How do we manage hyperhemolysis syndrome.

BACKGROUND: Hyperhemolysis syndrome (HHS) is a catastrophic anemia characterized by destruction of both donor and patient red blood cells (RBC). HHS occurs after transfusion and can cause significant morbidity and mortality. Given the difficulty in diagnosing and managing this process, we provide a detailed overview of our treatment protocol. STUDY DESIGN AND METHODS: Members of the Transfusion Medicine and Hematology faculty at our institution collaborated in an iterative process to produce a consensus approach to patients with HHS. RESULTS: We present diagnostic criteria for HHS: recent transfusion within past 7 days (up to 21 days), rapid hemoglobin decline to below the pretransfusion level (usually hemoglobin drop >25% from pretransfusion), a significant decrease in HbA% (in patients with sickle cell disease or beta thalassemia), low or decreasing reticulocyte count in a patient with worsening anemia, and laboratory evidence of hemolysis. We also describe an in-depth approach to management focusing on optimizing hematopoiesis while dampening the immune response. CONCLUSION: We provide a comprehensive approach to the diagnosis and management of HHS based on contemporary literature and clinical experience designed to optimize outcomes for patients.

National Trends in Hospitalization for Fever and Neutropenia in Children with Cancer, 2007-2014.

OBJECTIVE: To assess the trends of inpatient resource use and mortality in pediatric hospitalizations for fever with neutropenia in the US from 2007 to 2014. STUDY DESIGN: Using National (Nationwide) Inpatient Sample (NIS) and International Classification of Diseases, Ninth Revision, Clinical Modification codes, we studied pediatric cancer hospitalizations with fever with neutropenia between 2007 and 2014. Using appropriate weights for each NIS discharge, we created national estimates of median cost, length of stay, and in-hospital mortality rates. RESULTS: Between 2007 and 2014, there were 104 315 hospitalizations for pediatric fever with neutropenia. The number of weighted fever with neutropenia hospitalizations increased from 12.9 (2007) to 18.1 (2014) per 100 000 US population. A significant increase in fever with neutropenia hospitalizations trend was seen in the 5- to 14-year age group, male sex, all races, and in Midwest and Western US hospital regions. Overall mortality rate remained low at 0.75%, and the 15- to 19-year age group was at significantly greater risk of mortality (OR 2.23, 95% CI 1.36-3.68, P = .002). Sepsis, pneumonia, meningitis, and mycosis were the comorbidities with greater risk of mortality during fever with neutropenia hospitalizations. Median length of stay (2007: 4 days, 2014: 5 days, P < .001) and cost of hospitalization (2007: $8771, 2014: $11 202, P < .001) also significantly increased during the study period. CONCLUSIONS: Our study provides information regarding inpatient use associated with fever with neutropenia in pediatric hospitalizations. Continued research is needed to develop standardized risk stratification and cost-effective treatment strategies for fever with neutropenia hospitalizations considering increasing costs reported in our study. Future studies also are needed to address the greater observed mortality in adolescents with cancer.

Temporal trends of splenectomy in pediatric hospitalizations with immune thrombocytopenia.

BACKGROUND: Splenectomy is considered an effective treatment for immune thrombocytopenia (ITP) with 70-80% response rate. However, its current use is limited in children with ITP. It is unclear if the rates of splenectomy have changed over time. Using a large nationally representative database, we aimed to study the trends of splenectomy in pediatric hospitalizations with ITP, and the factors associated with splenectomy during these encounters. METHODS: Using National (Nationwide) Inpatient Sample (NIS), and international classification of diseases (9th revision), clinical modification (ICD-9-CM) codes, we studied pediatric ITP hospitalizations with occurrence of total splenectomy between 2005 and 2014. RESULTS: Out of 37,844 weighted ITP hospitalizations from 2005 to 2014; total splenectomy was performed in 954 encounters. Splenectomy rate declined over time (3.4% [2005-2006] to 1.6% [2013-2014], P < 0.001) with the younger age (≤5 years) having the most notable decline (0.91% [2005-2006] to 0.14% [2013-2014], P < 0.001). Splenectomy had higher odds of being performed electively than non-electively (odds ratio [OR]: 19.34, 95% confidence interval [CI]: 12.06-31.02, P < 0.001). Encounters with intracranial bleed were associated with the occurrence of splenectomy (OR: 17.87, 95% CI: 5.07-62.97, P < 0.001). Intracranial bleed (P < 0.001), gastrointestinal bleed (P < 0.01), sepsis (P < 0.001), and thrombosis (P < 0.001) were associated with longer length of stay and higher cost of hospitalization. CONCLUSIONS: Overall, splenectomy rates consistently declined over time. Intracranial hemorrhage during hospitalizations with ITP was associated with occurrence of splenectomy. Future studies should continue to reevaluate the rates of splenectomy in pediatric ITP in the presence of various second-line pharmacologic agents.

A 14-year-old boy with extranodal natural killer cell lymphoma of the nose, nasopharynx, larynx, and trachea in remission 6years after primary diagnosis. A longitudinal case report.

Nasal type extranodal natural killer/T-cell lymphoma (ENKTL) is a rare lymphoma in the USA and Europe but endemic in East Asia and in areas of South and Central America. Clinically natural killer cell lymphomas are divided into three categories; nasal, non-nasal and aggressive lymphoma/leukemia subtypes. ENKTL, nasal type occurs in the nose and can extend to the upper aero-digestive tract as reported in this longitudinal case study. This is a longitudinal report of progress of a 14-year-old boy with ENKTL originating in the nasal cavity with subsequent extension and recurrence in the contralateral nose, nasopharynx, larynx and trachea presenting with varying degrees of respiratory problems and eventually, respiratory distress. Caregiver refusal of stem cell transplantation prompted an alternative diagnostic and therapeutic approach. Clinical course with recurrences, extensions and remissions over 6years with tailored endoscopic surgical treatment and radiochemotherapy is documented to present a guide in the multidisciplinary management of this rare disease.

Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model.

Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS.

Treatment of infantile hemangiomas with sirolimus in a patient with PHACE syndrome.

Infantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regress satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. We present an infant with PHACE syndrome and segmental IH that failed conventional first-line therapies. Treatment with sirolimus provided benefit with regression of the cutaneous IH. As an inhibitor of the mammalian target of rapamycin (mTOR) pathway, the effective use of sirolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of IHs.

Head Lice Infestation: An Unusual Cause of Iron Deficiency Anemia in a 13-Year-Old Female.

Pediculosis is a parasitic infestation of the human head and body by Pediculus humanus. This is a benign condition commonly seen in children and capable of causing severe pruritus. The parasite thrives on human blood and in some cases, the volume of blood loss over time could be large enough to precipitate anemic symptoms in the patient. We describe the case of a 13-year-old girl who presented with shortness of breath on exertion, palpitations, and easy fatigability. An incidental finding of Pediculus humanus capitis infestation was made during physical examination. Complete laboratory investigations did not reveal other possible causes of anemia, leading to a diagnosis of iron deficiency anemia (IDA) secondary to severe chronic pediculosis. This case highlights a rare and unusual cause of IDA in children caused by pediculosis, and the need for a thorough investigation, close follow-up, and treatment.

GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis.

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.