Back to the future of oridonin: again,compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo

繁体中文药(TCM ) 广泛地并且成功地被过去常 intreating 病从发炎到癌症，并且从药草和矿物质的混合物在驯养疾病的各种各样的类型正在起越来越重要的作用，由 artemisinin 和砷三氧化物(ATO ) 例示。Artemisinin (或用汉语的 Qinghaosu ) 从称为香甜的苦恼的植物被孤立(Artemisia annua；或用汉语的 Qinghao ) 它在中国被用作退热的疗法超过 1500 年了。 Artemisinin 有出色的 parasiticidalproperties 试管内和体内，并且现在是抗疟药 agents.ATO 的最重要的班之一一普通，与古老的哲学为一些严重疾病很长时间在中国被用作一个治疗学的代理人的自然地发生的物质“对待罪恶与一有毒”。在 1990 年代， ATO 被显示能在尖锐 promyelocytic 的高集中在低剂量 andapoptosis 引起部分区别白血病(APL ) 房间，并且与 relapsed 或倔强的 APL 在 90% 病人导致完全的宽恕。这些范例建议 TCM 不仅为中国人民，而且为整个人是财富房子。与差的预后为疾病从 TCM 开发基于证据的治疗学的途径是我们的责任。

Erythropoietin Receptor Positive Circulating Progenitor Cells and Endothelial Progenitor Cells in Patients with Different Stages of Diabetic Retinopathy

Objective To investigate the possible involvement of erythropoietin (EPO)/erythropoietin receptor (EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR). Methods EPOR positive circulating progenitor cells (CPCs: CD34+) and endothelial pro-genitor cells (EPCs: CD34+KDR+) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients without diabetes (n=7), non-proliferative DR (NPDR, n=7), proliferative DR (PDR, n=8), and PDR complicated with diabetic nephropathy (PDR-DN, n=7). Results The numbers of EPOR+ CPCs and EPOR+ EPCs were reduced remarkably in NPDR compared with the control group (both P<0.01), whereas rebounded in PDR and PDR-DN groups in varying degrees. Similar changes were observed in respect of the proportion of EPOR+ CPCs in CPCs (NPDR vs. control, P<0.01) and that of EPOR+ EPCs in EPCs (NPDR vs. control, P<0.05). Conclusion Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the impaired vascular regeneration in NPDR, whereas it might aggravate retinal neovasculariza-tion in PDR due to a rebound of EPOR+ EPCs associated with ischemia.

Evaluation of retinal and choroidal changes in patients with Alzheimer’s type dementia using optical coherence tomography angiography

AIM:To evaluate the changes in fundus parameters in patients with Alzheimer’s type dementia(ATD)using optical coherence tomography angiography(OCTA),to record flash electroretinograms(ERG)using the RETeval system and to explore changes in retinal function.METHODS:Twenty-nine patients with ATD and 26 age-matched normal subjects were enrolled.All subjects underwent OCTA scans to analyse the superficial retinal vessel parameters in the macular area,including the vessel length density,the vessel perfusion density and the area of foveal avascular zone(FAZ),as well as the choroidal thickness.The differences between the patients with ATD and the normal control group were compared and explored the relevant factors affecting vessel parameters.We also recorded the flash ERGs using the RETeval system and intended to explore changes in retinal function by analysing the ERG image amplitude in patients with ATD.RESULTS:The vessel parameters[Pvessel length density=0.005 and Pvessel perfusion density=0.006]and average choroid thickness(P<0.001)in the macular area of the ATD group was less than the control group.The FAZ area was statistically significantly enlarged in the ATD group(P<0.001).These parameters were correlated with the Mini-Mental State Examination(MMSE)score and the Montreal Cognitive Assessment(MoCA).CONCLUSION:Patients with ATD exhibit decreases in the parameters associated with fundus.In addition,these indicators significantly correlate with the MMSE score and the MoCA score.OCTA may be an adjunct tool with strong potential to track changes in the diagnosis and monitoring the progression of the disease.

Organotypic Models for Functional Drug Testing of Human Cancers

In the era of personalized oncology,there have been accelerated efforts to develop clinically relevant platforms to test drug sensitivities of individual cancers.An ideal assay will serve as a diagnostic companion to inform the oncologist of the various treatments that are sensitive and insensitive,thus improving outcome while minimizing unnecessary toxicities and costs.To date,no such platform exists for clinical use,but promising approaches are on the horizon that take advantage of improved techniques in creating human cancer models that encompass the entire tumor microenvironment,alongside technologies for assessing and analyzing tumor response.This review summarizes a number of current strategies that make use of intact human cancer tissues as organotypic cultures in drug sensitivity testing.

Management and operation of extra-large Fangcang hospitals:experience and lessons from containing the highly contagious SARS-CoV-2 Omicron in Shanghai,China

Introduction Omicron is more contagious and stealthier than the previous strains.The basic reproduction number of Omicron is around 8–12,whereas that of the previous mainstream strain Delta is only 5–8[1].Omicron’s symptoms are relatively mild[2]compared with Delta’s symptoms;however,Omicron’s transmission ability is very strong,and its risk to children and the elderly remains high[3].In addition,the vaccine’s preventive effect on Omicron has weakened.Therefore,Omicron can easily cause a rapid outbreak in a city.The population density of megacities and the limited public health resources further exacerbate the difficulty of Omicron prevention and control.

Chinese Society of Clinical Oncology(CSCO) diagnosis and treatment guidelines for malignant lymphoma 2021(English version)

1. General guidelines2. Diagnosis3. Staging4. Treatment4.1 Diffuse large B-cell lymphoma(DLBCL)4.2 Follicular lymphoma(FL)4.3 Mantle cell lymphoma(MCL)4.4 Marginal zone lymphoma(MZL)4.5 Burkitt lymphoma(BL)4.6 CLL/Small lymphocytic lymphoma(SLL)4.7 Extra-nodal natural killer/T-cell lymphoma(ENKTCL), nasal type4.8 Peripheral T-cell lymphoma(PTCL)4.9 HL4.10 Primary central nervous system lymphoma5. Prognosis Lymphomas are a group of heterogeneous diseases.

Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease

BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.

Efficacy and safety of combined decitabine and ruxolitinib in the treatment of chronic myelomonocytic leukemia

Objective The aim of the study was to evaluate the clinical efficacy of decitabine(DEC)combined with ruxolitinib(RUX)in the treatment of chronic myelomonocytic leukemia(CMML).Methods The clinical characteristics of 12 patients with CMML were analyzed retrospectively and subsequent target sequencing was performed to investigate the efficacy of the combined treatment with DEC and RUX and the molecular signatures therein.Results Among the 12 cases,clinical improvement was observed in all patients(100%),spleen reduction was observed in six patients(67%),and hematologic improvement was observed in four patients(33%).In the CMML-1 group,the overall response was 50%(3/6),one case achieved complete response,one achieved bone marrow remission,and one achieved hematological improvement.In the CMML-2 group,the overall response was 17%(1/6),one case achieved complete response,four showed disease progression(PD),and one exhibited no response.As expected,ASXL1 mutation was predictive for the outcome of CMML(hazard ratio of 2.97,95%confidence interval of 1.21–7.06;P=0.02).Conclusion The use of DEC combined with RUX in the treatment of CMML effectively improved the clinical response and quality of life,especially for CMML-1 patients.Ongoing clinical trials will further evaluate the safety and efficacy of this novel therapeutic approach.

Positron emission tomography-adapted therapy in low-risk diffuse large B-cell lymphoma:results of a randomized,phase Ⅲ,non-inferiority trial

Background:The current standard of care for non-bulky diffuse large B-cell lymphoma(DLBCL)patients with an International Prognostic Index(IPI)of 0 is four cycles of rituximab plus cyclophosphamide,doxorubicin,vincristine and prednisone(R-CHOP)but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear.This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography(PET-CT,Deauville 1-3),irrespective of age and other IPI risk factors(IPI 0-1).Methods:This was an open-label,randomized,phaseⅢ,non-inferiority trial.Patients aged 14-75 years with newly diagnosed low-risk DLBCL,according to IPI,achieving PET-CT confirmed complete response(CR)after four cycles of R-CHOPwere randomized(1:1)between four cycles of rituximab(4R-CHOP+4R arm)or two cycles of R-CHOP plus two cycles of rituximab(6R-CHOP+2R arm).The primary endpoint was 2-year progression-free survival(PFS),conducted in the intention-to-treat population.Safety was assessed in patients with at least one cycle of assigned treatment.The non-inferiority margin was-8%.Results:A total of 287 patients were included in the intention-to-treat analysis,the median follow-up was 47.3 months,and the 2-year PFS rate was 95%(95%confidence interval[CI],92%to 99%)and 94%(95%CI,91%to 98%)for the 4R-CHOP+4R and 6R-CHOP+2R arm.The absolute difference in 2-year PFS between the two arms was 1%(95%CI,-5%to 7%),supporting the non-inferiority of 4R-CHOP+4R.Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm(16.7%versus 76.9%),with decreased risk of febrile neutropenia(0.0%versus 8.4%)and infection(2.1%versus 14.0%).Conclusions:For newly diagnosed low-risk DLBCL patients,interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might have high-risk biological features or develop resistance.Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low-risk,non-bulky DLBCL with interim PET-CT confirmed CR.

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Exploration of the financing and management model of a children＇s critical disease security system in China based on the implementation of Shanghai Children Hospital Care Aid

This study is designed to serve as a reference for the establishment of health security systems for children＇s critical diseases. Through analysis of the operation of Shanghai Children Hospital Care Aid （SCHCA）, this study explored the financing model and management of a children＇s critical disease healthcare system and analyzed the possibility of expanding this system to other areas. It is found that a premium as Iow as RMB 7 per capita per year under SCHCA can provide high-level security for children＇s critical diseases. With the good experience in Shanghai and based on the current basic medical insurance system for urban residents and the new rural cooperative medical scheme （NRCMS）, it is necessary and feasible to build a health security system for children＇s critical diseases at the national level.

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia

The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

E674Q(Shanghai APP mutant),a novel amyloid precursor protein mutation,in familial late-onset Alzheimer's disease

Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel missense mutation,APP E674Q(also named“Shanghai APP”),was detected in a Chinese index patient with typical late-onset AD(LOAD)who developed memory decline in his mid-70s.The results from neuroimaging were consistent with AD,where widespread amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-secretase cleavage site and the well-studied Swedish APP mutation(KM670/671NL),which was predicted to be pathogenic in silico.Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1.The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ.Furthermore,we applied an adeno-associated virus(AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice.AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain,implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation.Collectively,we report a strong amyloidogenic effect of the E674Q substitution in AD.To our knowledge,E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

It has been known that,the novel coronavirus,2019-nCoV,which is considered similar to SARS-CoV,invades human cells via the receptor angiotensin converting enzyme II(ACE2).Moreover,lung cells that have ACE2 expression may be the main target cells during 2019-nCoV infection.However,some patients also exhibit non-respiratory symptoms,such as kidney failure,implying that 2019-nCoV could also invade other organs.To construct a risk map of different human organs,we analyzed the single-cell RNA sequencing(scRNA-seq)datasets derived from major human physiological systems,including the respiratory,cardiovascular,digestive,and urinary systems.Through scRNA-seq data analyses,we identified the organs at risk,such as lung,heart,esophagus,kidney,bladder,and ileum,and located specific cell types(i.e.,type II alveolar cells(AT2),myocardial cells,proximal tubule cells of the kidney,ileum and esophagus epithelial cells,and bladder urothelial cells),which are vulnerable to 2019-nCoV infection.Based on the findings,we constructed a risk map indicating the vulnerability of different organs to 2019-nCoV infection.This study may provide potential clues for further investigation of the pathogenesis and route of 2019-nCoV infection.

Molecular classification and precision therapy of cancer： immune checkpoint inhibitors

On May 23, 2017, the US Food and Drug Administration （FDA） approved a treatment for cancer patients with positive microsatellite instability-high （MSI-H） markers or mismatch repair deficient （dMMR） markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-l/ programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantlgen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as ＂genetic interpreters＂ or ＂genetic translators＂ and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Background Freezing of gait(FOG)is a common,disabling symptom of Parkinson’s disease(PD),but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers.The main focus of this review is to summarize the possible mechanisms underlying FOG,the risk factors for screening and predicting the onset of FOG,and the clinical trials involving various therapeutic strategies.In addition,the limitations and recommendations for future research design are also discussed.Main body In the mechanism section,we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG.In the risk factor section,gait disorders,PIGD phenotype,lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence.In the treatment section,we summarized the clinical trials of pharmacological and non-pharmacological treatments.Despite the limited effectiveness of current medications for FOG,especially levodopa resistant FOG,there were some drugs that showed promise such as istradefylline and rasagiline.Non-pharmacological treatments encompass invasive brain and spinal cord stimulation,noninvasive repetitive transcranial magnetic stimulation(rTMS)or transcranial direct current stimulation(tDCS)and vagus nerve stimulation(VNS),and physiotherapeutic approaches including cues and other training strategies.Several novel therapeutic strategies seem to be effective,such as rTMS over supplementary motor area(SMA),dual-site DBS,spinal cord stimulation(SCS)and VNS.Of physiotherapy,wearable cueing devices seem to be generally effective and promising.Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration.Several risk factors of FOG have been identified,but need combinatorial optimization for predicting FOG more precisely.Although firm conclusions cannot be drawn on therapeutic efficacy,the literature suggested that some therapeutic strategies showed promise.

Hemiballism-hemichorea induced by ketotic hyperglycemia: case report with PET study and review of the literature

Hemiballism-hemichorea(HB-HC)is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients.Here we report two elderly female patients with acute onset of involuntary movements induced by hyperglycemia with positive urine ketones.We described the computed tomography and magnetic resonance imaging findings in these two patients,which is similar to that of non-ketotic hyperglycemic HB-HC patients.FDG-PET was performed and the glucose metabolism in the corresponding lesion in these two patients was contradictory with each other.We tried to clarify the underlying mechanisms of HB-HC and explain the contradictory neuroradiological findings in FDG-PET as being performed at different clinical stages.

The China Alzheimer Report 2022

China’s population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated,especially Alzheimer’s disease(AD)and related dementias(ADRD).AD’s incidence rate,morbidity,and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals,families and society.The‘Healthy China Action’plan of 2019-2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD.This report describes related epidemiological trends,evaluates the economic burden of the disease,outlines current clinical diagnosis and treatment status and delineates existing available public health resources.More specifically,it examines the public health impact of ADRD,including prevalence,mortality,costs,usage of care,and the overall effect on caregivers and society.In addition,this special report presents technical guidance and supports for the prevention and treatment of AD,provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation.

Homoharringtonine synergy with oridonin in treatment of t(8;21) acute myeloid leukemia

Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8;21) acute myeloid leukemia (AML).Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8;21) AML.Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations,whereas oridonin can induce t(8;21) AML cell apoptosis and AE cleavage.Therefore,studies should explore the efficacy of combination therapy with oridonin and HHT in t(8;21) AML.In this study,we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8;21) AML cell line and mouse model.The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis.Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage.HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1,thus enhancing the effects of oridonin.The combination of oridonin and HHT prolonged t(8;21) leukemia mouse survival.In conclusion,oridonin and HHT exert synergistic effects against t(8;21) leukemia in vivo and in vitro,thereby indicating that their combination may be an effective therapy for t(8;21) leukemia.

Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy:China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study

Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies.In this study,we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n=3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression,which included the following variables: male patients,induction chemotherapy for newly diagnosed or relapsed disease,neutropenia,neutropenia longer than 10 days,hypoalbuminemia,central-venous catheter,and history of IFD.The patients were classified into three groups,which had low (0-10,~1.2%),intermediate (11-15,6.4%),and high risk (> 15,17.5%) of IFD.In the validation set (n=1389),the IFD incidences of the groups were ~1.4%,5.0%,and 21.4%.In addition,we demonstrated that antifungal prophylaxis offered no benefits in low-risk patients,whereas benefits were documented in intermediate (2.1% vs.6.6%,P=0.007) and high-risk patients (8.4% vs.23.3%,P=0.007).To make the risk score applicable for clinical settings,a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established,and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD.In conclusion,an objective,weighted risk score for IFD was developed,and it may be useful in guiding antifungal prophylaxis.