Meta-analysis; Overall response rate

PMID:
30223267
DOI:
10.1159/000493494
[Indexed for MEDLINE]
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12.
BMC Bioinformatics. 2018 Sep 12;19(1):322. doi: 10.1186/s12859-018-2344-6.

Priority-Lasso: a simple hierarchical approach to the prediction of clinical outcome using multi-omics data.

Author information

1
Institute for Medical Information Processing, Biometry and Epidemiology, University of Munich, Munich, Germany. simonklau@ibe.med.uni-muenchen.de.
2
Institute for Medical Information Processing, Biometry and Epidemiology, University of Munich, Munich, Germany.
3
Department of Internal Medicine III, University of Munich, Munich, Germany.

Abstract

BACKGROUND:

The inclusion of high-dimensional omics data in prediction models has become a well-studied topic in the last decades. Although most of these methods do not account for possibly different types of variables in the set of covariates available in the same dataset, there are many such scenarios where the variables can be structured in blocks of different types, e.g., clinical, transcriptomic, and methylation data. To date, there exist a few computationally intensive approaches that make use of block structures of this kind.

RESULTS:

In this paper we present priority-Lasso, an intuitive and practical analysis strategy for building prediction models based on Lasso that takes such block structures into account. It requires the definition of a priority order of blocks of data. Lasso models are calculated successively for every block and the fitted values of every step are included as an offset in the fit of the next step. We apply priority-Lasso in different settings on an acute myeloid leukemia (AML) dataset consisting of clinical variables, cytogenetics, gene mutations and expression variables, and compare its performance on an independent validation dataset to the performance of standard Lasso models.

CONCLUSION:

The results show that priority-Lasso is able to keep pace with Lasso in terms of prediction accuracy. Variables of blocks with higher priorities are favored over variables of blocks with lower priority, which results in easily usable and transportable models for clinical practice.

KEYWORDS:

Cox regression; Lasso; Multi-omics data; Penalized regression; Prediction model; Priority-lasso

PMID:
30208855
PMCID:
PMC6134797
DOI:
10.1186/s12859-018-2344-6
[Indexed for MEDLINE]
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13.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1376-1391. doi: 10.1080/14756366.2018.1490734.

Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents.

Author information

1
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin , People's Republic of China.
2
b School of Pharmaceutical Sciences , Guangzhou Medical University , Guangzhou , People's Republic of China.
3
c Department of Hematology , Yantai Yuhuangding Hospital, Qingdao University Medical College , Yantai , People's Republic of China.

Abstract

A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound 7l showed greatly improved potency against AML progenitor cell line KG1a with IC50 value of 0.7 μM, and the efficacy was 8.7-folds comparing to that of PTL (IC50 = 6.1 μM). Compound 7l induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells. Furthermore, 7l suppressed the colony formation of primary human leukaemia cells. Moreover, compound 12, the salt form of 7l, prolonged the lifespan of mice in two patient-derived xenograft models and had no observable toxicity. The preliminary molecular mechanism study revealed that 7l-mediated apoptosis is associated with mitogen-activated protein kinase signal pathway. On the basis of these investigations, we propose that 12 might be a promising drug candidate for ultimate discovery of anti-LSCs drug.

KEYWORDS:

MAPK pathway; Parthenolide; dithiocarbamate; leukaemia stem cell; synthesis

PMID:
30208745
PMCID:
PMC6136352
DOI:
10.1080/14756366.2018.1490734
[Indexed for MEDLINE]
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14.
JAMA. 2018 Sep 11;320(10):995-1004. doi: 10.1001/jama.2018.12512.

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

Author information

1
The Hospital for Sick Children, Toronto, Ontario, Canada.
2
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
3
St Jude Children's Research Hospital, Memphis, Tennessee.
4
University of California, San Francisco, Benioff Children's Hospital, San Francisco.
5
Children's Oncology Group, Monrovia, California.
6
University of Southern California, Los Angeles, California.
7
City of Hope, Duarte, California.
8
Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburg, Pennsylvania.
9
Moffitt Cancer Center and Research Institute, Tampa, Florida.
10
Children's Healthcare of Atlanta, Egleston, Atlanta, Georgia.
11
McMaster Children's Hospital, Hamilton, Ontario, Canada.
12
Child Health Evaluation Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.

Abstract

Importance:

Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children.

Objective:

To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT.

Design, Setting, and Participants:

In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017.

Interventions:

Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214).

Main Outcomes and Measures:

The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects.

Results:

A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%-34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%-13.0%; P = .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1%; risk difference, 10.8%; 95% CI, 4.2%-17.5%; P = .002). There were no significant differences in severe infection (3.6% vs 5.9%; risk difference, 2.3%; 95% CI, -1.1% to 5.6%; P = .20), invasive fungal disease (2.9% vs 2.0%; risk difference, -1.0%; 95% CI, -3.4% to 1.5%, P = .41), C difficile-associated diarrhea (2.3% vs 5.2%; risk difference, 2.9%; 95% CI, -0.1% to 5.9%; P = .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3%; risk difference, 4.8%; 95% CI, -1.6% to 11.2%; P = .15) or at 12 months (10.1% vs 14.4%; risk difference, 4.3%; 95% CI, -3.4% to 12.0%; P = .28) between the levofloxacin and control groups.

Conclusions and Relevance:

Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.

PMID:
30208456
PMCID:
PMC6143098
[Available on 2019-03-11]
DOI:
10.1001/jama.2018.12512
[Indexed for MEDLINE]
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15.
16.
N Engl J Med. 2018 Sep 13;379(11):1028-1041. doi: 10.1056/NEJMoa1804714.

Mutation Clearance after Transplantation for Myelodysplastic Syndrome.

Author information

1
From the Department of Pathology and Immunology (E.J.D.), the Department of Medicine, Division of Oncology (M.A.J., C.A.M., N.E., J.S., K.E., J.R., S.E.H., K.B., L.D.W., M.J.C., I.P., J.S.W., G.L.U., D.C.L., J.F.D., P.W., T.J.L., M.J.W.), the McDonnell Genome Institute (G.S.C., C.A.M., H.A., R.S.F., C.C.F., M.O.), the Department of Medicine, Division of Hospital Medicine (R.S.), and Siteman Biostatistics Shared Resource, Siteman Cancer Center (K.T.), Washington University School of Medicine in St. Louis, St. Louis; and Massachusetts General Hospital Cancer Center, Boston (T.A.G.).

Abstract

BACKGROUND:

Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for patients with myelodysplastic syndrome (MDS). The molecular predictors of disease progression after transplantation are unclear.

METHODS:

We sequenced bone marrow and skin samples from 90 adults with MDS who underwent allogeneic hematopoietic stem-cell transplantation after a myeloablative or reduced-intensity conditioning regimen. We detected mutations before transplantation using enhanced exome sequencing, and we evaluated mutation clearance by using error-corrected sequencing to genotype mutations in bone marrow samples obtained 30 days after transplantation. In this exploratory study, we evaluated the association of a mutation detected after transplantation with disease progression and survival.

RESULTS:

Sequencing identified at least one validated somatic mutation before transplantation in 86 of 90 patients (96%); 32 of these patients (37%) had at least one mutation with a maximum variant allele frequency of at least 0.5% (equivalent to 1 heterozygous mutant cell in 100 cells) 30 days after transplantation. Patients with disease progression had mutations with a higher maximum variant allele frequency at 30 days than those who did not (median maximum variant allele frequency, 0.9% vs. 0%; P<0.001). The presence of at least one mutation with a variant allele frequency of at least 0.5% at day 30 was associated with a higher risk of progression (53.1% vs. 13.0%; conditioning regimen-adjusted hazard ratio, 3.86; 95% confidence interval [CI], 1.96 to 7.62; P<0.001) and a lower 1-year rate of progression-free survival than the absence of such a mutation (31.3% vs. 59.3%; conditioning regimen-adjusted hazard ratio for progression or death, 2.22; 95% CI, 1.32 to 3.73; P=0.005). The rate of progression-free survival was lower among patients who had received a reduced-intensity conditioning regimen and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 than among patients with other combinations of conditioning regimen and mutation status (P≤0.001). Multivariate analysis confirmed that patients who had a mutation with a variant allele frequency of at least 0.5% detected at day 30 had a higher risk of progression (hazard ratio, 4.48; 95% CI, 2.21 to 9.08; P<0.001) and a lower 1-year rate of progression-free survival than those who did not (hazard ratio for progression or death, 2.39; 95% CI, 1.40 to 4.09; P=0.002).

CONCLUSIONS:

The risk of disease progression was higher among patients with MDS in whom persistent disease-associated mutations were detected in the bone marrow 30 days after transplantation than among those in whom these mutations were not detected. (Funded by the Leukemia and Lymphoma Society and others.).

PMID:
30207916
DOI:
10.1056/NEJMoa1804714
[Indexed for MEDLINE]
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17.
Medicine (Baltimore). 2018 Sep;97(36):e12214. doi: 10.1097/MD.0000000000012214.

Whole exome sequencing detects CHST3 mutation in patient with acute promyelocytic leukemia: A case report.

Author information

1
Department of Hematology, Provincial Hospital Affiliated to Shandong University.
2
Department of Diagnostics, Shandong University School of Medicine, Jinan, China.

Abstract

RATIONALE:

Acute promyelocytic leukemia (APL) is a kind of acute myeloid leukemia, which was characterized by the presence of PML/RARα fusion gene. Mutations in CHST3 have been previously reported to be associated with a rare phenotype of skeleton dysplasia, known as Spondyloepiphyseal dysplasia. Here we reported 1 patient with APL with CHST3 mutations.

PATIENT CONCERNS:

An 18-year-old girl was referred to the Hematology Department because of a lasting history (10 days) of repeated fever and bleeding on skin. The girl was of short stature for age and with short fingers. Double nail beds were short with anti-nail deformity.

DIAGNOSES:

She was diagnosed with APL according to the 2016 WHO classification after a MICM analysis (bone marrow morphology [M], immunophenotype [I], cytogenetics [C], and molecular biology [M]). Whole exome sequencing revealed complex heterozygous mutations on CHST3. Further confirmation showed that 1 mutation (c.155T>G; p.Leu52Arg) was from her father and the other mutation (c.1414G>A; p.Glu472Lys) was from her mother.

INTERVENTIONS:

The patient received Idarubicin (8 mg/m) injection intravenous drip for 3 days based on all-trans retinoic acid and arsenic trioxide induction therapy.

OUTCOMES:

The patient died from disseminated intravascular coagulation and multiple organ hemorrhage at 9 days after diagnosis.

LESSONS:

This case describes a patient with APL with complex heterozygous mutations on CHST3. Carbohydrate sulfotransferases were found to play an important role in metastatic spread of tumor cells. Whether the mutation status of CHST3 gene has relationship with APL pathogenesis and prognosis is unknown.

PMID:
30200136
PMCID:
PMC6133617
DOI:
10.1097/MD.0000000000012214
[Indexed for MEDLINE]
Free PMC Article
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18.
Medicine (Baltimore). 2018 Sep;97(36):e12119. doi: 10.1097/MD.0000000000012119.

A quality-of-life system to evaluate children with leukemia in China.

Wang Z1,2,3,4, Mo L2,3,4,5, Jiang X2,3,4,6, Liu Y1,2,3,4, Shi L1,2,3,4.

Author information

1
The Academy of Pediatrics of Chongqing Medical University.
2
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University.
3
China International Science and Technology Cooperation Base of Child Development and Critical Disorders.
4
Chongqing Key Laboratory of Pediatrics, Chongqing, China.
5
VIP Outpatient.
6
Nursing Department.

Abstract

The scale for assessing the quality of life (QOL) of children with leukemia of different ages is vacant in China.Items for developing a QOL scale were selected through a literature review, interviews with 58 parents and children with leukemia by Delphi method, which involved pediatric oncologists, psychologists, and pediatricians. The initial items were formulated through 2 rounds of the Delphi method and statistical analyses. The formulated scale was pre-tested for reliability and validity. A method was adopted to weight the importance of items within the evaluation index system.The final scale includes 5 dimensions. There are 10 secondary items for age 2 to 4 years, 12 secondary items for all other age groups, and 29, 46, 52, and 50 tertiary items for the age groups 2 to 4 years, 5 to 7 years, 8 to 12 years, and 13 to 18 years, respectively. The authority coefficient for experts was 0.75, with Kendall's W coefficient P < .01, for both rounds. The entire Cronbach alpha was >0.9, and the content validity >0.75. The weights of the first-grade items are: 0.201, 0.203, 0.198, 0.201, and 0.198.This quality-of-life scale for children with leukemia in China has demonstrated reliability and validity, while a further validity assessment is required.

PMID:
30200097
PMCID:
PMC6133475
DOI:
10.1097/MD.0000000000012119
[Indexed for MEDLINE]
Free PMC Article
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20.
Arq Bras Cardiol. 2018 Aug;111(2):226-227. doi: 10.5935/abc.20180110.

Unexpected Mass in the Left Atrium.

[Article in English, Portuguese]

Author information

1
Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisboa - Portugal.
2
Anatomopathology Department, Santa Maria University Hospital, CHLN, Faculty of Medicine, University of Lisbon, Lisboa - Portugal.
PMID:
30183992
PMCID:
PMC6122916
DOI:
10.5935/abc.20180110
[Indexed for MEDLINE]
Free PMC Article
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