Abstract
Background
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus known as a cause of infectious mononucleosis (IM). While most EBV infection is mild and self-limited, severe EBV diseases such ...as severe IM, EBV-associated hemophagocytic lymphohistiocytosis (HLH) and EBV-associated acute liver failure (ALF) may occur on rare occasions. Interestingly, the severe EBV disease with ALF may occasionally present with overlapping features of HLH; however, it remains unknown if the presence or absence of HLH reflects a distinctive underlying pathophysiology of EBV infection. To investigate the clinical and pathological characteristics of EBV-associated ALF among children, we conducted a single-center, retrospective study at the largest tertiary children’s hospital in Japan.
Methods
We enrolled children under 18 years old who required medical management in the intensive care unit due to primary EBV infection between January 2010 and April 2021. Patients with underlying immunodeficiencies and other medical conditions were excluded. Clinical data, type of EBV-infected cell lineage, and pathological exam were reviewed.
Fourteen patients with EBV-associated ALF were identified in the initial screening, and two were excluded (due to underlying medical conditions). Thus, the details of 12 patients were further analyzed. Five patients fulfilled the criteria for HLH, while seven presented as isolated ALF only.
Results
The most common symptoms of these patients include fever (92%), vomiting (58%), and consciousness disturbance (100%). EBV loads were higher when HLH co-existed (median 2,700 copies/μg of DNA vs. 130,000 copies/μg of DNA, p = 0.01). Identification of EBV-infected cells revealed that the most common cell type was CD8+T cells (8/12, 80%), followed by CD3+T cells (1/12, 10%), and CD19+ cells (2/12, 20%). EBV infected in both CD8+T and CD19+ cells in one case and EBV-infected cells were not identified in two cases. In addition, an increase of activated CD8+ T cells (CD3+CD8+HLA-DR+) was observed in both HLH and ALF cases. Among 12 patients with ALF, seven patients underwent life-saving liver transplantation (LT) due to ALF. Of five patients with ALF+HLH, all patients received corticosteroid, four received cyclosporin or etoposide, and one underwent hematopoietic stem cell transplantation (HSCT). Overall mortality is 17% (2/12 patients), and both patients were complicated with HLH.
Conclusion
This study suggests that HLH and ALF can be an indistinguishable spectrum of severe EBV disease, and the underlying pathogenesis may be associated with the unusual type of EBV-infected cells. Hence, the identification of EBV-infected cells should be considered to guide the diagnosis and treatment. Our study also revealed that LT and cytotoxic anti-inflammatory therapy effectively treated patients with EBV-associated ALF with or without HLH, given the high mortality (>70%) of this disease spectrum. Further studies investigating EBV-associated ALF pathology are warranted to determine optimal management.
Abstract
Background
Patients with Staphylococcus aureus colonization of an intravascular catheter, but without bacteremia, had a 14% chance of developing subsequent S. aureus bacteremia after ...removing the central venous catheter. However, information on the frequency and outcomes of subsequent bacteremia due to Gram-negative rods (GNRs) is limited, particularly in children.
Methods
We conducted a single-center, retrospective, case-control study. Clinical information including age, sex, immune status, bacterial culture results from both catheter tips and the blood, and outcomes were extracted from electronic medical records. Patients were included if the central venous catheter tip culture was positive for GNRs, but the concurrent blood culture (within one day before or after catheter removal) was negative. Subsequent bacteremia was defined as bacteremia caused by the same organism(s) as the catheter tip culture within six months of catheter removal. Clinical characteristics were compared between patients with and without subsequent GNR bacteremia.
Results
During the study period, 49 cases < 18 years of age that were positive for central venous catheter tip culture but negative for concurrent blood cultures were identified. Median (interquartile range) age was 0 (0-4.5) years and male sex was 44.9%. Pseudomonas aeruginosa was the most common isolate (n=18, 36.7%), followed by Escherichia coli (n=8, 16.3%) and Klebsiella spp. (n=8, 16.3%). Subsequent GNR bacteremia developed in 6 (12.2%) patients. The median (range) days between catheter removal and the occurrence of subsequent GNR bacteremia was 16.5 (3-35) days. The median age and the proportion of immunocompromised cases were higher in patients with subsequent bacteremia than in those without subsequent bacteremia (8 years vs 0 years, P=0.011 and 6 100% vs 21 48.8%, P=0.027, respectively). The presence of antibiotic treatment at catheter removal was similar between these two groups (n=4 66.7% vs n=25 58.1%, P=1.0).
Conclusion
The frequency of subsequent GNR bacteremia in children was 12.2%. Immunocompromised patients may be at higher risk for developing subsequent GNR bacteremia.
Disclosures
Kensuke Shoji, MD, PhD, AstraZeneca K.K.: Honoraria|Gilead Sciences, Inc.: Honoraria|KYORIN Pharmaceutical Co.,Ltd.: Honoraria|Meiji Seika Pharma Co., Ltd.: Honoraria|Nippon Becton Dickinson Company, Ltd.: Honoraria|Novartis Pharma Co., Ltd.: Honoraria|Viatrs, Inc: Honoraria
Abstract
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the ...inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.
Methods
We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.
Results
A novel risk locus in the USP7 gene (rs74010351, odds ratio OR = 1.44, 95% confidence interval CI = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.
Conclusions
These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
Abstract
Treatment strategy for trilateral retinoblastoma (TRb: very rare RB with brain tumor) or retinoblastoma with central nervous system (CNS) involvement is not established yet. We ...retrospectively reviewed our seven cases of these rare almost fatal tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 3). Only one had RB family history. Their affected eyes were bilateral 3, unilateral 3 and no 1. Their CNS involvements were suprasellar tumor 4, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Three of the suprasellar tumor patients had spinal metastasis. Four of the seven patients were TRb and one were genetically classified suprasellar retinoblastoma. All of them were treated with chemotherapy and four received high-dose chemotherapy. Three brain tumors of four TRb almost disappeared with chemotherapy. Two of them also received radiotherapy but relapsed. Although one radiation-free long-term TRb survivor developed secondary osteosarcoma, he got remission again and live 5 more years. One CSF positive Rb patient with chiasm invasion died of disease 11 months later. The other patient had no chiasm invasion nor CSF involvement at diagnosis, but his CSF cytology turned to positive after his second cycle of chemotherapy. He got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 4 years. 2-year RFS and 2-year OS of all patients were 40% and 60%. Although our TRb patients responded to chemotherapy, it was difficult to avoid radiotherapy except one. Data accumulation is necessary for better treatment of these cancer-predisposed patients.
Epigenetic alterations, including histone acetylation, contribute to the malignant transformation of hematopoietic cells and disease progression, as well as the emergence of chemotherapy resistance. ...Targeting histone acetylation provides new strategies for the treatment of cancers. As a pan-histone deacetylase inhibitor, panobinostat has been approved by the US Food and Drug Administration for the treatment of multiple myeloma and has shown promising antileukemia effects in acute lymphoblastic leukemia (ALL). However, the underlying drug resistance mechanism in ALL remains largely unknown. Using genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 (CRISPR/Cas9) screening, we identified mitochondrial activity as the driver of panobinostat resistance in ALL. Mechanistically, ectopic SIRT1 expression activated mitochondrial activity and sensitized ALL to panobinostat through activating mitochondria-related apoptosis pathway. Meanwhile, the transcription level of SIRT1 was significantly associated with panobinostat sensitivity across diverse tumor types and thus could be a potential biomarker of panobinostat response in cancers. Our data suggest that patients with higher SIRT1 expression in cancer cells might benefit from panobinostat treatment, supporting the implementation of combinatorial therapy with SIRT1 or mitochondrial activators to overcome panobinostat resistance.
•Genome-wide CRISPR/Cas9 screening in the ALL cell line identified mitochondrial activity as the driver of panobinostat resistance.•SIRT1 expression sensitized ALL to panobinostat through activating mitochondrial activity and the mitochondria-related apoptosis pathway.
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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities
, we discovered that ...44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
Abstract
BACKGROUND
Primary diffuse leptomeningeal primitive neuroectodermal tumor (PDL PNET) is a rare embryonal brain tumor which arises primarily in the meninges without an intraparenchymal mass. ...Few previous reports of this condition exist, and the clinical outcomes are poor. We herein report a case of a child with PDL PNET and present a cursory review of the literature. CASE: A 3-year-old female patient was seen at a local clinic due to vomiting, headaches, and seizures. As a head MRI revealed hydrocephalus but no mass, acute encephalopathy was initially diagnosed. She received steroid pulse therapy, but the symptoms progressed to hallucination and lethargy. Another MRI at the 1-month follow-up revealed diffuse leptomeningeal enhancement. Thereafter she was transferred to our hospital. A spine MRI revealed spinal dissemination. She underwent a dura mater biopsy, and the pathological analysis led to the diagnosis of PDL PNET. She received chemotherapy consisting of vincristine, cyclophosphamide, etoposide, cisplatin, and intrathecal methotrexate injections two months after the initial presentation. The progressive hydrocephalus was managed with external ventricular drainage. Two weeks after the first cycle of chemotherapy the hydrocephalus resolved, and the external ventricular drainage was removed. A follow-up MRI showed that the leptomeningeal enhancement decreased during the four cycles of chemotherapy without radiotherapy. The patient is scheduled to receive high-dose chemotherapy as consolidation therapy.
CONCLUSION
PDL PNET is extremely rare, and its diagnosis is often delayed. Treatment of PDL PNET is very difficult due to its aggressive course, and surgical resection is impossible. Early diagnosis may help improve outcomes.
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