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Introduction  May-Thurner syndrome (MTS) is a vascular anatomic variant resulting in compression of the left common iliac vein by the right common iliac artery, affecting approximately 22% of the population. In adults, following acute deep vein thrombosis (DVT) of the iliofemoral veins, the incidence of postthrombotic syndrome (PTS) and recurrent DVT are high if treated with anticoagulation alone, warranting adjunctive treatment with thrombolysis and stent placement. However, there is paucity of literature documenting the course of treatment and associated outcomes in pediatric patients with MTS. Methods  A retrospective chart review of pediatric patients (≤ 18 years of age) with radiologic confirmation of MTS with or without DVT evaluated and/or treated at our institution from January 1, 2005 through December 31, 2015 was conducted. Results  Seventeen patients (4 male; 13 female) were identified. Median age was 15.4 years (range 8.8-17.1 years) with a median follow-up of 1.2 years (range 0.4-7.5 years). Thirteen (76.5%) patients presented with left lower extremity DVT. Management included catheter-directed thrombolysis ( n  = 5), systemic thrombolysis ( n  = 1), and mechanical thrombectomy ( n  = 1). Fifteen patients were treated with anticoagulation including two patients with endovascular stents without DVT. Median duration of anticoagulation was 6.3 months (range 3.2-18.7 months). Ten patients (59%) underwent stent placements. Complete and partial thrombus resolution was noted in six patients each and no resolution in one patient. Four patients had recurrence/progression of thrombus ( n  = 3 with stents) at a median time of 29 days (range 12-495 days). No bleeding complications were observed. Clinically documented or self-reported PTS was noted in 8 patients (62%). Conclusion  There are no clear guidelines for MTS management in children and adolescents. In our cohort, thrombolysis, anticoagulation, or stent placements were not associated with bleeding risks, with recurrence/progression of DVT and signs and symptoms of PTS noted in 30 and 62%, respectively. Further studies are needed to determine a standardized treatment approach of the pediatric patient with MTS with or without thrombosis., Competing Interests: Conflict of Interest None declared.

Pediatric hematologists/oncologists face complex situations such as breaking bad news, treatment/clinical trials discussions, and end-of-life/hospice care. With increasing diversity in patient and physician populations, cultural competency and sensitivity training covering different aspects of pediatric hematology/oncology (PDHO) care can help improve health care delivery and reduce disparities. Though it is considered a required component of fellowship training, there is no clearly defined curriculum meant specifically for PDHO fellows-in-training (PDHO-F). A national online survey of 356 PDHO-F and 67 PDHO program directors (PDHO-PD) was conducted to assess the educational experience, perceptions about identifying barriers including one's own biases and trainee comfort in delivering culturally sensitive care in various PDHO relevant clinical situations. One hundred and eleven (31.2%) PDHO-F and 27 (40.3%) PDHO-PD responded. 30.6% of PDHO-F "strongly agreed/agreed" they received comprehensive cross-cultural communication (CCC) training. The top two teaching methods were faculty role modeling and informal teaching. Majority of CCC training is in medical school or residency and only 10.8% of PDHO-F reported that most of their CCC training was in fellowship. In most clinical situations, there was a modest direct correlation between the fellow's level of agreement that they received comprehensive CCC training and their comfort level. Comfort level with some clinical situations was also significantly different based on year of training. Fellowship training programs should have CCC curricula which use experiential learning models and lay the foundation for promoting cultural awareness, self-reflection, and better patient-physician partnerships which can eventually adapt to and surmount the challenges unique to the physician's chosen field of practice.

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus.

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., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

High-dose methotrexate has been a treatment for osteosarcoma; however, its nephrotoxic effects are considerable. Carboxypeptidase-G2 (glucarpidase) was approved by the US Food and Drug Administration in 2012 for treatment of toxic methotrexate levels. We report our experience using glucarpidase under compassionate use before Food and Drug Administration approval in 2 patients who had delayed methotrexate clearance and prolonged kidney injury despite glucarpidase administration. Our results show that patients with methotrexate toxicity may require repeated doses of glucarpidase in addition to supportive measures, such as dialysis.

Background: After decades of practice of pediatric cardiac surgery, postoperative bleeding due to the immaturity of hemostasis, hemodilution, and hypothermia remains a concern. Recently, a new approach for adult coagulopathy after bypass has emerged. Prothrombin complex concentrates (PCCs), designed to treat bleeding in hemophilia patients, are safely and efficiently used off label for hemorrhage after bypass. However, optimal dosing, indications and contraindications, and laboratory tests to assess the efficacy of PCC use in children have not yet been established. This literature review outlines the challenges of bypass-related coagulopathy, the pharmacology, and the experience in use of PCCs, with a focus on their potential in pediatric cardiac surgery., Methods: After a thorough literature search of MEDLINE, Scopus, and Ovid databases using the term "prothrombin complex concentrate AND pediatric," 23 relevant articles were selected., Results: The data supporting successful use of PCCs in acquired coagulopathy after cardiac surgery in adults have been increasing. Although small volume, low immunogenicity, efficiency, and speed in correcting coagulopathy are attractive qualities of PCCs for pediatric practice, current evidence is only anecdotal. The main concerns are unknown dosing regimens, the inability to closely monitor the effects of PCCs in real time, and a possibility of thrombotic complications, which can be particularly devastating in young congenital cardiac patients whose lives frequently depend upon the patency of artificial shunts., Conclusions: Extensive, high-quality research is warranted to fill in the gaps of knowledge regarding using PCCs in pediatric cardiac practice., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: A subset of patients with common variable immunodeficiency (CVID) develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with early mortality., Objective: To determine a set of clinical and/or laboratory parameters that correlate with GLILD., Methods: A retrospective, nested case-control (patients with CVID diagnosed with GLILD compared with patients with CVID without a diagnosis of GLILD) medical record review was undertaken at Mayo Clinic, Rochester, MN. Network and univariate analysis was used to identify clinical and laboratory parameters at the time of diagnosis that are associated with GLILD., Results: Twenty-six cases with radiologic evidence of GLILD were included in this study. Eighteen cases (69%) cases had coexistent splenomegaly with lower IgA levels (P = .04) compared with the controls. Patients with low IgA levels (<13 mg/dL) also had percentage expansion of low CD21 B cells (CD21low >5%) (P = .007). Univariate analysis revealed that splenomegaly (odds ratio [OR], 17.3; 95% confidence interval [CI], 3.9-74.5), history of immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) (OR, 4.8; 95% CI, 1.1-20.2), low IgA level (OR, 3.6; 95% CI, 1.2-11.9), and percentage expansion of CD21low (OR, 5.8; 95% CI, 1.6-24.7) were independently associated with GLILD. Logistic regression analysis revealed that splenomegaly, history of ITP or AIHA, low IgA level, and percentage expansion of CD21low B cells are highly sensitive in predicting presence of GLILD (area under the receiver operating curve of 0.86)., Conclusion: Presence of splenomegaly, history of ITP or AIHA, low serum IgA level, and percentage expansion of CD21low B cells may be useful to identify a group of patients at high risk for development of GLILD., (Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Children with chronic ulcerative colitis (CUC) are at increased risk for venous thromboembolism, especially after colectomy procedures. We aim to review our patients with CUC who underwent a colectomy and suffered intra-abdominal thrombosis; moreover we wanted to define thrombotic incidence and outcomes, Methods: In this is IRB approved retrospective study, we reviewed our patients who underwent colectomy for CUC from January 1999 to December 2011 for development of intra-abdominal thrombosis., Results: Of 366 patients with CUC who underwent colectomy, 15 (4%) were diagnosed with a venous thromboembolism. All patients presented with acute abdominal pain. The locations of thrombus formation varied: 13 (87%) developed thrombi in the portal vein, 4 (27%) in the splenic vein, 2 (13%) in the superior mesenteric vein, 1 (7%) in the hepatic vein, and 1 (7%) in the hepatic artery. The mean number of post-operative days at diagnosis of thrombus was 38.7 days (range 3-180 days). Fourteen patients (93%) underwent anticoagulation for treatment. The mean number of days of anticoagulant therapy until documented resolution of thrombus on imaging was 96.3 days (range 14-364 days). All thrombi resolved with therapy. There was no mortality during follow-up., Conclusions: Four percent of our pediatric patients with chronic ulcerative colitis who underwent colectomy developed symptomatic intra-abdominal venous thromboembolism. 3 to 6 months of anticoagulant therapy is adequate treatment in almost all patients. Practitioners should have a high index of suspicion for intra-abdominal venous thrombus when these patients complain of abdominal pain postoperatively. Based on our experience, prophylactic anticoagulation should be strongly considered peri-operatively in this population., (© 2014.)

Objective: While post-thrombotic syndrome (PTS) is increasingly recognized in children with a history of deep vein thrombosis (DVT), its impact on the health-related quality of life (HRQoL) is unknown. Our objective was to evaluate the association between the PTS and HRQoL by surveying a cohort of patients treated at our institution for DVT., Materials/methods: All unique pediatric patients (0-18 years) treated for a DVT at the Mayo Clinic during the 15-year period, 1995-2009 were identified. A previously validated PTS survey instrument and age appropriate Pediatric Quality of Life inventory, version 4 (PedsQL 4.0) were mailed to eligible patients. Linear regression models were fit to compare the HRQoL scores between PTS groups (none, mild, moderate/severe), after adjusting for the presence of potential covariates., Results: Of the 90 respondents, 65 (72%) reported signs and/or symptoms of PTS. Mean age (± SD) at DVT diagnosis and survey completion were 12.8 (± 6.1) and 19.3 (± 7.7) years, respectively. Self-report PedsQL 4.0 module was completed by 79 patients, and 34 guardians completed the parent-proxy module. Patients with moderate to severe PTS reported significantly worse total HRQoL score (mean ± SD, 71.3 ± 13.4) as compared to patients with mild PTS (84.8 ± 14.2) and no PTS (83.4 ± 14) (P = 0.001)., Conclusion: Moderate to severe PTS has a significant impact on self-reported HRQoL as measured using the generic PedsQL 4.0. Further research is warranted to develop a venous disease-specific quality of life measure for children with a history of DVT., (© 2013 Wiley Periodicals, Inc.)

Instruction in hematopathology at Mayo Medical School has evolved from instructor-guided direct inspection under the light microscope (laboratory method), to photomicrographs of glass slides with classroom projection (projection method). These methods have not been compared directly to date. Forty-one second-year medical students participated in this pilot study, a prospective, randomized, crossover study measuring educational performance during a hematology pathophysiology course. The students were randomized to one of two groups. All students received the same didactic lectures in the classroom and subsequent case-based review of peripheral blood smears using either laboratory or projection methods, on day one with a crossover to the other method on day two. Pre- and post-test examinations centered on morphology recognition measured educational performance on each day, followed by a questionnaire identifying the student's favored method. There was no significant difference in the pre-test and post-test scores between the two teaching methods (rank-sum P = 0.43). Students overwhelmingly preferred the projection method and perceived it as superior (76%), although post-test scores were not significantly different. Student's recommended method was split with 50% favoring the projection method, 43% favoring a combined approach, and 23% noting logistical challenges to the laboratory. In this study, the laboratory and projection method were equivalent in terms of educational performance for hematopathology among medicals students. A classroom-based approach such as the projection method is favored, given the large class sizes in undergraduate medical education, as well as the ergonomic challenges and additional resources required for large group instruction in a laboratory setting., (© 2013 American Association of Anatomists.)

Kasabach-Merritt phenomenon (KMP) is a rare thrombocytopenic consumption coagulopathy associated with an enlarging tufted angioma or kaposiform hemangioendothelioma. We report a case series of patients with KMP and discuss the treatment options and outcomes. Nine patients with a diagnosis of KMP were identified through retrospective chart review-6 had "definite KMP" and 3 had "less likely KMP." The hematologic features of KMP and those of chronic coagulopathy seen with other vascular malformations can be similar, which makes KMP difficult to distinguish.

We report the successful use of anti-CD20 therapy in a child with refractory myasthenia gravis (MG), an antibody-mediated autoimmune disease, who did not respond to conventional therapy. After initiation of anti-CD20 therapy, clinical improvement (muscular strength, pulmonary function) was observed.