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Background: Ε-Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use., Objectives: To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders., Methods: We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria., Results: Thirty-two patients were included (median age, 3 years; male, n = 23). Diagnoses were VWD (n = 17), haemophilia (n = 5), FVII deficiency (n = 3), inherited platelet disorder (n = 4), ITP (n = 2), and combined FV and FVII deficiencies (n = 1). Thirty-two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n = 28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value > .1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS., Conclusions: CTXAw appears to be an effective, safe, and low-cost alternative option to EACA OS for young children with bleeding disorders., (© 2024 John Wiley & Sons Ltd.)

Minnesota has the largest Somali diaspora in the world. Uniquely, the Minnesotan Somali diaspora utilizes traditional healing practices along with Western medicine. Therefore, medical providers who regularly interact with Somali patients must be aware of traditional healing practices. A scoping review inclusive of three databases (Embase Classic + Embase, Ovid MEDLINE, PsychINFO) was conducted. Fifty-eight studies met established criteria. Traditional medicine is performed with conventional medicine. Illnesses are acknowledged to be caused by a malfunctioning body, evil eye, and/or zar (possession). Examples of the utilization of dawo dhaqmeed (traditional practices) included ilko dacowo (dental enucleation), khat (catha edulis), guboow (use of a fire-heated object), cupping, xoq (scraping), xidhayn (female genital mutilation), duugto (massage), baan (nutrition), herbs, caano geel (camel milk), Qur'anic healing, prayer, zam zam (holy water), tahliil liquid (blessed water), and amulets. Practices ranged from benign to harmful. Identifying Somali traditional healing practices is the first step in understanding the health of the Somali community in Minnesota., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Post-transplant lymphoproliferative disorder (PTLD) is a complication of immunosuppressive therapy following solid organ or hematopoietic cell transplantation. Initial treatment typically includes a reduction of immunosuppression with or without rituximab. However, the optimal therapy for PTLD with plasmacytic differentiation is unclear. We present 3 cases of pediatric patients with plasmacytic PTLD. Two patients received a standard rituximab-based approach and relapsed, prompting additional chemotherapy. The third patient was treated with a novel regimen of bortezomib, dexamethasone, and daratumumab. This regimen was safe, well-tolerated, and resulted in a 2-year remission. Larger studies are needed to further explore this regimen., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ariagno, Ragoonanan, Khazal, Mahadeo, Cisneros, Zinter, Blacken, Mohan, Lehmann, Ferdjallah, Mara and Kohorst.)

Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our experience using letermovir as CMV prophylaxis in pediatric hematopoietic cell transplantation (HCT) recipients. Pediatric patients (age <20 years) undergoing allogeneic HCT and receiving letermovir prophylaxis in the Mayo Clinic Pediatric Bone Marrow Transplant Program were eligible for inclusion in this retrospective chart review. Medical records were reviewed to evaluate letermovir dosing, CMV levels, laboratory values, and reports of adverse effects. Between October 2020 and April 2022, 9 patients age 4 to 19 years undergoing allogeneic HCT in the Pediatric Bone Marrow Transplant Program received letermovir prophylaxis, either 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg/day. Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients. Two patients received letermovir for secondary CMV prophylaxis after initial treatment with ganciclovir/valganciclovir, and the remaining 7 received letermovir for primary prophylaxis. One patient, a 20-kg 6-year-old female receiving 240 mg (12 mg/kg), experienced low-level CMV viremia while on letermovir. No other patients experienced CMV reactivation while on letermovir prophylaxis. In 2 patients, transient mild transaminitis was noted within the first weeks of letermovir therapy, which resolved without intervention, and its relationship to letermovir could not be clearly established. Letermovir administration was feasible and well tolerated as CMV prophylaxis in our small cohort of pediatric patients undergoing HCT. Larger, prospective studies are warranted to confirm the safety and efficacy of letermovir in children. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cytomegalovirus (CMV), like other herpesviruses, has the unique ability to establish latent infection with subsequent reactivation during periods of stress and immunosuppression. Herpesviruses cause potentially devastating disease, particularly in hematopoietic stem cell transplant (HSCT) recipients. CMV is especially of concern in HSCT recipients given the high community seroprevalence, high risk of reactivation and high risk of transmission from HSCT donors to recipients causing primary infection after transplantation. The risk of CMV infection and severity of CMV disease varies depending on the underlying disease of the HSCT recipient, donor and recipient CMV status prior to HSCT, type of conditioning therapy in preparation for HSCT, allogeneic versus autologous HSCT, donor graft source, timing of infection in relation to HSCT, and other patient comorbidities. Different strategies exist for prevention (e.g., preemptive therapy vs. universal prophylaxis) as well as management of CMV disease (e.g., antiviral therapy, augmenting immune reconstitution, cytotoxic T-cell therapy). The purpose of this narrative review is to discuss diagnosis, prevention, and management of CMV infection and disease at different stages of HSCT, including key points illustrated through presentations of complex cases and difficult clinical scenarios. Traditional and novel strategies for CMV management will be discussed in the context of these unique clinical cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RR received research grants from Gilead, Regeneron and Roche (funds given to the institution) on topics not directly related to this report; serves as member of the Data Safety Monitoring Board and serves as Board of Director of the American Society of Transplantation., (© 2022 Hiskey, Madigan, Ristagno, Razonable and Ferdjallah.)

The osteopetroses are a group of rare genetic diseases caused by osteoclast dysfunction or absence. The hallmark of osteopetrosis is generalized increased bone mineral density (BMD). However, the bone is fragile and fractures are common. Autosomal recessive osteopetrosis is usually a severe disorder and often life-threatening in childhood. We present male siblings with autosomal recessive osteopetrosis due to biallelic variants in TCIRG1 who survived childhood and underwent hematopoietic stem cell transplant (HSCT) in adulthood. One sibling died of posttransplant complications. After transplant, the other sibling had improvement of multiple clinical parameters, including some decline in BMD Z -scores by dual-energy X-ray absorptiometry (DXA) and cessation of fractures. However, spine quantitative computed tomography 11 years after transplant demonstrated an anvil pattern of sclerosis with BMD Z -score of +18.3. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the tibia demonstrated near complete obliteration of the marrow space combined with an unusual cortical phenotype, suggesting extensive cortical porosity at the distal tibia. This case highlights that despite successful transplantation and subsequent improvement in clinical parameters, this patient continued to have significantly elevated bone density and decreased marrow space. Transplant-associated increased cortical porosity is multifactorial and occurs in two-thirds of non-osteopetrotic patients undergoing HSCT. This finding after transplant in osteopetrosis may suggest particular sensitivity of the cortical bone to resorptive activity of transplanted osteoclasts. The case also suggests HR-pQCT may be a useful modality for imaging and assessing the therapeutic effects on bone in individuals with osteopetrosis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Eltrombopag is approved for the treatment of chronic immune thrombocytopenia purpura (ITP) in pediatric patients 1 year and older who have demonstrated an insufficient response to corticosteroids and intravenous immunoglobulin. We present the case of a 2-year-old boy with chronic immune thrombocytopenia purpura who developed life-threatening adverse effects of acute liver failure, metabolic acidosis and encephalopathy with standard drug dosing. To our knowledge, this is the first case of eltrombopag-induced hepatic encephalopathy highlighting the critical need for prescribers to exercise caution when prescribing eltrombopag in the pediatric setting., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Osteosarcoma has a poor prognosis due to chemo-resistance and/or metastases. Increasing evidence shows that long non-coding RNAs (lncRNAs) can play an important role in drug sensitivity and cancer metastasis. Using osteosarcoma cell lines, we identified a positive correlation between the expression of a lncRNA and ANRIL, and resistance to two of the three standard-of-care agents for treating osteosarcoma-cisplatin and doxorubicin. To confirm the potential role of ANRIL in chemosensitivity, we independently inhibited and over-expressed ANRIL in osteosarcoma cell lines followed by treatment with either cisplatin or doxorubicin. Knocking-down ANRIL in SAOS2 resulted in a significant increase in cellular sensitivity to both cisplatin and doxorubicin, while the over-expression of ANRIL in both HOS and U2OS cells led to an increased resistance to both agents. To investigate the clinical significance of ANRIL in osteosarcoma, we assessed ANRIL expression in relation to clinical phenotypes using the osteosarcoma data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset. Higher ANRIL expression was significantly associated with increased rates of metastases at diagnosis and death and was a significant predictor of reduced overall survival rate. Collectively, our results suggest that the lncRNA ANRIL can be a chemosensitivity and prognosis biomarker in osteosarcoma. Furthermore, reducing ANRIL expression may be a therapeutic strategy to overcome current standard-of-care treatment resistance.

Despite major advances in antimicrobial prophylaxis and therapy, opportunistic infections remain a major cause of morbidity and mortality after pediatric hematopoietic cell transplant (HCT). Risk factors associated with the development of opportunistic infections include the patient's underlying disease, previous infection history, co-morbidities, source of the donor graft, preparative therapy prior to the graft infusion, immunosuppressive agents, early and late toxicities after transplant, and graft-vs.-host disease (GVHD). Additionally, the risk for and type of infection changes throughout the HCT course and is greatly influenced by the degree and duration of immunosuppression of the HCT recipient. Hematopoietic cell transplant recipients are at high risk for rapid clinical decompensation from infections. The pediatric intensivist must remain abreast of the status of the timeline from HCT to understand the risk for different infections. This review will serve to highlight the infection risks over the year-long course of the HCT process and to provide key clinical considerations for the pediatric intensivist by presenting a series of hypothetical HCT cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ferdjallah, Young and MacMillan.)

Prolonged neutropenia increases the risk for lethal invasive fungal infections (IFIs) such as those caused by Rhizopus species. Isavuconazonium sulfate is a new triazole that lacks pediatric dosing recommendations. Clinical courses of 4 pediatric patients with IFIs in the peri-allogeneic hematopoietic cell transplantation (alloHCT) period between 2015 and 2017 were reviewed. The reviews included previously unreported pharmacokinetic and safety data, and the IFIs included Rhizopus . Isavuconazonium sulfate was initiated with a loading dose followed by daily dosing, adjusted to a goal trough concentration of >3 mg/L based on adult literature. This target was achieved at a median of 7 days, demonstrating varying rates of metabolism. Renal insufficiency, electrolyte disturbances, and transaminitis were noted, although attribution was confounded by other alloHCT complications. One patient survived infection-free to hospital discharge and 1 of 3 deceased patients had evidence of an unresolved IFI (case 2). Case 2 was subtherapeutic for 39% of the duration of treatment, compared with others at an average of 29%, suggesting this target trough to be clinically relevant because case 2 demonstrated positive sinus and nasal cultures for Rhizopus on autopsy. We recommend initiation of isavuconazonium 10 mg/kg with a maximum dose of 372 mg. A loading dose of 10 mg/kg is used every 8 hours for 6 doses followed by 10 mg/kg dosing every 24 hours. Monitoring must continue beyond steady state. If early monitoring is not possible, we recommend a first drug level at week 3. If dose increases are required, a partial reload has been more successful instead of increasing daily doses. Further larger studies are needed to demonstrate optimum dosing in pediatric patients., Competing Interests: Disclosures. This research was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grants KL2TR002492 and UL1TR002494. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2021.)

Sweet's syndrome associated with relapse of leukemia suggests abnormal neutrophil response to transformation of dysfunctional leukemia blast cells, and hence, relapse should be excluded in similar clinical situation., Competing Interests: None declared., (© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

MEST of the kidney are a benign group of tumors with very rare incidence of malignant transformation. First described in 1998, this tumor has never been reported in a transplanted organ before. We present a unique case of de novo MEST in a donor kidney 4 years after transplant into a pediatric patient. Although removal of the lesions is curative without risking malignant transformation, in this case, surgical removal was not attempted to prevent reduction in transplant longevity. In this unique report of MEST in a transplanted kidney, we describe the patient/transplant outcomes without MEST resection., (© 2019 Wiley Periodicals, Inc.)