A case of VEXAS syndrome associated with EBV-associated hemophagocytic lymphohistiocytosis.

Vacuoles, E1, X-linked, autoimmunity, somatic (VEXAS) syndrome is characterized by a pathogenic mutation in UBA1, which leads to protean complications including autoimmunity and myelodysplasia. A 56-year-old man with steroid-dependent, later steroid-refractory cutaneous polyarteritis nodosa and Sweet syndrome developed recurrent daily fever, macrocytic anemia, thrombocytopenia, acute hypoxic respiratory failure, and anasarca. He was eventually diagnosed with Epstein-Barr virus (EBV) viremia and hemophagocytic lymphohistiocytosis (HLH). He improved clinically with rituximab, ruxolitinib, and increased glucocorticoids before expiring from Pseudomonas sepsis. UBA1 exon 3 mutational analysis in myeloid enriched peripheral blood revealed a c.122T>C (p.Met41Thr) pathogenic variant, consistent with VEXAS syndrome. We describe the first case of EBV-associated HLH in a patient diagnosed with VEXAS syndrome. Early identification of this syndrome will be important in order to offer potential therapies before life-threatening complications arise.

Hyperammonemia From Ureaplasma Infection in an Immunocompromised Child.

Idiopathic hyperammonemia is a rare, poorly understood, and often lethal condition that has been described in immunocompromised patients. This report describes an immunocompromised patient with acute myelogenous leukemia who developed persistent hyperammonemia up to 705 µmol/L (normal, 0 to 47 µmol/L) refractory to multiple different therapies. However, after beginning azithromycin and then doxycycline therapy for Ureaplasma species infection, the patient showed immediate and sustained clinical improvement and resolution of ammonia levels. Recognizing disseminated Ureaplasma species infection as a potential cause of idiopathic hyperammonemia, an unexplained, often fatal condition in immunocompromised patients, and empirically treating for this infection could potentially be lifesaving.

Host and Graft Factors Impacting Infection Risk in Hematopoietic Cell Transplantation.

Infection contributes significantly to morbidity and mortality in hematopoietic cell transplantation. A complex interplay of host, graft, and technical factors contributes to infectious risk in the recipient. Host factors such as age, underlying disease, and comorbidities; central venous access; and the preparative regimen contribute to mucosal disruption, organ dysfunction, and immunodeficiency before hematopoietic cell transplantation. Graft factors, including donor histocompatibility, cell source, and graft components, along with immunosuppression and graft-versus-host disease, contribute to the speed of immune reconstitution. Evaluation of these factors, plus previous and posttransplant exposure to pathogens, is necessary to best assess an individual recipient's infection risk.

A Cetuximab-Mediated Suicide System in Chimeric Antigen Receptor-Modified Hematopoietic Stem Cells for Cancer Therapy.

Using gene modification of hematopoietic stem cells (HSC) to create persistent generation of multilineage immune effectors to target cancer cells directly is proposed. Gene-modified human HSC have been used to introduce genes to correct, prevent, or treat diseases. Concerns regarding malignant transformation, abnormal hematopoiesis, and autoimmunity exist, making the co-delivery of a suicide gene a necessary safety measure. Truncated epidermal growth factor receptor (EGFRt) was tested as a suicide gene system co-delivered with anti-CD19 chimeric antigen receptor (CAR) to human HSC. Third-generation self-inactivating lentiviral vectors were used to co-deliver an anti-CD19 CAR and EGFRt. In vitro, gene-modified HSC were differentiated into myeloid cells to allow transgene expression. An antibody-dependent cell-mediated cytotoxicity (ADCC) assay was used, incubating target cells with leukocytes and monoclonal antibody cetuximab to determine the percentage of surviving cells. In vivo, gene-modified HSC were engrafted into NSG mice with subsequent treatment with intraperitoneal cetuximab. Persistence of gene-modified cells was assessed by flow cytometry, droplet digital polymerase chain reaction (ddPCR), and positron emission tomography (PET) imaging using 89Zr-Cetuximab. Cytotoxicity was significantly increased (p = 0.01) in target cells expressing EGFRt after incubation with leukocytes and cetuximab 1 µg/mL compared to EGFRt+ cells without cetuximab and non-transduced cells with or without cetuximab, at all effector:target ratios. Mice humanized with gene-modified HSC presented significant ablation of gene-modified cells after treatment (p = 0.002). Remaining gene-modified cells were close to background on flow cytometry and within two logs of decrease of vector copy numbers by ddPCR in mouse tissues. PET imaging confirmed ablation with a decrease of an average of 82.5% after cetuximab treatment. These results give proof of principle for CAR-modified HSC regulated by a suicide gene. Further studies are needed to enable clinical translation. Cetuximab ADCC of EGFRt-modified cells caused effective killing. Different ablation approaches, such as inducible caspase 9 or co-delivery of other inert cell markers, should also be evaluated.

Clinical characteristics and outcomes of PTLD following intestinal transplantation.

Post-transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single-center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy-proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow-up time of 6.4 (1.6-14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re-ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.

Creation and evaluation of a cancer survivorship curriculum for pediatric resident physicians.

PURPOSE: There is a paucity of formal clinician education concerning cancer survivorship care, which produces care barriers and poorer outcomes for survivors of childhood cancer. To address this, we implemented a curriculum in childhood cancer survivorship care for pediatric residents at the University of California, Los Angeles (UCLA). We examined the efficacy of this curriculum following program completion. METHODS: A case-based curriculum was created and integrated within existing educational structures using Kern's model. We utilized the retrospective pre-posttest method to evaluate participating residents' knowledge, clinical skills, and attitudes towards cancer survivorship topics before and after receiving the curriculum. Pre-posttest items were compared using paired t tests and one-sided binomial tests. We analyzed free-response question items for major themes using constant comparative methods. RESULTS: Thirty-four residents completed the curriculum and its evaluation. Each assessment item significantly increased from pre- to post-curriculum; p < 0.05. Greater than 40% of residents improved in all but one assessment item post-curriculum; p < 0.05. Residents reported the curriculum enhanced their pediatric knowledge base (M = 3.24; SD = 0.65) and would recommend it to other residency programs; M = 3.24; SD = 0.69. Major themes included residents' request for additional oncofertility information, training in counseling survivors, and cancer survivorship training opportunities. CONCLUSIONS: A cancer survivorship curriculum can successfully increase trainees' knowledge, clinical skills, and comfort in discussing topics relevant to survivorship care. IMPLICATIONS FOR CANCER SURVIVORS: With increasing numbers of childhood cancer survivors living into adulthood, residents will likely treat this population regardless of intended career path. This curriculum represents one method to deliver formal cancer survivorship training.

Associations Between Pediatric Palliative Care Consultation and End-of-Life Preparation at an Academic Medical Center: A Retrospective EHR Analysis.

OBJECTIVES: Our aim in this study was to understand usage patterns of pediatric palliative care (PPC) consultation and associations with end-of-life preparation among pediatric patients who are deceased. METHODS: We reviewed 233 pediatric mortalities. Data extraction from the electronic health record included determination of PPC consultation by using Current Procedural Terminology codes. Diagnoses were identified by International Classification of Disease codes and were classified into categories of life-threatening complex chronic conditions (LT-CCCs). Data analysis included Student's t test, Wilcoxon rank test, Fisher's exact test, χ2 test, and multivariable logistic regression. RESULTS: The overall PPC consultation rate for pediatric patients who subsequently died was 24%. A PPC consultation for patients admitted to the pediatric ward and PICU was more likely than for patients cared for in the NICU (31% vs 12%, P < .01) and was more likely for those with an LT-CCC (40% vs 10%, P < .01), particularly malignancy (65% vs 35%, P < .01). Also noted were increased completion of Physician Orders for Life-Sustaining Treatment forms (8 vs 0, P < .01) and increased documentation of mental health disorders (60% vs 40%, P = .02). CONCLUSIONS: Our findings suggest that PPC consultation for patients in the pediatric ward and PICU is more likely among patients with a greater number of LT-CCCs, and is associated with increased Physician Orders for Life-Sustaining Treatment preparation and documentation of mental health disorders. Patients at risk to not receive PPC consultation are those with acute illness and patients in the NICU.

Herpes Zoster Meningitis Presenting With a Cerebrospinal Fluid Leukemoid Reaction in an Adolescent With preB-ALL in Remission.

A 19-year-old girl with a history of precursor B acute lymphoblastic leukemia in remission presented with fever, headache, and a skin rash. Cerebrospinal fluid (CSF) examination reported pleocytosis with blast-like cells concerning for a central nervous system leukemic relapse. After the patient showed significant improvement on intravenous acyclovir, a repeat lumbar puncture revealed normalization of CSF. The abnormal CSF cells were reviewed and ultimately determined to be activated and atypical lymphocytes. The patient recovered uneventfully. Atypical lymphocytes resembling leukemic blasts are an unusual finding in viral meningitis. Varicella zoster virus reactivation should be considered during initial evaluation for central nervous system relapse of leukemia.

Same sibling marrow following cord allogeneic transplantation as therapy for second relapse acute promyelocytic leukemia in a pediatric patient.

Optimal therapy for relapsed APL in pediatric patients is controversial. Allogeneic HSCT is an alternative, with event-free survival of 70-75%. We report a pediatric patient with APL who relapsed 28 months after CBT from her sibling and then was treated with BMT from the same donor. Bone marrow was selected for higher cell dose, donor availability, and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months after BMT. This case suggests the potential role of GVL activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients.