Improving Timely Antibiotic Administration for Pediatric Oncology Patients With Neutropenic Fever Seen in the Emergency Department.

Objective: To improve the care for pediatric oncology patients with neutropenic fever who present to the emergency department (ED) by administering appropriate empiric antibiotics within 60 minutes of arrival. Patients and Methods: We focused on improving the care for pediatric oncology patients at risk of neutropenia who presented to the ED with concern for fever. Our baseline adherence to the administration of empiric antibiotics within 60 minutes for this population was 53% (76/144) from January 1, 2010, to December 21, 2014. During 2015, we reviewed data monthly, finding 73% adherence. We used the Lean methodology to identify the process waste, completed a value-stream map with input from multidisciplinary stakeholders, and convened a root cause analysis to identify causes for delay. The 4 causes were as follows: (1) lack of staff awareness; (2) missing patient information in electronic medical record; (3) practice variation; and 4) lack of clear prioritization of laboratory draws. We initiated Plan-Do-Study-Act cycles to achieve our goal of 80% of patients receiving appropriate empiric antibiotics within 60 minutes of arrival in the ED. Results: Five Plan-Do-Study-Act cycles were completed, focusing on the following: (1) timely identification of patients by utilizing the electronic medical record to initiate a page to the care team; (2) creation of a streamlined intravascular access process; (3) practice standardization; (4) convenient access to appropriate antibiotics; and (5) care team education. Timely antibiotic administration increased from 73%-95% of patients by 2018. More importantly, the adherence was sustained to greater than 90% through 2021. Conclusion: A structured and multifaceted approach using quality improvement methodologies can achieve and sustain improved patient care outcomes in the ED.

Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Hepatosplenic γδ T-cell lymphoma of two adolescents: Case report and retrospective literature review in children, adolescents, and young adults.

HSTCL is a highly aggressive malignancy with a poor prognosis. Case series and accounts have reported the use of different chemotherapy regimens with diverse patient outcomes. Most long-term survivors had undergone high-dose chemotherapy with autologous or allogeneic HCT. We describe two pediatric patients with HSTCL who were treated with chemotherapy followed by allogeneic HCT. Both patients are alive and in complete remission 2 and 8 years after therapy. Multiagent chemotherapy followed with allogeneic HCT seems to provide patients who have chemotherapy-sensitive disease a long-term disease-free survival.

Thrombotic and hemorrhagic complications in children and young adult recipients of Hematopoietic Stem Cell Transplant (HSCT).

BACKGROUND: Overall incidence of hemostatic complications in pediatric recipients of Hematopoietic Stem Cell Transplant (HSCT) is scarcely studied. This retrospective review explored the incidence and underlying risk factors of bleeding and thrombotic complications in children. PROCEDURE: Clinical characteristics, hemorrhagic events (HE), thrombotic events (TE) and follow up data were abstracted from medical records on patients aged <21 years undergoing HSCT during January 2000-June 2015. RESULTS: From start of conditioning until last follow up, 238 pediatric patients were reviewed during this study. There were 16 symptomatic thrombotic complications in 15 patients, along with 13 major bleeding events. Incidence of HE or TE was higher in allogeneic HSCT compared to autologous HSCT (p = 0.02). Severe thrombocytopenia could not be identified as a major contributor to bleeding. All patients with HE had platelets between 20,000-50,000 × 109/L, except one patient, who had platelets <20,000 × 109/L. All patients with hemorrhagic cystitis (n = 7) had received cyclophosphamide (Cy). For patients with sinusoidal obstruction syndrome, conditioning included either busulfan (Bu)/Cy (n = 5), Cy with total body irradiation (n = 4), or thiotepa (n = 2). Among allogeneic HSCT recipients, 60% of HE and 92% with TE had underlying myeloid neoplasms. Graft versus Host disease contributed to both types of complications (p = 0.07), although not reaching statistical significance. CONCLUSIONS: Allogeneic pediatric HSCT patients had higher overall risk of hemorrhagic or thrombotic complications compared to autologous recipients in this study. HSCT for myeloid malignancies was a risk factor for higher complications.

Hyperbaric oxygen as a treatment modality in cyclophosphamide-induced hemorrhagic cystitis.

Late-onset HC is a well-recognized complication associated with cyclophosphamide/acrolein-induced toxicity. It poses a management challenge when hyperhydration and bladder irrigation do not result in clinical improvement as desired. The data regarding use of hyperbaric oxygen therapy (HBO2) as an early treatment modality in this clinical setting are limited. We present 2 cases, that were refractory to hyperhydration and bladder irrigation but responded to HBO2. They were treated with 20-30 daily sessions over weekdays with 100% oxygen for 90 minutes at 2 atmospheric pressure units (2 atm). Both patients reported improved symptoms within the first 15 sessions, and hematuria diminished by 20 sessions. Hyperbaric oxygen is a less invasive, outpatient therapy that is effective for treatment of HC and is tolerated well by young patients.

Combined intraocular and systemic rituximab for ocular lymphoproliferative disorder with extranodal marginal zone lymphoma-type morphology after heart transplant.

Post-transplant lymphoproliferative disorder (PTLD) has rarely been associated with ocular manifestations. We report a case of bilateral ocular involvement by PTLD with histopathologic features of extranodal marginal zone (MALT) lymphoma in an 8-year-old boy following orthotopic heart transplantation. The anterior segment disease was treated successfully using a combination of intraocular and systemic injections of humanized anti-CD20 antibody (rituximab).

Optimal approach to assessing T-cell function in haematopoietic cell transplant recipients.

Standardised approaches to functional immune assessment after haematopoietic cell transplantation (HCT) are lacking. A 12-year-old girl with relapsed acute myelogenous leukaemia, 2 years post-unrelated HCT, underwent immunological evaluation prior to receiving live vaccinations. Assessment of standard immune parameters and T-cell proliferation to phytohaemagglutinin was reassuring. She was given Varicella vaccination based on usual post-transplant protocols but was hospitalised 10 days later with localised Varicella infection (vaccine strain). Following recovery, she underwent further assessment that showed reduced T-cell proliferation to an anti-CD3 stimulation panel (anti-CD3 alone, soluble anti-CD3+ anti-CD28 and soluble anti-CD3+ plus exogenous IL-2). On reassessment, 7 months later, T-cell responses to anti-CD3 stimulation were normal and she was revaccinated without further incident. Measurement of T-cell proliferation to anti-CD3 stimulants likely yields more useful information about global T-cell function and should be strongly considered prior to live vaccine administration post-allogeneic haematopoietic transplant.

Cell-Based Therapy for Myocardial Dysfunction After Fontan Operation in Hypoplastic Left Heart Syndrome.

Myocardial dysfunction after Fontan palliation for univentricular congenital heart disease is a challenging clinical problem. The medical treatment has a limited impact, with cardiac transplant being the ultimate management step. Cell-based therapies are evolving as a new treatment for heart failure. Phase 1 clinical trials using regenerative therapeutic strategies in congenital heart disease are ongoing. We report the first case of autologous bone marrow-derived mononuclear cell administration for ventricular dysfunction, 23 years after Fontan operation in a patient with hypoplastic left heart syndrome. The cells were delivered into the coronary circulation by cardiac catheterization. Ventricular size decreased and several parameters reflecting ventricular function improved, with maximum change noted 3 months after cell delivery. Such regenerative therapeutic options may help in delaying and preventing cardiac transplant.

Comparison of Patient-Reported Outcomes in 5-Year Survivors Who Received Bone Marrow vs Peripheral Blood Unrelated Donor Transplantation: Long-term Follow-up of a Randomized Clinical Trial.

IMPORTANCE: Bone marrow or peripheral blood from unrelated donors may be used for hematopoietic cell transplantation. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. OBJECTIVE: To compare patient-reported outcomes between patients randomized to receive 1 of 2 graft types for unrelated donor transplantation. DESIGN, SETTING, AND PARTICIPANTS: This follow-up of a randomized clinical trial included English- or Spanish-speaking patients 16 years or older participating in a multicenter randomized clinical trial of unrelated donor bone marrow (BM) vs peripheral blood (PB) (N = 551) in hematopoietic cell transplantation for hematologic neoplasms. Patient-reported outcomes were collected from patients at enrollment and 0.5, 1, 2, and 5 years after transplantation. INTERVENTIONS: Unrelated donor BM or PB hematopoietic cell transplantation. MAIN OUTCOMES AND MEASURES: Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Mental Health Inventory, occupational functioning, Lee Chronic Graft-vs-Host Disease Symptom Scale. RESULTS: At 5 years after transplantation, 102 BM and 93 PB participants were alive and eligible for assessment (age ≥40 years or older: 104 [53.5%] male: 101 [51.8%]). The mean (SE) Mental Health Inventory Psychological Well-Being scores (78.9 [1.7] vs 72.2 [1.9]; P = .01; higher better) and Lee chronic graft-vs-host disease symptom scores (13.1 [1.5] vs 19.3 [1.6]; P = .004; lower better) were significantly better for BM recipients, adjusting for baseline scores and missing data. Recipients of BM were also more likely to be working full or part-time than recipients of PB (odds ratio, 1.5; 95% CI, 1.2-2.0; P = .002), adjusting for work status before transplantation. With a median follow-up of 73 months (range, 30-121 months) for survivors, no differences in survival (40% vs 39%; P = .84), relapse (32% vs 29%; P = .47), or treatment-related mortality (29% vs 32%; P = .44) between BM and PB were observed. CONCLUSIONS AND RELEVANCE: Recipients of unrelated donor BM had better psychological well-being, less burdensome chronic GVHD symptoms, and were more likely to return to work than recipients of PB at 5 years after transplantation. Bone marrow should be the standard of care for these types of transplant procedures. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00075816.

Neonatal renal vein thrombosis: role of anticoagulation and thrombolysis--an institutional review.

Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.

Congenital amegakaryocytic thrombocytopenia: a case report of pediatric twins undergoing matched unrelated bone marrow transplantation.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder that presents with thrombocytopenia in infancy and evolves into bone marrow failure over time. Allogeneic hematopoietic stem cell transplant remains the only curative treatment option. We report our experience with identical twin sisters diagnosed with CAMT and treated successfully with matched unrelated donor bone marrow transplants. Before the transplant, 1 twin developed pancytopenia, whereas the other had a relatively benign clinical course. Choice of conditioning regimens was based on their pretransplant bone marrow cellularity and presence or absence of panyhypoplasia. Both twins tolerated the procedure well with no significant complications.

Prevalence and risk factors for post thrombotic syndrome after deep vein thrombosis in children: a cohort study.

BACKGROUND: While post thrombotic syndrome (PTS) is increasingly recognized as a frequent and potentially serious complication of deep vein thrombosis (DVT) in children, limited information is available regarding predictors of PTS. METHODS: Using the Mayo Clinic Master Diagnostic Index, all pediatric patients (age 0 to 18 years) with a potential DVT based on ICD-8 codes over the 15-year period, 1995 to 2009 were identified. A validated PTS survey instrument was mailed to eligible patients followed by a second mailing and three reminder phone calls for non-responders. Baseline clinical and radiographic characteristics were abstracted from patient medical records and tested as potential predictors of PTS using logistic regression. Associations were summarized by calculating odds ratios (OR) and corresponding 95% confidence intervals. RESULTS: Ninety patients agreed to participate. The mean age (±SD) at DVT diagnosis and survey completion were 12.8 (±6.1) and 19.3 (±7.7) years, respectively. Fifty three respondents (59%) reported mild PTS whereas 12 (13%) reported moderate-to-severe PTS. Pain (34%) and dilated blood vessels (40%) were the most frequent PTS symptom and sign, respectively. On multivariate analysis, predictors of PTS included duration between incident DVT and survey completion (OR 1.75; 95% CI: 1.08-2.84) and number of thrombosed vein segments (OR 1.40; 95% CI: 1.05-1.86). CONCLUSION: Over 70% of children with DVT report subsequent symptoms or signs of PTS, though only 13% report clinically significant, moderate-to-severe PTS. Number of thrombosed vein segments at diagnosis and time duration between incident DVT and survey completion were independent predictors of PTS.