Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia.

Different conditioning regimens have been evaluated in matched-related donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acquired severe aplastic anemia (SAA) with varying results. In this manuscript, we report our experience with fludarabine (120mg/m2), very low dose cyclophosphamide (1200mg/m2) and antithymocyte globulin (7.5mg/kg). Low dose total body irradiation (2Gy) was added to the conditioning regimen for patients older than 15 years. Nineteen patients (median age 23years) underwent transplant between 2008 and 2015. The majority (89%) were younger than 40 years. Stem cell source was BM (n=11) or PBSC (n=8). GvHD prophylaxis consisted of cyclosporine and either a short course of methotrexate (n=9) or mycophenolate mofetil (n=10). Eighteen (94.7%) patients achieved sustained engraftment. The median times to neutrophil and platelet engraftments were 19 (range: 14-34) and 17.1 (range: 12-25) days, respectively. The day-30 cumulative incidence of neutrophil and platelet engraftment was 89.4% and 94.7%, respectively. No secondary graft rejection was observed. The 1-year cumulative incidence of aGvHD (grade II-IV) and cGvHD was 11.7% and 0%, respectively. The 2-year GvHD-free survival rate was 78.6% (95% CI: 52.5-91.4%). Fludarabine-based reduced intensity regimen for MRD allo-HSCT in SAA compares favorably to other available regimens. This regimen deserves further investigations with larger cohort of patients.

Complete heart block in a patient with acute lymphoblastic leukaemia: teicoplanin as a possible cause and review of literature.

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin is a glycopeptide antibiotic used against documented or presumed methicillin-resistant infections. We report a 31-month-old boy with acute lymphocytic leukaemia who developed permanent complete atrioventricular block (CAVB) necessitating pacemaker insertion after receiving teicoplanin for Staphylococcus epidermidis bacteremia. CASE SUMMARY: Clinical assessment of the child revealed febrile neutropenia. After thorough assessment and work-up, the patient was started on teicoplanin intravenously after which he had sudden onset of bradycardia. Electrocardiography showed CAVB that eventually required permanent pacemaker insertion. Twenty-nine months from the incident, the patient is doing well. WHAT IS NEW AND CONCLUSION: We report on a case of teicoplanin-associated CAVB in a child with acute lymphoblastic leukaemia (ALL). This is one of only two similar cases reported in the literature. Teicoplanin remains the most probable cause. The use of teicoplanin should be approached cautiously in the setting of immunosuppression. Whether VZV contributed and teicoplanin triggered remains speculative. Physicians should be aware of this possible complication.

Addition of ketamine to propofol for initiation of procedural anesthesia in children reduces propofol consumption and preserves hemodynamic stability.

BACKGROUND: There is no ideal anesthesia protocol to perform short invasive procedures in pediatric oncology. The combination of propofol and ketamine may offer advantages over propofol alone. METHODS: In a prospective, randomized, double-blind study, we analyzed 63 consecutive procedures performed in 47 oncology children. All patients received 1 mug/kg fentanyl, followed by propofol 1 mg/kg in group P (n=33) or propofol 0.5 mg/kg and ketamine 0.5 mg/kg in group PK (n=30) for the initiation of anesthesia. The need for supplementation with propofol and/or fentanyl to maintain an adequate level of anesthesia was recorded. The hemodynamic and respiratory profile, recovery time and the occurrence of side effects were compared. RESULTS: Significantly more children required propofol (100% vs. 83.3%) and fentanyl (75.5% vs. 43.3%) rescue doses, and developed hypotension (63.6% vs. 23.4%) and bradycardia (48.5 vs. 23.4%) in group P compared with group PK, with a comparable incidence of respiratory adverse events and recovery times. However, 40% of children in group PK were agitated following recovery compared with 6% in group P. CONCLUSIONS: The combination of propofol and ketamine for invasive procedures in pediatric oncology resulted in reduced propofol and fentanyl consumption and preserved hemodynamic stability, but more children in the combination group recovered with agitation.

Role of temozolomide in spinal cord low grade astrocytomas: results in two paediatric patients.

BACKGROUND: The optimal treatment of low grade intramedullary spinal cord tumours remains controversial. In many cases the tumours continue to progress even after surgery and radiation. Effective chemotherapy may be an important therapeutic adjunct in this setting. Temozolomide is widely used for brain gliomas, yet its role in the management of spinal cord tumours has not been reported. PROCEDURE: Two paediatric patients with low grade spinal cord astrocytomas were diagnosed to have progression of the tumour in spite of surgery and radiotherapy. They received temozolomide, 200 mg/m2 daily for five days every four weeks for 10 cycles, and were followed serially. RESULTS: Stabilization of the spinal tumour in both patients was observed at 18 months of follow-up. One of the patients developed haematological toxicity requiring platelet transfusion and dose reduction. CONCLUSION: Based on our findings in two paediatric patients, temozolomide may be a useful agent in the management of progressive recurrent low grade spinal cord astrocytomas.

Assessment of barriers to bone marrow donation by unrelated African-American potential donors.

African Americans have a lower registration rate for becoming potential bone marrow and stem cell donors. The same attitudes and behaviors are exhibited in regard to solid organ and blood donations, causing a serious under-representation of the African-American population in the donor pool. In our efforts to increase donor availability for African Americans through a project funded by the Medical University of South Carolina, we used a survey to determine the reasons African Americans do not participate as donors for bone marrow. We surveyed 589 African Americans, a great majority of whom were women. Our survey identified major barriers to donation to be the lack of awareness that transplantation can save lives, the cost of donation, and the lack of opportunities to donate. The most effective interventions in increasing donation have been to provide both educational programs preceding marrow drives and the opportunity to donate. Through these efforts, the number of potential African-American donors has increased from 768 (accrued over a period of 12 years) to 1977 in less than 2 years. We conclude that a minority recruitment program targeting African-American volunteers for the National Marrow Donor Program (NMDP) should include an education component addressing the most common barriers before drives.

Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony-stimulating factor associated with the acute chest syndrome in patients with sickle cell disease.

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.

Multicenter comparison of magnetic resonance imaging and transcranial Doppler ultrasonography in the evaluation of the central nervous system in children with sickle cell disease.

PURPOSE: To compare the results of standardized magnetic resonance imaging (MRI) of the brain and transcranial Doppler (TCD) ultrasonography of cerebral arteries in school-aged children with sickle cell disease to determine the correlation between these two different neurodiagnostic tests. PATIENTS AND METHODS: Data were analyzed from 78 children with sickle cell disease (mean age 11 yrs) who participated in both the Cooperative Study of Sickle Cell Disease (CSSCD) and the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Patients who had experienced an overt stroke were excluded. MRI findings were classified as normal or "silent infarct." Results of TCD were classified as normal, conditional, or abnormal, based on the time-averaged maximum mean flow velocity in the proximal middle cerebral and distal internal carotid arteries. RESULTS: Of 61 patients who had a normal MRI examination, 11 (18%) had either conditional (5 patients) or abnormal (6 patients) TCD results. Among 17 patients in whom silent infarction was seen on MRI, only 5 (29%) had a conditional (1 patient) or abnormal (4 patients) TCD velocity. Thus, discordant results were seen in 23 patients: 12 in which the TCD result was normal and the MRI abnormal; 11 in which the TCD velocity was elevated and the MRI normal. CONCLUSIONS: Abnormal TCD and MRI examinations reveal different aspects of the pathophysiology of central nervous system (CNS) injury in sickle cell disease and are often discordant. Although TCD abnormality is predictive of overt stroke, the lack of concordance between TCD and MRI findings suggests a need to develop more sensitive and specific indicators of early CNS pathology, such as neuropsychometric testing and positron-emission tomography (PET) scans, and to obtain more information about microvascular pathologic processes that may affect CNS function.

Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis.

Measurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the "best" treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Costs, charges, and reimbursements for persons with sickle cell disease.

PURPOSE: The aims of this study were to describe health care costs and charges for patients with sickle cell disease (SCD) and identify predictors of high use. PATIENTS AND METHODS: Patients with SCD were identified by International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes from a university hospital's administrative databases from January 1, 1996, to September 30, 1997. Clinical and administrative data were gathered on each patient for all hospital admissions and ambulatory clinic visits. Logistic regression models were used to determine predictors of high health care use. RESULTS: A total of 947 patients with SCD were identified, 73% of whom resided within three South Carolina counties. On average, there were 0.9 admissions per patient per year and 8.0 outpatient visits per patient per year. Mean inpatient hospital charges, physician charges, and direct hospital costs per admission were $7290, $1589, and $5405, respectively, and the average length of stay was 4.5 days. Mean hospital charges, physician charges, and direct hospital costs per outpatient visit were $305, $169, and $688, respectively. Forty percent of the inpatient hospital charges were accounted for by only 4.2% of the patients. Residing in a distant county and being admitted with a diagnosis of painful respiration were found to be predictors of excessive charges and expenses beyond expected reimbursements. CONCLUSIONS: Patients with SCD are frequent users of health care services. Charges and costs are distributed disproportionately across these patients. Predictors of excessive hospital charges include living geographically distant from the hospital and being admitted with a diagnosis of painful respiration.

Postdural puncture headache in paediatric oncology patients.

PURPOSE: Previous studies have not determined the correlation between dural puncture and postural headache in paediatric patients. Furthermore, no studies have evaluated the correlation between atypical headache and dural puncture in the paediatric population. Therefore, we prospectively analyzed the incidence of typical postdural puncture headache (PDPHA) and atypical headache in paediatric oncology patients following dural puncture. METHODS: The study population consisted of 66 paediatric patients undergoing 128 consecutive procedures, including 99 lumbar punctures and 29 bone marrow aspirations without concomitant lumbar puncture. Patients were prospectively randomized into four groups: Group I, preteens (< 13 yr) undergoing lumbar puncture, Group II, adolescents (13-21 yr) undergoing lumbar puncture, Group III, preteens undergoing bone marrow aspiration, and Group IV, adolescents undergoing bone marrow aspiration. The presence and description of headache was documented immediately after dural puncture or bone marrow aspiration, and on post-procedure days # 1, 3 and 5 by personnel blinded to the type of procedure. RESULTS: There was an increase in the incidence of headache (9.1%) after lumbar puncture in patients < 21 yr relative to patients undergoing bone marrow aspiration (P < 0.05). No difference was found between the incidence of typical PDPHA after dural puncture in preteens and adolescents. There was also no difference in the incidence of atypical headache after dural puncture or after bone marrow aspiration among preteens and adolescents. CONCLUSIONS: Paediatric patients experience an increased incidence of typical postdural puncture headache after dural puncture compared with age-matched patients undergoing bone marrow aspiration only. Atypical headache is relatively common in the paediatric population after dural puncture or bone marrow aspiration.

Survival with combined modality therapy after intracerebral recurrence of pleuropulmonary blastoma.

BACKGROUND: We present and discuss the successful treatment of pleuropulmonary blastoma metastatic to the brain using a multimodality regimen with surgery, high-dose chemotherapy and radiation therapy. PROCEDURE: A 3-year-old boy referred to our institution with bilateral pulmonary cysts was diagnosed with pleuropulmonary blastoma (PPB). Initial treatment included surgery and multiagent chemotherapy with vincristine, dactinomycin, cyclophosphamide, cisplatin, and doxorubicin. One year after the completion of therapy, his PPB recurred as an intracerebral metastasis, and required further treatment with a multimodality salvage regimen. The child was successfully treated with a subtotal surgical resection, followed by high-dose cyclophosphamide, and radiation therapy. He is now disease-free 24 months later. RESULTS: Intracerebral metastases of PPB have been a uniformly fatal complication of this tumor. Postsurgical chemotherapy and radiation therapy appear to have contributed to the prolonged survival and potential for cure in our patient. CONCLUSIONS: The use of this multimodality regimen may be warranted in other patients with recurrent PPB metastatic to the brain.

Transient therapy-related myelodysplastic syndrome associated with monosomy 7 and 11q23 translocation.

Secondary acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) are known to develop in patients previously treated with different chemotherapeutic regimens. Nonrandom chromosomal abnormalities have been demonstrated in these therapy-related myeloid disorders which often evolve into refractory AML. The prognosis of these patients with conventional chemotherapy has been dismal and only allogeneic bone marrow transplantation offers a potential cure. We describe two patients who developed MDS after chemo/radiotherapy and had a spontaneous recovery. One patient was treated with MOPP-ABVD hybrid therapy for Hodgkin's disease, developed pancytopenia, marrow hypoplasia and dyserythropoiesis associated with monosomy 7. The other was treated with a combination of chemotherapy including VP-16 for Ewing's sarcoma, developed thrombocytopenia, marrow hypoplasia and dyserythropoiesis associated with an 11q23 translocation. Both patients received rhG-CSF after their cycles of chemotherapy and were considered for a bone marrow transplant. Marrow aspirates at frequent intervals showed gradual disappearance of the abnormal clone with parallel normalization of the peripheral count. In both patients G-CSF might have played a role in the development of the abnormal clone. We suggest that patients with therapy-related MDS without excess of blasts could be closely monitored for karyotypic and hematological improvement rather than transplanted immediately.

Progressive autologous graft-versus-host disease induced by cyclosporin A.

The development of graft-versus-host disease (GVHD) in patients undergoing allogeneic bone marrow transplantation for leukemias and lymphomas has been associated with a lower incidence of relapse. This phenomenon is thought to be secondary to the anti-tumor effect of adoptively transferred cells. Cyclosporin A (CsA) therapy is known to cause autologous and syngeneic GVHD in experimental models and humans, and has been used in patients undergoing autologous bone marrow transplantation. It has been the consensus to date that CsA-induced autologous GVHD is generally mild, confined to the skin, self-limiting and non-life-threatening. We report by case of severe and progressive GVHD induced by CsA in a child following autologous bone marrow transplantation for acute lymphoblastic leukemia in second remission.

Myelodysplasia associated with Turner syndrome.

PURPOSE: This study reports the association of myelodysplasia with Turner syndrome. PATIENT AND METHODS: An 11-year-old girl with Turner syndrome was found to have mild macrocytic anemia that persisted during 2 years. RESULTS: Examination of the bone marrow revealed dyserythropoietic features with multinucleation consistent with refractory anemia. Levels of hemoglobin F were also markedly elevated (57%). She also had transient neutropenia and thrombocytopenia, as well as abnormal platelet function studies. The hematopoietic abnormalities were mild and may have been missed were she not followed for her hypertension and aortic coarctation. CONCLUSIONS: Myelodysplastic syndromes in children are frequently associated with chromosomal abnormalities, but an association with Turner syndrome has not been previously described. This could be due to the fact that mild hematopoietic abnormalities in these patients may not be investigated.

Neurologic complications following bone marrow transplantation for sickle cell disease.

A boy with sickle cell anemia underwent bone marrow transplantation (BMT). He was normal on neurological examination, but had radiologic evidence of an old left frontal lobe infarct, multiple cerebral vascular stenoses and moyamoya collaterals. After BMT he developed seizures with extension of the infarct and subarachnoid hemorrhage. One year later angiography revealed worsening stenosis of the M1 segments of both middle cerebral arteries. At that time an increase in von Willebrand's factor with decreased large molecular weight multimers (LvWF) was observed. We speculate that LvWF dependent, shear-induced platelet aggregation, together with endothelial damage may have contributed to the development of neurologic complications in this patient.

Serum levels of GM-CSF are elevated in patients with thrombocytopenia.

Serum levels of GM-CSF, IL-3 and IL-6 were measured in patients with immune thrombocytopenia (ITP), non-immune thrombocytopenia (NIT), autoimmune haemolytic anaemia (AIHA) and neutropenia. 8/10 children with ITP had elevated serum levels of GM-CSF (mean 18.4 pg/ml) while thrombocytopenic, but only two had detectable levels (mean 4.5 pg/ml) after normalization of the platelet count. In patients with NIT a significant inverse correlation between platelet count and serum levels of GM-CSF was observed. IL-3 and IL-6 levels were not significantly elevated in thrombocytopenic patients and only two of the nine patients with either AIHA or neutropenia had detectable levels of GM-CSF. Thus, GM-CSF may play a role in the response of severe thrombocytopenia.

Characterization of c-kit expression by primitive hematopoietic progenitors in umbilical cord blood.

Human umbilical cord blood (CB) appears to be an exciting new source of transplantable stem cells for a variety of clinical conditions. In this study, we have attempted to further characterize the primitive progenitors in CB. First we analyzed the effects of early-acting growth factors on blast cell colony formation from CD34+ progenitors. Addition of Steel factor (SF), interleukin-6 (IL-6), or granulocyte colony-stimulating factor (G-CSF) to cultures containing interleukin-3 enhanced blast cell colony formation. These results indicated that cell cycle-dormant progenitors are present in CB. Next, based on results obtained in the murine system, we tested whether c-kit expression could separate the CB progenitors into cycle-dormant vs. cycle-active progenitors. Cells were separated into CD34+ c-kit-, c-kitlow, and c-kithigh. The results suggested that the c-kitlow population contains the majority of cycle-dormant progenitors and the c-kithigh population contains most of the forming cells were in the c-kitlow population, while the opposite is true for other colony-forming cells. Expression of c-kit may be useful in identifying CB progenitors with long-term engraftment capability.

Adult Wilms' tumor: prognostic and management considerations.

Wilms' tumor is the most common malignant tumor of the urinary tract in children but is rare in adults. Although histologically the tumors appear to be the same, successful treatment with multimodal therapy is much more common in childhood. We report on 2 patients with adult, anaplastic, Stage IV Wilms' tumor, one of which was discovered during pregnancy and was managed successfully with chemotherapy, including ifosfamide, carboplatinum, and etoposide. As more patients are properly identified and treatment outcomes with chemotherapeutic regimens documented, better therapeutic approaches in adult Wilm's tumor will be developed, resulting in improved survival.

Phenotypic analysis of early hematopoietic progenitors in cord blood and determination of their correlation with clonogenic progenitors: relevance to cord blood stem cell transplantation.

Human cord blood (CB) can be utilized as a source of transplantable stem cells. In the clinical setting, the numbers of clonogenic progenitors and nucleated cells are used as indirect measures of the stem cell content of CB samples. In an attempt to define other parameters of engraftment potential, we have determined the numbers of CD34+ cells, and of CD34+ cells co-expressing CD38 and/or HLA-DR in 17 CB samples. At the same time, clonogenic progenitors were assayed in the presence of erythropoietin and different combinations of rhIL-3, rhG-CSF, rhGM-CSF, rh-Steel Factor and medium conditioned by the PU34 primate cell line. Unseparated CB contained a mean of 14.8 x 10(4) CD34+ cells/mL. CD34+CD38-, CD34+DR+ and CD34+DR+ CD38- cells represented 12.2%, 91% and 10% of all CD34+ cells, respectively. Linear regression analysis demonstrated that the total number of CD34+ cells, as well as the different subsets, correlated positively with the numbers of total colonies and day 14 CFU-GM. Furthermore, the proportion of CD34+CD38- cells was significantly higher than has been reported for adult marrow. Cord blood CD34+CD38- and CD34+DR+ cells have a high proliferative potential and are enriched for primitive hematopoietic progenitors. Thus, we conclude that a single collection of CB could be sufficient to engraft an adult recipient, and that quantitation of CD34+ cells and their subsets may be useful in determining the engraftment potential of CB samples.