• Chimerism
• Conditioning
• Donor
• HLH
• Immunodeficiency
• Stem cell transplant

• Humans
• Lymphohistiocytosis, Hemophagocytic/therapy
• Hematopoietic Stem Cell Transplantation/methods
• Child
• Transplantation Conditioning/methods
• Adult
• Transplantation, Homologous

• CDR3
• HLH
• Immune rearrangement
• Immune repertoire
• TCR

• IL-1 blockade
• IL-1 receptor antagonist
• anakinra
• dengue
• dengue with warning signs
• interleukin-1 blockade
• severe dengue
• trial

• Wellcome Trust

• cytokine storm syndromes
• cytokines
• hyperinflammation
• immune response
• yin-yang

• Humans
• Cytokine Release Syndrome/immunology
• Yin-Yang
• Cytokines/metabolism
• Cytokines/immunology
• Animals
• Inflammation/immunology

• UM1 TR004538 NCATS NIH HHS

• Humans
• Lymphohistiocytosis, Hemophagocytic/genetics
• Lymphohistiocytosis, Hemophagocytic/etiology
• Mutation
• fas Receptor/genetics
• Female
• Male
• Middle Aged
• Lymphoma, T-Cell/genetics
• Lymphoma, T-Cell/complications
• Adult
• Signal Transduction
• Killer Cells, Natural/metabolism
• Aged
• Genetic Predisposition to Disease

• P30 CA008748 NCI NIH HHS
• P50 CA254838 NCI NIH HHS
• K08 CA267058 NCI NIH HHS

• Adolescents
• Familial HLH
• Hemophagocytic lymphohistiocytosis (HLH)
• Primary immunodeficiency
• Secondary HLH
• Young adults

• Humans
• Adolescent
• Young Adult
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/genetics
• Lymphohistiocytosis, Hemophagocytic/therapy
• Genetic Predisposition to Disease
• Neoplasms/complications
• Mutation

• HLH-related gene variants
• Hemophagocytic lymphohistiocytosis (HLH)
• adult secondary HLH
• severe HLH in adults

• Adult
• Humans
• Adolescent
• Lymphohistiocytosis, Hemophagocytic/genetics
• Lymphohistiocytosis, Hemophagocytic/therapy
• Alleles
• Genotype
• Signaling Lymphocytic Activation Molecule Associated Protein/genetics
• X-Linked Inhibitor of Apoptosis Protein/genetics

• Allogeneic hematopoietic stem cell transplantation
• Hemophagocytic lymphohistiocytosis
• Heterozygous mutation
• PRF1

• Male
• Humans
• Adult
• Lymphohistiocytosis, Hemophagocytic/genetics
• Lymphohistiocytosis, Hemophagocytic/therapy
• Perforin/genetics
• Mutation
• Mutation, Missense
• Hematopoietic Stem Cell Transplantation

• hlh
• h-score
• pakistan
• primary
• secondary

• Adult
• Humans
• Child
• Retrospective Studies
• Lymphohistiocytosis, Hemophagocytic/complications
• Tertiary Care Centers
• Fibrinogen
• Ferritins

• Adult
• Child
• Humans
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/therapy
• Macrophage Activation Syndrome/diagnosis
• Macrophage Activation Syndrome/etiology
• Macrophage Activation Syndrome/therapy
• Consensus
• Physicians
• Advisory Committees

• K23 GM148827 NIGMS NIH HHS
• L30 AI147146 NIAID NIH HHS
• Z99 AI999999 Intramural NIH HHS

• Still's disease, adult-onset
• arthritis, juvenile
• cytokines
• inflammation

• Child
• Adult
• Humans
• United States
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/therapy
• Lymphohistiocytosis, Hemophagocytic/etiology
• Macrophage Activation Syndrome/diagnosis
• Macrophage Activation Syndrome/etiology
• Macrophage Activation Syndrome/therapy
• Rheumatology
• Consensus

• R01 HD098428 NICHD NIH HHS
• Z99 AI999999 Intramural NIH HHS
• L30 AI147146 NIAID NIH HHS
• K12 HD047349 NICHD NIH HHS
• K23 GM148827 NIGMS NIH HHS

• Epstein-Barr virus
• Hemophagocytic lymphohistiocytosis
• Lymphoma
• Overall survival
• Prognosis

• 82100207 National Natural Science Foundation of China
• 81720108002 National Natural Science Foundation of China
• BK20210962 Natural Science Foundation of Jiangsu Province
• 2020ZKZB01 Translational Research Grant of NCRCH

• children
• early predictive factor
• kawasaki disease
• macrophage activation syndrome
• retrospective case-control study

• IFN-β
• STING
• UNC13D
• innate immunity
• proinflammatory cytokines

• Endoplasmic Reticulum/metabolism
• Signal Transduction
• Immunity, Innate
• Interferon-beta/genetics
• Interferon Type I

• National Natural Science Foundation of China (NSFC)

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, which can be primary (due to genetic mutation) or secondary to malignancy, infection and rheumatologic diseases. Data concerning Belgian patients with adult HLH are lacking.

This retrospective study was performed in a teaching hospital in Belgium. All cases of adult HLH, from December 2010 to April 2022, were reviewed. Patients with more than five HLH-2004 criteria and/or HScore >80% were included in the study. The objective of our study was to describe clinical and biological characteristics of patients with HLH and attempt to look for variables associated with mortality.

Fifty-two patients were included in the final analysis. Mean age (SD) of patients was 48 (18) years old, and 29 patients were of male gender (56%). The underlying diseases associated with HLH were malignancy (M-HLH) in 22 patients, infection related HLH in 20 patients, rheumatologic disease related HLH in 7 patients, idiopathic in 2 patients and secondary to pregnancy in 1 patient. Overall mortality, mortality at 30 days and 90 days were 24/52 (46%), 13/52 (25%) and 4/52 (10%), respectively. In univariate analysis, malignancy, male sex, age and disseminated intravascular coagulation (DIC) were associated with mortality (p < 0.05). In multivariate analysis, only age was significantly associated with mortality (odds ratio, 1.053; 95% confidence interval, 1.016–1.092; p 0.005).

In our study, the most frequent triggers were malignancy and infectious agent followed by rheumatologic disease. Risk factors for mortality were age, male sex, malignancy and DIC, but only age remained significant in multivariate analysis. Treatment guidelines are mainly based on pediatric patients, and it is important for physician to describe adult patients’ outcome to better understand this disease and adapt treatment.

• funding agencies in the public, commercial, or not-for-profit sectors

Familial hemophagocytic lymphohistiocytosis (HLH) is a rare genetic and life-threatening immunodeficiency disease. Here, we present a 38-year-old male who initially developed multiple annular to irregular erythema accompanied by a fever after COVID-19 vaccination. He was diagnosed with HLH with evidence of leukocytopenia in a full blood test, elevations of ferritin and sCD25, decreased NK cell function, and hemophagocytosis of a bone marrow biopsy specimen. A genetic examination revealed two probable disease-causing heterozygous mutations on UNC13D associated with type 3 familial HLH. A review of the case reports relevant to HLH following COVID-19 vaccination and the cutaneous manifestations of HLH with genetic defects suggests the necessity that individuals with preexisting immune dysregulation or diseases not classified should be cautious about COVID-19 vaccination and reminds clinicians that various recalcitrant skin lesions may be a sign of HLH.

• Adult
• Epstein-Barr Virus Infections
• Herpesvirus 4, Human
• Humans
• Leukemia
• Lymphohistiocytosis, Hemophagocytic
• Male
• Neoplasms
• Retrospective Studies

• National Natural Science Foundation of China
• Natural Science Foundation of Jiangsu Province

Complex crosstalk between tumor cells and platelets is closely related to the development, relapse, and drug resistance of hepatocellular carcinoma (HCC). Therefore, an intensive analysis of the relationship between platelet-related genes and the effectiveness of immunotherapy is necessary for improving the poor prognosis of HCC patients.

Genes associated with platelets in the GeneCards database were collected and were used to identify molecular subtypes using a non-negative matrix decomposition algorithm (NMF) and constructed a platelet-related genes-based prognostic stratification model by the LASSO-Cox regression and stepwise Cox regression analysis. The effect of this feature on the immune microenvironment of HCC and the response to immune checkpoint inhibitors was also explored.

After identifying two molecular subtypes, we constructed a platelet-related genes-based prognostic stratification model that can be effectively used for immune checkpoint inhibitor (PD1, PD-L1, PD-L2, and CTLA4) efficacy and prognosis prediction in HCC patients, which was subsequently validated using patient samples from ICGC, GSE14520 and a small sample size clinical cohort. We also found downregulation of PAFAH1B3 remarkably inhibited the proliferation and migration ability of Hep3B cells by cytological experiments.

We constructed a prognostic classifier based on platelet-related genes that could effectively classify HCC patients for prognostic prediction and provide new light on the selection of optimal individualized antiplatelet therapy for HCC patients in future clinical practice.

• is no funding

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan–Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.

• Adult
• Humans
• Lymphohistiocytosis, Hemophagocytic/therapy
• Lymphoma
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Survival Rate

• Natural Science Foundation of Jiangsu Province

• hemophagocytic lymphohistiocytosis (HLH)
• macrophage activation syndrome (MAS)
• mortality rate
• pediatric patients
• prognostic factor

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.

• cytotoxic lymphocyte
• degranulation
• digenic
• hemophagocytic lymphohistiocytosis
• natural killer cell
• variants

• Adaptin protein
• cancer
• cargo protein
• cellular pathology
• clathrin
• intracellular trafficking
• virus infection

• Adaptor Proteins, Vesicular Transport/metabolism
• Apoptosis
• Biological Transport
• Cell Proliferation
• Humans
• Signal Transduction

• PRF1
• STX11
• STXBP2
• UNC13D
• vietnamese

• immunogenetics
• viral infection

• Adaptor Protein Complex 3/genetics
• Adaptor Protein Complex 3/metabolism
• Adaptor Protein Complex beta Subunits/genetics
• Adaptor Protein Complex beta Subunits/metabolism
• Aged
• COVID-19/genetics
• COVID-19/immunology
• COVID-19/metabolism
• COVID-19/pathology
• Cytokine Release Syndrome/genetics
• Humans
• Lymphohistiocytosis, Hemophagocytic/genetics
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Middle Aged

• Emergency Research Project of Tongji Hospital of Huazhong University of Science and Technology (2020kfyXGYJ045, to Dr. JZ);Key Program of the National Natural Science Foundation of China (81830008, to Dr. JZ)
• the National Natural Science Foundation of China (81770211 to Dr. MX)
• the National Natural Science Foundation of China (81873454 to Dr. XL)
• Emergency Research Project of Hubei province (2020FCA006, to Dr. WW)
• The Social Development, Project of Jiangsu Province (BE2017659 to Dr. QW); Beijing Natural Science Foundation (M21022, to Dr. QW)

• Adult
• Chronic Disease
• Class I Phosphatidylinositol 3-Kinases/genetics
• Epstein-Barr Virus Infections/genetics
• Fatal Outcome
• Gain of Function Mutation
• Humans
• Lymphohistiocytosis, Hemophagocytic/genetics
• Male
• Primary Immunodeficiency Diseases/genetics
• Young Adult

• EBV-associated T/NK-cell lymphoproliferative disease
• gene sequencing
• germline mutation
• hemophagocytic lymphohistiocytosis
• lymphocyte cytotoxicity
• primary immunodeficiencies

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Child
• Child, Preschool
• China/epidemiology
• Female
• Genetic Predisposition to Disease
• Herpesvirus 4, Human/genetics
• Herpesvirus 4, Human/pathogenicity
• Humans
• Infant
• Killer Cells, Natural/pathology
• Killer Cells, Natural/virology
• Lymphoproliferative Disorders/epidemiology
• Lymphoproliferative Disorders/genetics
• Lymphoproliferative Disorders/pathology
• Lymphoproliferative Disorders/virology
• Male
• Middle Aged
• Mutation/genetics
• Neoplasm Proteins/genetics
• T-Lymphocytes/pathology
• T-Lymphocytes/virology
• Young Adult

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motor neurons, causing muscle atrophy, bulbar palsy, and pyramidal tract signs. However, the aetiology and pathogenesis of ALS have not been elucidated to date. In this study, a competitive endogenous RNA (ceRNA) network was constructed by analyzing the expression profiles of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) that were matched by 7 ALS samples and 4 control samples, and then a protein-protein interaction (PPI) network was constructed to identify the genes related to ALS. Gene Ontology (GO) was used to study the potential functions of differentially expressed mRNAs (DEmRNAs) in the ceRNA network. For the ALS and control groups, 247177 potential lncRNA-mRNA ceRNA relationship pairs were screened. Analysis of significant relationship pairs demonstrated that the PPI modules formed by the MALAT1-regulated SYNRG, ITSN2, PICALM, AP3B1, and AAK1 genes may play important roles in the pathogenesis of ALS, and these results may help to characterize the pathogenesis of ALS.

Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder with high mortality. The aim of this review is to update clinical management of relapsed/refractory HLH in adults, with a focus on current and new therapies.

We searched relevant articles in Embase and PUBMED with the MESH term “hemophagocytic lymphohistiocytosis; refractory; relapsing; adult.”

One hundred eight papers were found; of these, 22 were retained for this review. The treatment of HLH in adult is based on the HLH-94 regimen. The response rate is lower than in pediatric patients, and 20–30% are refractory to this therapy. DEP regimen and allogenic hematopoietic stem cell transplantation (HSCT) are associated with complete response and partial response in 27% and 49.2%, respectively. However, many patients fail to achieve a stable condition before HSCT, and mortality is higher in them. New drugs have been developed, such as emapalumab, ruxolitinib, and alemtuzumab, and they may be used as bridges to the curative HSCT. They are relatively well tolerated and have few or mild side effects. With these agents, the rate of partial response ranges from 14.2% to 100%, while the rate of complete response is highly variable according to study and medication used. The number of patients who achieved HSCT ranged from 44.8% to 77%, with a survival rate of 55.9% to 100%. However, the populations in these studies are mainly composed of mixed-age patients (pediatric and adult patients), and studies including only adult patients are scarce.

Relapsed or refractory HLH in adult patients is associated with poor outcome, and consolidation with HSCT may be required in some cases. Mortality related to HSCT is mainly due to active HLH disease before HSCT and post HSCT complications. New drugs, such as empalumab, ruxolitinib, and alemtuzumab are interesting since these agents may be used as bridges to HSCT with increases in the numbers of patients proceeding to HSCT and survival rate.

• doxorubicin
• emapalumab
• etoposide
• haemophagocytic lymphohistiocytosis
• hematopoietic stem cell transplantation
• methylprednisolone regimen
• refractory

Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.

We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.

The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.

• Familial hemophagocytic lymphohistiocytosis
• Perforin
• PRF1 mutation
• Late-onset
• Case report

• Emapalumab
• chemotherapy
• hemophagocytic lymphohistiocytosis
• interferon-γ
• monoclonal antibodies

• Anemia
• Hemophagocytic
• Hypertriglyceridemia
• Lymphohistiocytosis
• Prognosis

• HLH
• MA-HLH
• anakinra
• sHLH

• Actin cytoskeleton
• Immune cells
• Neutrophils
• Primary immunodeficiency