Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); KMT2A/EPS15, Following Blinatumomab Therapy.

We report a 6 month-old infant girl with t(1;11)(p32;q23), KMT2A/EPS15-rearranged B-acute lymphoblastic leukemia (B-ALL) that was refractory to traditional ALL-directed chemotherapy. Following administration of blinatumomab, she experienced lineage switch from B-ALL to acute myeloid leukemia (AML). Myeloid-directed chemotherapy resulted in clearance of AML by flow cytometry, though a residual CD19+ B-ALL population persisted (0.14%). Following bridging blinatumomab, the patient achieved B-ALL and AML remission, as measured by flow cytometry. The patient subsequently underwent allogeneic hematopoietic stem cell transplant. Unfortunately, she relapsed with CD19+ B-ALL one-month post-transplantation. Next generation sequencing study of IGH/IGL using ClonoSEQ® analysis detected 3 dominant sequences all present in her original B-ALL, lineage switched AML, and post-transplant relapsed B-ALL, though the latter showed an additional 4 sequences, three of which were present at low abundance in the original diagnostic sample. The presence of the same clones throughout her disease course suggests cellular reprogramming and differentiation following chemotherapy and immunotherapy. This is the first reported case of lineage switch of B-ALL with t(1;11) and also the first report of a lineage switch case that used ClonoSEQ® to define the clonality of the original B-ALL, lineage switched AML, and relapsed B-ALL.

A fatal case of bortezomib-induced lung toxicity in a young adult heart transplant recipient.

Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody-mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20-year-old man 7 years post-HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R-3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class-II donor-specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m2 ). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high-dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post-mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib-induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.

Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation.

BACKGROUND: Retained gadolinium from gadolinium-based contrast agents (GBCAs) used in MR exams has been inferred based on signal changes on serial brain MRI and subsequently demonstrated pathologically in adults. Retention has been similarly inferred in children but pathological demonstration in pediatric patients is limited. The long-term effects of retained gadolinium are unknown but are potentially of greater concern in children given their increased vulnerability from continuing development and their expected longer period of exposure. Several factors can influence gadolinium retention. In adults as well as in children, greater accumulation has been demonstrated based on MR signal changes with linear compared with macrocyclic gadolinium chelates, attributed to lower chelate affinity with linear agents. Effects of age at exposure on retention are unknown, while differences in GBCA washout rates are still under investigation and might affect gadolinium retention relative to time of GBCA administration. OBJECTIVE: The purpose of this study was to confirm whether gadolinium brain deposits are present in pediatric patients who received GBCAs and to quantify the amounts present. MATERIALS AND METHODS: Brain autopsy specimens from 10 pediatric patients between 1 year and 13 years of age who underwent at least one contrast-enhanced MR exam were analyzed for elemental gadolinium using inductively coupled plasma mass spectrometry. Brain samples included white matter, basal ganglia (putamen, globus pallidus), thalamus, dentate nucleus and tumor tissue as available. Type and dose of contrast agent, number and timing of contrast-enhanced MR exams and renal function (estimated glomerular filtration rate [eGFR]) were documented for each child. RESULTS: Patient exposures ranged from 1 dose to 20 doses of GBCAs including both macrocyclic and linear ionic agents. Gadolinium was found to be present in brain tissue in all children and was generally highest in the globus pallidus. Those who received only macrocyclic agents showed lower levels of gadolinium retention. CONCLUSION: This study demonstrates pathological confirmation of gadolinium retention in brain tissue of a series of pediatric patients exposed to GBCAs including not only linear ionic agents but also macrocyclic agents with both nonionic and ionic compounds. The distribution and deposition levels in this small pediatric population are comparable with the findings in adults. While the clinical significance of these deposits remains unknown, at this point it would be prudent to exert caution and avoid unnecessary use of GBCAs in pediatric patients.

Improving Time to Antibiotics for Pediatric Oncology Patients With Suspected Infections: An Emergency Department-Based Quality Improvement Intervention.

OBJECTIVE: Studies in pediatric patients with fever and neutropenia demonstrate that shorter time to antibiotics is associated with a decrease in pediatric intensive care unit admissions and in-hospital mortality. In 2012, a 2-phase quality improvement intervention was implemented in a pediatric emergency department (ED) to improve care for this high-risk patient population.The objective was to determine if the introduction of (1) a rapid absolute neutrophil count (ANC) test and (2) a standardized prearrival process decreased time to antibiotics for febrile hematology/oncology(heme/onc) patients presenting to the ED. METHODS: The rapid ANC test introduced in February 2012 decreased turn-around-times in the laboratory from 60 to 10 minutes. The standardization of the prearrival communication between the heme/onc team and ED was implemented in August 2012 as part of a clinical standard work pathway for heme/onc patients who presented to the ED with fever and possible neutropenia. Time from arrival to the ED to administration of first antibiotic was measured.Data from January 2011 to December 2013 were analyzed using statistical process control. RESULTS: Seven hundred eighteen encounters for 327 patients were included. After the rapid ANC test, the proportion of patients who received antibiotics within 60 minutes of arrival increased from 47% to 60%. There was further improvement to 69% with implementation of the clinical standard work pathway. Mean time to antibiotics decreased from 83 to 65 minutes (21% decrease). CONCLUSION: This 2-phase quality improvement intervention increased the proportion of patients who received antibiotics within 60 minutes of arrival to the ED. Similar processes may be implemented in other pediatric EDs to improve timeliness of antibiotic administration.

Adalimumab-Induced Cutaneous Lupus Erythematosus in a 16-Year-Old Girl with Juvenile Idiopathic Arthritis.

Tumor necrosis factor α (TNF-α) antagonists are used in the treatment of numerous autoimmune conditions. Adalimumab is the first monoclonal antibody to TNF-α and is used to treat juvenile idiopathic arthritis. A growing body of literature associates anti-TNF-α therapies with several adverse dermatologic manifestations, including drug-induced lupus erythematosus (LE). We describe a case of cutaneous LE in a 16-year-old girl treated with adalimumab for juvenile idiopathic arthritis. The temporal association between her presenting symptoms and adalimumab initiation and gradual improvement after stopping biologic therapy suggest adalimumab-induced cutaneous LE. With increasing use of anti-TNF therapies in children, the potential for drug-induced LE should not be overlooked.

Immune cell function assay in pediatric heart transplant recipients.

The ImmuKnow ICFA reports ex vivo CD4 lymphocyte activation to quantify immunosuppression. Limited organ and age-specific data exist for pediatric heart transplant recipients. We sought to examine their normative values and ICFA's association with rejection/infection. A total of 380 ICFAs from 58 heart transplant recipients (6.5/recipient) were studied retrospectively. The median age at the time of their first ICFA was 5.3 yr (IQR 2.4-12.1 yr). ICFA levels during immunologic stability (n = 311) were a median of 305 (IQR: 172-483) and mean of 353 (s.d. ± 224) ng ATP/mL. ICFA levels trended lower with advancing age. ICFA levels during immunologic stability increased over time from transplant after the first six months but were not correlated with calcineurin inhibitor levels or the type used. There is no association between ICFA values during stability and rejection (median 368 ATP ng/mL; IQR 153-527) or infection (median 293 ATP ng/mL; IQR 198-432). In contrast to the manufacturer's suggested ranges, the immunologic stable ranges in pediatric cardiac recipients were very different. ICFA values during immunologic stability are related to time from transplant in pediatric heart recipients. ICFA's ability to discriminate rejection or infection from immunologic stability was not demonstrated.

Isolated appendiceal typhlitis masquerading as perforated appendicitis in the setting of acute lymphoblastic leukemia.

Abdominal pain is common during chemotherapy for childhood leukemia. Clinically differentiating typhlitis from appendicitis can be difficult. We present an 8-year-old boy with abdominal pain in the setting of acute lymphoblastic leukemia and neutropenia. Following appendectomy for presumed appendicitis, pathology revealed appendiceal typhlitis. Diagnostic and treatment considerations are discussed.

Malignant progression in two children with multiple osteochondromas.

Multiple Osteochondromas (MO) is a disease of benign bony growths with a low incidence of malignant transformation. Secondary chondrosarcoma in children is rare even in children with MO. Making a diagnosis of malignancy in low-grade cartilage tumors is challenging and requires consideration of clinical, radiographic, and histopathological factors. We report two cases of skeletally immature patients with MO who presented with rapidly enlarging and radiographically aggressive lesions consistent with malignant transformation. Both underwent allograft reconstruction of the involved site with no signs of recurrence or metastatic disease at a minimum of four-year follow-up.

Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?

A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Consideration of Maternal Anti-enterocyte IgA Transfer With Resulting Infantile Alloimmune Enteropathy.

Autoimmune enteropathy is a rare cause of infantile diarrhea. Cases typically involve infants with a protracted course of diarrhea found to have underlying autoimmune disease or immune dysfunction, leading to chronic intestinal inflammation. We describe a case of immune-mediated enteropathy in an infant with no identifiable autoimmune disease. The patient was exclusively breastfed by his mother who had Crohn's disease, and he was found to have circulating anti-enterocyte immunoglobulin A (IgA) antibody. There was no circulating anti-enterocyte immunoglobulin G or immunoglobulin M. The patient's disease and symptoms resolved with cessation of breastfeeding, and no immunomodulatory medications have been needed in 20 months of follow-up. The case raises suspicion for alloimmune disease, and it is hypothesized that intestinal injury was mediated by maternally transmitted anti-enterocyte IgA antibody.

Hematoxylin Bodies in Pediatric Bone Marrow Aspirates and their Utility in the Diagnosis of Systemic Lupus Erythematosus.

In our recent case report, the finding of lupus erythematosus (LE) cells in a bone marrow aspirate led to the diagnosis of systemic lupus erythematosus (SLE) and appropriate treatment, although the patient was not clinically suspected to have SLE. To determine whether LE cells are present in the bone marrow aspirates of SLE patients, but overlooked in routine bone marrow morphology review, bone marrow aspirates from 30 pediatric patients (15 with SLE and 15 with other diagnoses) evaluated by rheumatologists were reviewed. LE cells were found in the bone marrow aspirates of only 1 SLE patient and none in non-SLE patients. However, hematoxylin bodies were identified in 53% (8/15) of SLE patients. Neither hematoxylin bodies nor LE cells were found in the aspirates from patients with other disorders. Three additional pediatric patients identified prospectively were found to have hematoxylin bodies in the bone marrow aspirates. Although the diagnosis was not initially suspected, 2 of the 3 patients were subsequently diagnosed with SLE. All patients with hematoxylin bodies and SLE had antinuclear antibody titers ≥1:640 with a homogeneous staining pattern. In addition, bone marrow aspirates of 9 adult patients were reviewed, and neither LE cells nor hematoxylin bodies were identified. In summary, hematoxylin bodies were present in the bone marrow aspirates of many pediatric SLE patients, while LE cells were rare. The finding of hematoxylin bodies in pediatric bone marrow aspirates is a helpful and specific diagnostic clue that may lead to the diagnosis of SLE when other clinical features are nonspecific.

Evaluation of the Utility of Bone Marrow Morphology and Ancillary Studies in Pediatric Patients Under Surveillance for Myelodysplastic Syndrome.

OBJECTIVES: To evaluate the utility of flow cytometry, karyotype, and a fluorescence in situ hybridization (FISH) panel in screening children for myelodysplastic syndrome (MDS). METHODS: Bone marrow morphology, flow cytometry, karyotype, and FISH reports from 595 bone marrow specimens (246 patients) were analyzed. RESULTS: By morphology, 8.7% of cases demonstrated at least unilineage dysplasia and/or increased blasts. Flow cytometry identified definitive abnormalities in 2.8% of cases, all of which had abnormal morphology. Of the 42 cases (7.2%) with acquired karyotypic abnormalities, 26 had no morphologic dysplasia. With a 98.2% concordance between karyotype and MDS FISH, FISH only identified two additional cases, both with low-level (<4%) abnormalities. Peripheral blood count evaluation only identified the absence of thrombocytopenia to correlate with an absence of abnormal ancillary tests. CONCLUSIONS: The combination of morphologic evaluation and karyotype with judicious use of flow cytometry and MDS FISH is sufficient to detect abnormalities for these indications.

Adrenocorticotropin-secreting pancreatoblastoma.

We present a 3-year-old child with Cushing's syndrome due to an ACTH-secreting metastatic pancreatoblastoma. This malignancy is a rare cause of Cushing's syndrome, particularly at pediatric age. We describe her course including the use of ketoconazole to alleviate hypercortisolemia.

Spinal cord pilocytic astrocytoma with leptomeningeal dissemination to the brain. Case report and review of the literature.

Leptomeningeal dissemination of low-grade spinal cord gliomas is an uncommon event. The authors report a unique case of leptomeningeal dissemination of a spinal cord pilocytic astrocytoma (PCA) to the intracranial cerebral subarachnoid spaces in a child. A 2-year-old boy presented with a loss of balance and the inability to walk or stand. An intradural intramedullary spinal cord tumor was identified, and the lesion was subtotally resected and diagnosed by the pathology department to be a PCA. Subsequently, the patient had recurrences of the intradural intramedullary tumor at 6 months and 2 years after his original presentation. He underwent a repeated resection of the recurrent tumor and fenestration of an associated syrinx on both occasions. The pathological characteristics of the reresected tumor remained consistent with those of a PCA. Postoperative imaging after his last surgery revealed diffuse intracranial leptomeningeal dissemination into the cisternal space surrounding the midbrain, the suprasellar region, and the internal auditory canal, as well as nodular subarachnoid disease in the upper cervical region. The patient then underwent chemotherapy, and total spine magnetic resonance (MR) imaging 2 months later demonstrated stability in the size of the spinal cord tumor and a decrease in the associated syrinx. However, an MR image of the head demonstrated two new areas of supratentorial subarachnoid leptomeningeal spread of the primary spinal cord tumor at the 2-month follow-up examination. At the 6-month follow-up examination, MR imaging of the head and spine demonstrated stable metastatic disease. This case illustrates a unique instance of supratentorial leptomeningeal dissemination of an intramedullary spinal cord PCA in a child.

Is Identification of Lupus Erythematosus Cells Still Useful? A Case Report.

A 13-year-old girl presented with significant weight loss, depression, anemia, and neutropenia. The preliminary diagnosis was anorexia nervosa combined with depression. Due to peripheral cytopenia, a bone marrow biopsy was performed to rule out leukemia. Lupus erythematosus (LE) cells were found in the bone marrow aspirate, which prompted autoantibody testing, although clinically it was not suspected the patient had systemic lupus erythematosus (SLE). Further testing demonstrated very high levels of antinuclear antibodies (ANA) (>12 U) and anti-double strand DNA (dsNDA) (>1000 IU/mL), which confirmed the diagnosis of SLE. The patient was treated with steroids for SLE, and symptoms improved quickly. In conclusion, although the identification of LE cells as one of the diagnostic criteria for SLE has been obsolete, careful examination of bone marrow to identify LE cells is still very important in the diagnosis of unsuspected SLE.