Amir Mian

Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations

Background: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype–phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. Patients and methods: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. Results: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G→A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), ⩽2% in 18 (26%), 3–⩽5% in 10 (14%), >5% in 4 (6%), “reduced” in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008). Conclusion: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

Hemophagocytic lymphohistiocytosis secondary to Ehrlichia chaffeensis infection: a case report.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening condition that is characterized by fever, splenomegaly, and cytopenia in 2 or more peripheral blood lineages, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis. HLH may be primary or may be triggered by numerous etiologies, including infections. Identification of underlying etiology of HLH is important as proper treatment can completely resolve the disease process. We present a patient whose clinical presentation fulfilled the diagnostic criteria for HLH but whose illness was caused by infection with Ehrlichia chaffeensis, emphasizing the need to explore all possible etiologies during evaluation of patients presenting with illnesses consistent with HLH.

Antibiotic hypersensitivity in CF: Drug-induced life-threatening hemolytic anemia in a pediatric patient

Adverse reactions to antibiotics in patients with cystic fibrosis (CF) are a growing concern. We report the case of a pediatric patient with CF with multiple comorbidities and a history of drug reactions, who developed life-threatening piperacillin-induced immune hemolytic anemia. We review drug-induced hemolytic anemia (DIIHA) in particular, and antibiotic hypersensitivity in CF in general, including the frequency, pathogenesis, and risk factors. Finally, we discuss the treatment options and propose an algorithm for the management of drug-induced hypersensitivity reactions in patients with CF.

Standardized process used in the emergency department for pediatric oncology patients with fever and neutropenia improves time to the first dose of antibiotics.

Objectives This study aimed to evaluate the effect of a standardized process on time to the first dose of antibiotics in pediatric oncology patients presenting to the emergency department (ED) with fever and neutropenia (F-N). Methods A standardized process and order set were created to be used on all pediatric febrile neutropenic patients who presented to the ED of a large academic children’s hospital. The order set was used for patients with a known oncologic diagnosis, a fever greater than 38.3°C, and who were presumed or known to be neutropenic. A retrospective chart review was then performed for the 18 months before and the 6 months after implementation of the new process to evaluate if the time to the first dose of antibiotics was significantly reduced. Results A total of 130 occurrences of F-N were analyzed. This included 100 episodes before the implementation of the new process and 30 episodes afterward. The time to antibiotics being ordered was reduced by over half, with a median time of 72 minutes preprocess and 27 minutes postprocess implementation (P = 0.04). Median time from the arrival in the ED to the administration of the first dose of antibiotics was reduced by almost an hour, taking 154 minutes before the new process compared with 95 minutes after its implementation (P = 0.0001). Conclusions The use of a standardized process that uses a standardized order set can reduce the time to the first dose of antibiotics in pediatric oncology patients with F-N.

Biomarkers for risk stratification of febrile neutropenia among children with malignancy: A pilot study†

Patients receiving myelosuppressive chemotherapy remain at increased risk for developing febrile neutropenia (FN). For this heterogeneous population, a biomarker based risk stratification of FN patients may be a useful clinical tool. We hypothesized that serum biomarkers during initial presentation of an FN event could be predictive of subsequent clinical outcome.

Cardiac myeloid sarcoma: a case report and review of literature.

Myeloid sarcomas are rare extramedullary tumors composed of immature myeloid cells. Most cases are seen in childhood acute myelogenous leukemia (AML). They can develop at many sites, but cardiac involvement is a rare finding. We report the case of a 24-year-old woman who, after being in remission from AML for 10 years, developed an isolated cardiac myeloid sarcoma.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired‐like homeobox 2b (PHOX2B) non‐polyalanine‐repeat‐expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine‐repeat‐expansion mutation (PARM) (genotype 20/33) and developed high‐risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I131‐metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co‐morbidities. Pediatr Blood Cancer

More Than Meets the eye: A Presentation of Extramedullary Infiltration (AML-M7)

A 17-month-old previously healthy Caucasian female presented to an ambulatory pediatric clinic with a 4-day history of progressive proptosis of her right eye. Symptoms began 9 days prior to her visit with injection and increased lacrimation of the right eye associated with rhinorrhea, congestion, and cough. There was no history of fever, vomiting, trauma to the eye, pain, or visual disturbance. Her examination was significant for right-sided proptosis with downward and outward displacement of the eye associated with lacrimation. Impaired extraoccular movements were noted in the affected eye. The remainder of her physical examination was unremarkable. The patient underwent emergent CT scan of the orbits, which demonstrated a postseptal extracorporeal enhancing mass lesion in the right orbit with infiltration of the lateral wall and extension into the epidural space of the right middle cranial fossa (Figure 1). Ophthalmology and hematology-oncology were consulted as initial diagnostic possibilities included metastatic neuroblastoma, rhabdomyosarcoma (small-round-blue-cell-tumor), Langerhans cell histiocytosis, and lymphoma (Figure 2). Peripheral blood count showed mild anemia (hemoglobin 7.7 g/dL, hematocrit 23.2%), mild thrombocytopenia (platelet count 125 K/mL), and normal white blood cell count with normal differential without any abnormal mononuclear cells on review of blood smear. Incisional biopsy of the orbital mass was suggestive of “smallround-blue-cell tumor”; however, special stains were nonconfirmatory. Bone marrow aspirate showed trilineage hematopoiesis with normal maturation without any rosette tumor cells seen on morphology. Flow cytometery was inconclusive. Cytogenetic studies of excisional biopsy were consistent with acute megakaryoblastic leukemia (AML-M7), demonstrating a complex karyotype with characteristic t(1,22) (p13;q13) seen in infancy. AML-M7 is unique among acute leukemias in its tendency to present with extramedullary disease and, in particular, lytic bone lesions as seen in this case. Our patient was treated with standard multiagent chemotherapy with local radiation and promptly went into remission. She subsequently underwent cord blood stem cell transplant and continues to be disease free posttransplant with no associated long-term toxicity (Figures 3 and 4).

Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia

Efficacy of therapeutic strategies relative to patient‐ and family‐centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at‐home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.

Abstract LB-161: A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births

Purpose: While cancer risk is increased among children with chromosomal birth defects, less is known about associations between specific non-chromosomal structural birth defects and specific childhood cancers. To investigate these, we established a population-based retrospective cohort of >10 million children by pooling statewide registry data from four U.S. states (Texas, Michigan, North Carolina, and Arkansas) for the period 1992-2013. Methods: Individual level data from birth certificates, birth defects registries, and cancer registries were linked in each state; demographic and diagnostic variables were harmonized; and the data were pooled for the overall analysis. We used Cox proportional hazards models to evaluate associations between 60 birth defects and 31 childhood cancers when there were five or more comorbid cases. A hazard ratio (HR) and 95% confidence interval (CI) was calculated for each birth defect-childhood cancer (BD-CC) pairwise combination, adjusted for maternal age, infant sex, and state. The false discovery rate (FDR) was computed via the Benjamini-Hochberg procedure to account for multiple comparisons. Results: We identified 517,548 children with non-chromosomal structural birth defects and 14,774 children with cancer. The risk of any cancer was increased among children with any non-chromosomal structural defect compared to children without any birth defect (HR=2.6, 95% CI 2.4-2.7). Of 2,511 potential BD-CC combinations, we tested 606 where there were ≥5 comorbid cases and identified 496 BD-CC associations with significantly elevated HRs at a 5% FDR. No significant inverse associations were identified for any BD-CC combination. Notably, hepatoblastoma, astrocytoma, ependymoma, and extracranial germ cell tumors were each strongly associated with several birth defects. For example, the risk of hepatoblastoma was increased among children with atrial septal defects (HR=12.5, 95% CI 7.9-19.7) and craniosynostosis (HR=15.4, 95% CI 7.6-31.3). Astrocytoma and ependymoma were associated with central nervous system (CNS) defects (HR=6.7, 95% CI 4.6-9.8 and HR=7.4, 95%CI 3.5-15.7, respectively). Elevated risk of extracranial germ cell tumors was observed among children with CNS defects (HR=22.5, 95% CI 10.9-46.4) and obstructive genitourinary defects (HR=32.4, 95% CI 16.2-64.6). Conclusions: By pooling registry data across four U.S. states, we were able to evaluate specific BD-CC patterns and report several novel associations. Our findings suggest that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. These findings may inform research into the etiologies of childhood cancer, as well as new cancer surveillance protocols for children with non-chromosomal birth defects. This work was supported by the Cancer Prevention Research Institute of Texas. Citation Format: Jeremy M. Schraw, Tania A. Desrosiers, Wendy N. Nembhard, Glenn Copeland, Robert E. Meyer, Austin L. Brown, Tiffany M. Chambers, Heather E. Danysh, Saumya Sisoudiya, Chunqiao Luo, Amir Mian, Michael E. Scheurer, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-161.