Successful management with urgent haploidentical-peripheral blood stem cell transplantation for a patient with severe aplastic anaemia who developed disseminated fungal infection following immunosuppressive therapy.

Urgent haploidentical haematopoietic cell transplantation may be considered in cases of severe aplastic anaemia (SAA) without a human leukocyte antigen-matched donor and suffering from severe infection. However, deciding on allogeneic transplantation in the setting of active systemic infection is challenging due to poor outcomes. This report presents a case of disseminated Magnusiomyces capitatus infection in a 5-year-old male who underwent immunosuppressive therapy for hepatitis-associated SAA. To address the critical situation, granulocyte transfusion was promptly administered from the patient's mother, followed by unmanipulated haploidentical peripheral blood stem cell transplantation from the patient's father with posttransplant cyclophosphamide, ultimately resulting in successful rescue.

A Focused Review of Epstein-Barr Virus Infections and PTLD in Pediatric Transplant Recipients: Guidance From the IPTA and ECIL Guidelines.

Epstein-Barr Virus (EBV) diseases, including EBV-associated post-transplant lymphoproliferative disorder (PTLD) remain important causes of morbidity and mortality in children undergoing solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Despite progress in the prevention of EBV disease including PTLD (EBV/PTLD) in HCT, key questions in the prevention, and management of these infectious complications remain unanswered. The goal of this manuscript is to highlight key points and recommendations derived from the consensus guidelines published by the International Pediatric Transplant Association and the European Conference on Infections in Leukemia for children undergoing SOT and HCT, respectively. Additionally, we provide background and guidance on the use of EBV viral load measurement in the prevention and management of these children.

Chronic Epstein-Barr viral load carriage after pediatric organ transplantation.

Epstein-Barr virus (EBV) infection and EBV-associated post-transplant lymphoproliferative disorder (EBV/PTLD) is one of the most devastating complications occurring in pediatric solid organ transplant (SOT) recipients. Observations of SOT recipients undergoing serial EBV monitoring to inform reduction of immune suppression to prevent EBV-/PTLD has identified patients who maintain chronic high EBV load (CHL) in their blood. The CHL carrier state has been seen more commonly in pediatric compared to adult transplant recipients. Some but not all CHL may progress to EBV/PTLD. However, little is known regarding the biology of this CHL carrier state and the optimal clinical approach to CHL has not been established. This review summarizes the current knowledge and evidence of chronic high EBV load and introduces commonly adopted approaches from experts in this field.

Updated guidelines for chronic active Epstein-Barr virus disease.

Chronic active Epstein-Barr virus disease (CAEBV), formerly named chronic active Epstein-Barr virus infection, is characterized by systemic inflammation and clonal proliferation of Epstein-Barr virus (EBV)-infected T or NK cells. As CAEBV is a potentially life-threatening illness, appropriate diagnosis and therapeutic interventions are necessary for favorable clinical outcomes. Substantial evidence regarding the pathogenesis and treatment of CAEBV has been accumulated since previous guidelines for the diagnosis of CAEBV were proposed. To reflect this evidence, we updated the guidelines for the diagnosis and treatment of CAEBV to improve clinical management of the disease. The details of the updated guidelines are presented in this report. Diagnosis of CAEBV now requires confirmation of a high copy number of EBV genome and EBV-infected T or NK cells. An EBV DNA load ≥ 10,000 IU/mL in whole blood is proposed as the diagnostic cutoff value for CAEBV in this updated guideline. A standard treatment approach for CAEBV has not been established, and hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment. Chemotherapy can be administered to control disease activity before HSCT.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

BACKGROUND: Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. METHODS: This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. RESULTS: Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. CONCLUSIONS: In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Distinct association between chronic Epstein-Barr virus infection and T cell compartments from pediatric heart, kidney, and liver transplant recipients.

Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined. Here, we assessed the phenotypic, functional, and transcriptomic profiles of peripheral blood CD8+/CD4+ T cells, including EBV-specific T cells, in 77 pediatric heart, kidney, and liver Tx recipients and established the relationship between memory differentiation and progression toward exhaustion. Unlike kidney and liver HVL carriers, heart HVL carriers displayed distinct CD8+ T cells with (1) up-regulation of interleukin-21R, (2) decreased naive phenotype and altered memory differentiation, (3) accumulation of terminally exhausted (TEX PD-1+T-bet-Eomes+) and decrease of functional precursors of exhausted (TPEX PD-1intT-bet+) effector subsets, and (4) transcriptomic signatures supporting the phenotypic changes. In addition, CD4+ T cells from heart HVL carriers displayed similar changes in naive and memory subsets, elevated Th1 follicular helper cells, and plasma interleukin-21, suggesting an alternative inflammatory mechanism that governs T cell responses in heart Tx recipients. These results may explain the different incidences of EBV complications and may help improve the risk stratification and clinical management of different types of Tx recipients.

Pediatric Infectious Diseases Related to Transplantation: Insights From Japan.

Infectious diseases after transplantation account for significant morbidity and mortality in children undergoing transplantation; the importance of pediatric transplant infectious disease (TID) specialists has therefore been recognized. Although tremendous advancement continues in transplantation medicine, pediatric-specific data and evidence are limited. In Japan, the majority of TIDs had not been managed by infectious disease specialists because pediatric infectious diseases have not been recognized as a solo subspecialty until recently in Japan. However, in the last decade, there was a new movement for pediatric TID in Japan; some pediatric infectious disease specialists trained outside Japan have been playing an important role in managing pediatric TID in a few academic and pediatric institutions. In this review article, we introduce the current status of infectious complications related to pediatric hematopoietic cell and solid organ transplantation, highlighting currently available local evidence, common practice and issues in the field of pediatric TID in Japan.

Early Detection of Epstein-Barr Virus as a Risk Factor for Chronic High Epstein-Barr Viral Load Carriage at a Living-donor-dominant Pediatric Liver Transplantation Center.

BACKGROUND: Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorders (PTLDs) after pediatric liver transplantation (LT) account for significant morbidity and mortality. Knowledge of EBV kinetics, epidemiology, and outcomes among pediatric living-donor LT cases is largely lacking. This study aims to provide clinical information related to EBV infection, chronic high EBV load (CHL) carriage, and PTLD at a living-donor-dominant pediatric LT center. METHODS: A total of 5827 EBV load measurements from 394 LT recipients fulfilling inclusion criteria and their clinical data were analyzed. EBV loads >1000 copies/µg DNA (742 IU/µg DNA) were considered "high," and CHL was defined by persistence >6 mo. RESULTS: The highlighted results were as follows: (1) 94% of recipients underwent living-donor LT; (2) 80% of EBV seronegative recipients developed first EBV infection <2 y post-LT, and their EBV loads were consistently higher than those of seropositive recipients within <3 y post-LT but did not differ thereafter; (3) 61 (15%) recipients met CHL criteria, but none developed PTLD; (4) age <5 y, cytomegalovirus seronegative donors, and early development of EBV DNAemia <6 mo post-LT were independent risk factors for CHL; (5) the incidence of rejections after 1-y post-LT was comparably low among CHL carriers whose immunosuppression was minimized. CONCLUSIONS: Early detection of EBV following LT and CMV seronegative donors would facilitate risk stratification to prevent PTLD while titrating immunosuppression among pediatric LT recipients.

Elucidating Differences in Early-Stage Centrosome Amplification in Primary and Immortalized Mouse Cells.

The centrosome is involved in cytoplasmic microtubule organization during interphase and in mitotic spindle assembly during cell division. Centrosome amplification (abnormal proliferation of centrosome number) has been observed in several types of cancer and in precancerous conditions. Therefore, it is important to elucidate the mechanism of centrosome amplification in order to understand the early stage of carcinogenesis. Primary cells could be used to better understand the early stage of carcinogenesis rather than immortalized cells, which tend to have various genetic and epigenetic changes. Previously, we demonstrated that a poly(ADP-ribose) polymerase (PARP) inhibitor, 3-aminobenzamide (3AB), which is known to be nontoxic and nonmutagenic, could induce centrosome amplification and chromosomal aneuploidy in CHO-K1 cells. In this study, we compared primary mouse embryonic fibroblasts (MEF) and immortalized MEF using 3AB. Although centrosome amplification was induced with 3AB treatment in immortalized MEF, a more potent PARP inhibitor, AG14361, was required for primary MEF. However, after centrosome amplification, neither 3AB in immortalized MEF nor AG14361 in primary MEF caused chromosomal aneuploidy, suggesting that further genetic and/or epigenetic change(s) are required to exhibit aneuploidy. The DNA-damaging agents doxorubicin and γ-irradiation can cause cancer and centrosome amplification in experimental animals. Although doxorubicin and γ-irradiation induced centrosome amplification and led to decreased p27Kip protein levels in immortalized MEF and primary MEF, the phosphorylation ratio of nucleophosmin (Thr199) increased in immortalized MEF, whereas it decreased in primary MEF. These results suggest that there exists a yet unidentified pathway, different from the nucleophosmin phosphorylation pathway, which can cause centrosome amplification in primary MEF.

Baryon Asymmetry of the Universe from Lepton Flavor Violation.

Charged-lepton flavor violation (CLFV) is a smoking-gun signature of physics beyond the standard model. The discovery of CLFV in upcoming experiments would indicate that CLFV processes must have been efficient in the early Universe at relatively low temperatures. In this Letter, we point out that such efficient CLFV interactions open up new ways of creating the baryon asymmetry of the Universe. First, we quote the two-loop corrections from charged-lepton Yukawa interactions to the chemical transport in the standard model plasma, which imply that nonzero lepton flavor asymmetries summing up to B-L=0 are enough to generate the baryon asymmetry. Then, we describe two scenarios of what we call leptoflavorgenesis, where efficient CLFV processes are responsible for the generation of primordial lepton flavor asymmetries that are subsequently converted to a baryon asymmetry by weak sphaleron processes. Here, the conversion factor from lepton flavor asymmetry to baryon asymmetry is suppressed by charged-lepton Yukawa couplings squared, which provides a natural explanation for the smallness of the observed baryon-to-photon ratio.

FTIR study of the surface-ligand exchange reaction with glutathione on biocompatible rod-shaped CdSe/CdS semiconductor nanocrystals.

Semiconductor nanocrystals (SNCs) are an essential optical tool in life sciences. Application of SNCs to living systems requires that their surfaces be covered with biocompatible molecules. The surface capping of SNCs by glutathione (GSH) is an effective means to prepare biocompatible SNCs and involves replacement of the initial surface ligands with GSH. However, molecular insight into such ligand-exchange reactions remains elusive. Molecular insight into this process is important, because surface ligands significantly impact physical properties such as the stability and quantum yield of SNCs. In this study, we investigate the ligand-exchange reaction of GSH on rod-shaped CdSe/CdS SNCs by Fourier-transform infrared (FTIR) absorption spectroscopy. The structure and interactions of GSH on SNC surfaces are clarified. Quantitative determination of the GSH molar fraction on SNC surfaces reveals that ∼3% of the initial trioctylphosphine oxide (TOPO) ligand is retained. Concentration-dependent experiments show that the surface molar fraction of GSH impacts the physical properties, solubilization yields, and quantum yields of SNCs in a linear manner.

Mucosal-associated invariant T cells are activated in an interleukin-18-dependent manner in Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.

Mucosal-associated invariant T (MAIT) cells are a type of innate immune cells that protect against some infections. However, the involvement of MAIT cells in Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases (EBV-T/NK-LPD) is unclear. In this study, we found that MAIT cells were highly activated in the blood of patients with EBV-T/NK-LPD. MAIT cell activation levels correlated with disease severity and plasma IL-18 levels. Stimulation of healthy peripheral blood mononuclear cells with EBV resulted in activation of MAIT cells, and this activation level was enhanced by exogenous IL-18. MAIT cells stimulated by IL-18 might thus be involved in the immunopathogenesis of EBV-T/NK-LPD.

Factors associated with prolonged procedure time of embolization for trauma patients.

Aim: Limited information exists on the factors associated with prolonged procedural time in embolization for trauma patients. We clarified the clinical application of embolization in trauma patients and factors associated with a prolonged procedure time. Methods: Medical records of 162 trauma patients who underwent embolization between January 2007 and December 2020 at a regional trauma care center were reviewed retrospectively. Patients were divided into four embolized body regions: chest, abdomen, pelvis, and other. Patient demographics, trauma mechanism, physiology, trauma severity, embolization procedures, and 30-day mortality were examined. The outcomes were identifying an embolized body region, embolized arteries, and procedure time. Multiple regression model was created to investigate the factors associated with prolonged procedural time in embolization. Results: Embolization was mainly undertaken in pelvic fractures (n = 96, 59%) and abdominal organ injuries (n = 57, 35%) and extended to the chest (n = 17, 10%), and other (n = 20, 12%). Approximately 13% (n = 21) of patients underwent embolization in two or more regions. Embolization was more strictly performed in minor artery injuries, for example, external iliac (n = 15, 16%) and lumbar artery (n = 22, 23%) branches in pelvic fractures, and inferior phrenic artery (n = 2, 3.5%) branches in liver injuries. Multiple regression model indicated that the number of embolized arteries (P = 0.021) and number of embolized regions (P < 0.001) were associated with prolonged procedural time in embolization. Conclusions: Embolization for trauma patients extended to various trauma regions. In time-sensitive embolization, emergency interventional radiologists showed superior knowledge of expected embolizing arteries and factors associated with procedure time.

Successful hematopoietic stem cell transplantation with reduced dose of busulfan for Omenn syndrome.

Omenn syndrome (OS) is typically observed in the autosomal recessive form of severe combined immunodeficiency (SCID) with autoreactive manifestations, and it requires allogeneic hematopoietic stem cell transplantation. Unlike non-OS SCID, a conditioning regimen is usually required to eradicate T-cells; however, optimal conditioning regimens are not established mainly because of the rarity of OS. Here, we report a case of hematopoietic stem cell transplantation with a reduced dose of busulfan, as a conditioning regimen and successful engraftment with complete chimerism. OS was diagnosed in a one-month-old boy based on a diffuse erythematous rash, absent B-cells, and activated T-cells. Genetic analysis failed to identify causative mutations for OS/SCID, such as RAG1/2. Bone marrow transplantation was performed from his HLA-matched sister with a conditioning regimen consisting of targeted busulfan, fludarabine, and anti-thymocyte globulin. Cyclosporine had been administered before transplantation to control abnormal T-cell activation and continued for graft-versus-host disease (GVHD) prophylaxis. Engraftment was achieved on day 12, and no GVHD symptoms were observed. For stem cell transplantation for OS, prior control of autoreactive symptoms with immunosuppressants is important for safe transplantation and reduced intensity conditioning (RIC) can be an option to achieve sustained engraftment.

Hypersensitivity to mosquito bites: A versatile Epstein-Barr virus disease with allergy, inflammation, and malignancy.

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by transient intense skin reaction and systemic inflammation. Clinical presentation of HMB resembles other mosquito allergic responses, and it can also be difficult to clinically distinguish HMB from other severe allergic reactions. However, a distinctive pathophysiology underlies HMB. HMB belongs to a category of Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPD). Hence, HMB may progress to systemic diseases, such as hemophagocytic lymphohistiocytosis, chronic active EBV disease, and EBV-associated malignancies. A triad of elevated serum IgE, NK lymphocytosis, and detection of EBV DNA in peripheral blood is commonly observed, and identification of EBV-infected NK cells usually facilitates the diagnosis. However, the effective treatment is limited, and its precise etiology remains unknown. Local CD4+ T cell proliferation triggered by mosquito bites appears to help induce EBV reactivation and EBV-infected NK-cell proliferation. These immunological interactions may explain the transient HMB signs and symptoms and the disease progression toward malignant LPD. Further research to elucidate the mechanism of HMB is warranted for better diagnosis and treatment of HMB and other forms of EBV-associated LPD.

A Prospective Viral Monitoring Study After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation for Malignant and Nonmalignant Diseases.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many high-risk pediatric hematological malignant diseases (MD) and several nonmalignant diseases (NMD), including primary immune deficiencies. Infections must be managed to obtain better outcomes after HSCT. In this prospective observational study, viral monitoring was performed on 74 pediatric patients with MD and NMD who underwent HSCT. The incidence, risk factors, and impact of common opportunistic viral infections occurring within the first 100 days following HSCT were assessed. The viral pathogens included human herpesviruses, BK polyomavirus (BKV), adenovirus, parvovirus B19, and hepatitis B virus. In total, 52 (70%) patients had viral DNAemia, and 53% and 41% of patients developed human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) DNAemia, respectively. The risk factors were as follows: negative CMV serology for any viral infections; age ≥ 2 years and negative CMV serology for HHV-6; age ≥5 years and female sex for BKV. The risk of viral infection did not significantly differ between MD and NMD, and no risk factor was identified for viral disease, likely because of the small sample numbers. However, despite the absence of symptoms, CMV DNAemia was found to increase the risk of mortality. The findings of the current study could improve the risk stratification and the management of pediatric HSCT recipients.

The safety and feasibility of laparoscopic gastrectomy for gastric cancer in very elderly patients: short-and long-term outcomes.

PURPOSE: It remains unclear whether laparoscopic gastrectomy (LG) for gastric cancer is a suitable treatment for very elderly (VE) patients. We aimed to assess the safety and feasibility of LG for gastric cancer in VE patients. METHODS: We reviewed 226 consecutive patients who underwent LG between January 2010 and December 2016. We compared VE patients (age ≥ 80, n = 38) with non-elderly patients (age ≤ 79, n = 188). RESULTS: An ASA-PS score ≥ 2 was more common in VE group (86.8 vs. 48.9%; P < 0.01). There were no significant differences in the operating time, blood loss, postoperative hospital stay, or postoperative morbidity between the groups. The 3-year survival rate and 3-year disease-specific survival rate were lower in the VE group (53.7 vs. 85.6%; P < 0.0001, 78.5 vs. 92.4%; P = 0.0116). A univariate analysis showed that PS scores ≥ 2, Charlson comorbidity index ≥ 4, and pN stage were independent predictors of decreased overall survival rates in the VE group. A multivariate analysis showed total gastrectomy, a Charlson comorbidity index ≥ 4, and the pN stage to be independent predictors in the VE group. CONCLUSION: LG for gastric cancer is, thus, considered to be safe for patients aged 80 years or older. Total gastrectomy, a Charlson comorbidity index ≥ 4, and the pN stage were independent risk factors for a poor prognosis in these patients.

A Gastric Metastatic Lesion That Resembled Early-Stage Gastric Cancer on Endoscopy during Treatment for Recurrent Breast Cancer: A Case Report.

Breast cancer metastasis to the gastrointestinal tract is relatively rare. Patients with such disease often develop gastrointestinal symptoms, but it is sometimes asymptomatic. Endoscopic findings of gastric metastasis from breast cancer markedly vary from benign to malignant, and even in suspected malignant cases, it is often difficult to differentiate between primary and metastatic disease. We experienced a case in which an endoscopic examination performed during the treatment for metastatic breast cancer resembled an early-stage gastric cancer. A 71-year-old woman underwent curative surgery for right breast cancer 16 years previously. She underwent endoscopic submucosal dissection for early-stage gastric cancer 5 years ago. Two years ago, she developed metastatic disease in the lungs and mediastinal lymph nodes, and endocrine therapy was administered. At the same time, a follow-up endoscopy revealed a new elevated lesion, suspected to be an early-stage gastric cancer. However, histological diagnosis of the biopsy was metastasis of breast cancer. One and a half years later, a follow-up endoscopy revealed a gastric lesion that had reduced in size. She is still alive, having received a variety of systemic treatments. Patients with metastatic breast cancer are experiencing prolonged survival. Thus, follow-up endoscopy should be considered after the diagnosis of gastrointestinal metastasis considering the risk of lethal conditions, such as gastrointestinal bleeding and perforation. Our case serves as a reminder to clinicians how difficult it is to determine whether a gastric lesion is primary or metastatic based on endoscopic findings and the importance of communication with endoscopists and pathologists.

Fatal Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with virus-infected T cells after pediatric multivisceral transplantation: A proof-of-concept case report.

BACKGROUND: EBV-associated HLH driven by EBV-infected CD8+ T cells is a rare complication after pediatric solid organ transplantation. The etiology and disease spectrum of post-transplant EBV-HLH are poorly understood, and making a precise diagnosis and providing optimal treatment remain a challenge. METHODS/CASE DESCRIPTION/RESULTS: We report a 2-year-old multivisceral transplant recipient who developed fever and cytopenia with a persistent high EBV-load state. Repeated tissue examinations and CT scans could not identify a localized mass, which is the key to the diagnosis of PTLD as per the WHO classification. Hence, EBV-HLH was diagnosed by clinical manifestations as well as characterization of EBV-infected cells, pathological examination on cell block of pleural effusion and clonality analysis. This EBV-HLH did not respond to intensive chemotherapy, resulted in the recipient's death, acting similarly to hematological malignancy. CONCLUSIONS: Characterization of EBV-infected cells in peripheral blood should be considered when persistent high EBV loads develop with symptoms consistent with PTLD, but no evidence of localized mass, and the tissue diagnosis is unavailable after pediatric solid organ transplantation.