Oya Levendoglu-Tugal

Intravenous anesthesia with propofol for painful procedures in children with cancer

Objective To study the safety and efficacy of propofol-based intravenous anesthesia in children with cancer undergoing painful procedures. Methods This study is a retrospective analysis of data collected from 52 consecutive children who underwent 335 procedures using propofol anesthesia. These data were routinely collected in all patients: time to induction, duration of the procedure, time to recover, and the doses of the drugs used. Monitoring with electrocardiography and pulse oximetry was continuous during the procedure; blood pressures were recorded before and after the procedure and every 5 to 10 minutes during the procedure. The patients received one of these four propofol-based intravenous regimens according to the anesthesiologists preference: propofol only; propofol plus fentanyl; propofol plus midazolam; or propofol, fentanyl, and midazolam. The efficacy of sedation was rated by this scoring system: 3 = no movement during procedure; 2 = minimal movement that did not interfere with the procedure; 1 = moderate movement requiring physical restraint to complete the procedure. Results There were six episodes of mild hypoxia (oxygen saturation 85%–94%) and one episode of laryngospasm. None required intubation. Two patients had agitation and one patient had emesis during the postrecovery phase. There was no difference in the efficacy of sedation between the four regimens. Patients receiving the combination of propofol, fentanyl, and midazolam received the least amount of propofol and required the least time to recover. There were no life-threatening complications. Conclusions Propofol-based anesthesia, when administered by an anesthesiologist in a controlled setting, is safe and effective for performing painful procedures in children with cancer.

Infections Due to Nontuberculous Mycobacteria in Children with Leukemia

We reviewed the spectrum of infections due to nontuberculous mycobacteria (NTM) in children with leukemia. Three children acquired such infections. One patient developed pneumonia after the cessation of chemotherapy when Mycobacterium xenopi was identified in his lung biopsy specimen. He required 2 years of treatment with antituberculous agents and clarithromycin. Cultures of central and peripheral blood specimens from two patients yielded Mycobacterium fortuitum and Mycobacterium chelonae, respectively. Broviac catheters were likely the source of infection. Removal of the catheters and antibiotic treatment resulted in cure. Central venous catheters in leukemic children are potential sources of infection. For febrile neutropenic children with leukemia who do not respond to antibiotic therapy, cultures positive for diphtheroids or negative routine bacterial and fungal cultures should raise a suspicion for infections due to NTM. Systemic infections may require up to 2 years of therapy. Removal of the infected catheters during persistent or recurrent infections in necessary for control of the infection.

Long-term outcome of chronic idiopathic thrombocytopenic purpura in children.

Objectives: Children with chronic idiopathic thrombocytopenic purpura (ITP) generally have a favorable outcome, but it is not known whether there are any prognostic factors to predict outcome. The objectives of this study were to assess the spontaneous remission rate and the prognostic significance of age, gender, initial platelet count, initial treatment, and response to treatment. Methods: In this retrospective review of 62 consecutive children with chronic ITP, 37 were girls and 27 were 10 years of age or older (median age 9 years; range, 0.75-19). Results: Thirty-five patients (56%) achieved spontaneous remission (remission without splenectomy), 30 of them (48%) within 4 years from diagnosis. Twenty-eight (45%) were complete remissions (platelet counts of ≥100,000) and 7 (11%) were partial remissions (50,000-99,000). There was no significant difference in the spontaneous remission rate between the younger (<10 years) and older children (55.8% vs. 57.1%, P = 0.95) or between boys and girls (56% vs. 56.7%, P = 0.98). Similarly, platelet count at initial diagnosis, initial therapy, or response to initial therapy did not have any prognostic significance. All 14 patients who underwent splenectomy achieved complete remission. Conclusions: More than 50% of children with chronic ITP achieve spontaneous remission. Age, gender, platelet count at initial diagnosis, initial treatment, and response to initial treatment do not have any prognostic significance toward the outcome of chronic ITP.

Hemophagocytic lymphohistiocytosis presenting with thrombocytopenia in the newborn.

Hemophagocytic lymphohistiocytosis (HLH) may present with thrombocytopenia during the newborn period. Three neonates (one term and two preterm) presented during the newborn period with thrombocytopenia. Transient recovery occurred in two newborns. The diagnosis of HLH was made after the recurrence of thrombocytopenia and the clinical symptoms at 5 and 7 weeks. The third infant was a premature baby diagnosed at 8 days of age after manifesting the clinical and laboratory features of HLH. All three neonates were treated with chemotherapy and responded well. After hematologic and clinical remission was achieved, the two newborns received hematopoietic stem cell transplantation from allogeneic donors. The third neonate is currently receiving chemotherapy. Persistent or recurrent thrombocytopenia of undetermined cause during the neonatal period should raise the suspicion of HLH, even though other symptoms or signs are not yet evident.

Intravenous anti-D immune globulin-induced intravascular hemolysis in Epstein-Barr virus-related thrombocytopenia.

RhoD immune globulin intravenous (anti-D IGIV) increases platelet counts in patients who have not undergone splenectomy and are positive for RhoD with idiopathic thrombocytopenic purpura. After treatment, in most patients, anemia develops as a result of immune-mediated red cell destruction in the spleen. Although intravascular hemolysis (IVH) is not expected, life-threatening IVH has been recently reported by the Food and Drug Administration, and physicians are encouraged to report their experience with patients with idiopathic thrombocytopenic purpura in whom IVH develops after anti-D administration. Severe IVH was observed after treatment with anti-D IGIV in two adolescent girls with acute thrombocytopenia related to Epstein-Barr virus. They did not have hemolytic anemia before treatment. The authors believe that anti-D IGIV triggered an unusual virus-induced immune response causing hemolysis; therefore, anti-D IGIV should not be used in patients with Epstein-Barr virus-related thrombocytopenia, particularly during the acute phase of infection.

Corticosteroid prophylaxis for neurologic complications of intravenous immunoglobulin G therapy in childhood immune thrombocytopenic purpura.

To assess in a retrospective analysis if there is evidence suggesting corticosteroids can prevent the neurologic complications of intravenous immunoglobulin (IVIG) therapy in children with immune thrombocytopenic purpura (ITP). From March 1985 to September 1997, 112 children received IVIG (1 g/kg/day for one or two dosages) for the treatment of ITP. During the years 1990 to 1997, 23 children nonrandomly received a short course of prednisone (2 mg/kg/day during and for 3 days after the completion of IVIG therapy) as a prophylaxis against the neurologic complications of IVIG therapy. The authors analyzed the data of all 112 children and compared the incidence of neurologic complications in those who received prednisone prophylaxis with those who did not. The severity of the complications was assessed as follows: grade 1, headache only; grade 2, headache plus vomiting; grade 3, headache, vomiting, and fever; grade 4, headache, vomiting, fever, and meningeal signs (aseptic meningitis). Of the 23 children who received prednisone prophylaxis, 2 (8.7%) experienced headache and vomiting after the completion of prednisone prophylaxis. Of the 89 children without prednisone prophylaxis, 27 (30.3%) experienced neurologic symptoms of varying severity, including one patient with aseptic meningitis proven by examination of the spinal fluid. Twelve of these patients needed additional hospital care for the complications. Children receiving prednisone had a 78% lower risk of neurologic complications (OR = 0.22; CI = 0.05-0.90; P = 0.036). This retrospective study shows a short course of prednisone therapy, given during and until 3 days after the completion of IVIG infusion, is likely to decrease the incidence and severity of neurologic complications of IVIG in children with ITP.

DNA damage response as a biomarker in treatment of leukemias

Early assessment of cancer response to the treatment is of great importance in clinical oncology. Most antitumor drugs, among them DNA topoisomerase (topo) inhibitors, target nuclear DNA. The aim of the present study was to explore feasibility of the assessment of DNA damage response (DDR) as potential biomarker, eventually related to the clinical response, during treatment of human leukemias. We have measured DDR as reported by activation of ATM through its phosphorylation on Ser 1981 (ATM-S1981P) concurrent with histone H2AX phosphorylation on Ser139 (γH2AX) in leukemic blast cells from the blood of twenty patients, 16 children/adolescents and 4 adults, diagnosed with acute leukemias and treated with topo2 inhibitors doxorubicin, daunomycin, mitoxantrone or idarubicin. Phosphorylation of H2AX and ATM was detected using phospho-specific Abs and measured in individual cells by flow cytometry. The increase in the level of ATM-S1981P and γH2AX, varying in extent between the patients, was observed in blasts from the blood collected one hour after completion of the drug infusion with respect to the pre-treatment level. A modest degree of correlation was observed between the induction of ATM activation and H2AX phosphorylation in blasts of individual patients. The number of the studied patients (20) and the number of the clinically non-responding ones (2) was too low to draw a conclusion whether the assessment of DDR can be clinically prognostic. The present findings, however, demonstrate the feasibility of assessment of DDR during the treatment of leukemias with drugs targeting DNA.

Real-time quantitative PCR: Standardized detection of minimal residual disease in pediatric acute lymphoblastic leukemia

Purpose To develop a standardized real-time polymerase chain reaction (PCR) method of quantifying minimal residual disease (MRD) in patients with pre-B acute lymphoblastic leukemia (ALL). Patients and Methods In a series of 24 follow-up bone marrow (BM) samples in 11 patients (14 clonal markers), we performed real-time PCR assays using one consensus and one clone-specific primer for each marker. The markers analyzed included immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and TEL-AML1 rearrangements. Results We achieved a detection limit of 3.3 × 10−5 ± 1.2 × 10−5 and an accurate quantitation (r = −0.99) limit of 2.0 × 10−4 ± 8.8 × 10−5 blasts. Both inter- and intra-assay reproducibility were exceptional. Additionally, we found comparable results to those of a “gold standard” limiting-dilution PCR assay (r = 0.62). Conclusions The IgH, TCR and TEL-AML1 markers can be used as targets by real-time PCR under the same cycling profile, allowing quantitation of MRD in more 95% of patients with pre-B ALL. This standardized, real-time PCR technique should simplify monitoring MRD in clinical trials.

Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction.

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

Recurrent immune thrombocytopenic purpura in children.

Recurrent immune thrombocytopenic purpura (ITP) is defined as the recurrence of ITP after at least 3 months of remission sustained without treatment. Among 340 children with ITP, 14 had recurrent ITP (4.1%). Ten were females. The initial course was acute in 8 patients and chronic in 6. The median time to recurrence was 33 months (range 4–120). Only 1 patient had a second recurrence. Twelve (86%) achieved complete (n = 10) or partial (n = 2) remission, two of them after splenectomy. One patient continued to require treatment at 10 months from recurrence. One child died of intracranial hemorrhage despite aggressive treatment including splenectomy and craniotomy.