Radiologic placement of a low profile implantable venous access port in a pediatric population.

PURPOSE: To evaluate the feasibility and complications of placement of a low-profile venous access port in the chest in children requiring long-term venous access. METHOD: A low-profile peripheral arm port (PAS port; Sims Deltec, St. Paul, MN, USA) was implanted in the chest in 22 children over a 4-year period. The mean age of the study group was 6 years (range: 9 months to 20 years). Ports were placed for the administration of chemotherapy, hyperalimentation and frequent blood sampling. Sonographic guidance was used to access the internal jugular or subclavian vein in each case. A review of all inpatient and outpatient charts was undertaken to assess catheter performance and complications. RESULTS: Access to the central venous circulation was successfully achieved in each case without complication. Ports remained implanted for 6579 catheter-days (mean: 299 days). Ten ports have been removed. Of three patients (13%) experiencing device-related infections (0.45 infections/1000 catheter days), two (9.1%) were unresponsive to antibiotics and removed (0.3 infections/1000 catheter days). One port was removed because of pain in the shoulder adjacent to the port implantation site. One port was removed because of difficult access. The final port was removed in order to place a dual-lumen catheter prior to bone marrow transplant. Twelve ports remain implanted. Aspiration occlusion occurred in four patients (18%). Deep venous thrombosis did not occur in any patient. CONCLUSION: Low-profile chest ports placed by interventional radiologists in the interventional radiology suite can be placed in children as safely as traditional chest ports placed in the operating room. The incidence of infection, venous thrombosis and aspiration occlusion is comparable to that of ports placed operatively.

Long-term survival in an adolescent with widely metastatic renal cell carcinoma with rhabdoid features.

Renal cell carcinoma is rarely seen in children and adolescents. Patients with widespread disease at diagnosis have a particularly poor survival rate. Currently, all known chemotherapy has been ineffective in improving the median survival in patients with advanced disease. A 13-year-old black boy with stage IV renal cell carcinoma with rhabdoid features is a long-term disease-free survivor after aggressive multiagent chemotherapy. After the initial evaluation and histologic diagnosis of renal cell carcinoma, the patient received three courses of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin, cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor and erythropoietin (Epogen). After an almost complete response, a radical nephrectomy was performed and results demonstrated a solitary small nodule with viable tumor. After surgery, he received floxuridine infusion for 14 days by circadian schedule at 28-day intervals for a total of 1 year. The patient is well and free of disease 5 years after initial presentation. The dramatic response to treatment and long-term disease-free survival of this patient suggest this chemotherapeutic approach warrants additional investigation.

Congenital erythrocytosis with elevated erythropoietin level: an incorrectly set "erythrostat"?

PURPOSE: A child who was extensively evaluated for polycythemia is reported. Polycythemia, or erythrocytosis, is seen rarely in children. The mechanisms for congenital and/or familial erythrocytosis are discussed. PATIENT AND METHODS: A 10 1/2-year-old white girl was referred for evaluation of polycythemia, which was detected incidentally during an emergency room visit for a febrile illness. She underwent extensive evaluation to determine the cause of the polycythemia. The literature was reviewed to determine the occurrence of congenital and/or familial erythrocytosis in children and its various causes. RESULTS: Despite extensive evaluation, no specific cause of the erythrocytosis could be determined in our patient. The erythrocytosis appeared to be secondary to an inappropriately elevated serum erythropoietin concentration. Serum erythropoietin rose further after phlebotomy, suggesting nonautonomous hypersecretion. After a review of the literature, we hypothesize that she had an inappropriate erythropoietin expression related to an abnormality in the renal oxygen-sensing mechanism governing erythropoietin synthesis. DISCUSSION: A discussion of congenital and familial erythrocytosis is presented, and a review of the literature regarding the possible mechanisms causing erythrocytosis is included.

Intussusception in an infant with acute lymphoblastic leukemia: a case report and review of the literature.

PURPOSE: An ileocecal intussusception developed in a 7-month-old infant with acute lymphoblastic leukemia (ALL) during induction therapy. Gastrointestinal complications, especially intussusception, are rare in children with ALL. PATIENT AND METHODS: The history of a 7-month-old white boy with ALL in whom an ileocecal intussusception developed 1 week into induction chemotherapy was reviewed. In addition, a literature search was performed to determine the prevalence of this complication in children with acute leukemia. RESULTS: On day 4 of induction chemotherapy for B-lineage ALL, the infant developed abdominal distension with hypoactive bowel sounds. After a barium enema and abdominal computed tomography scan, the symptoms were determined to be caused by an ileocecal intussusception. Chemotherapy was resumed 1 week after immediate surgical intervention (reduction of intussusception and resection of the "leading edge") with an uneventful post-operative recovery. Histopathologic examination of the resected edge revealed an intact mucosa with areas of necrosis in the submucosa. This was associated with a dense lymphoid infiltrate composed of mature lymphocytes and leukemic cells, edema, and focal necrosis. Despite a 1-week delay in chemotherapy, a complete remission was documented at day 32. DISCUSSION: The prevalence of intussusception in children with ALL and its possible etiology are discussed. The pathologic changes, clinical manifestations, and treatment outcome are briefly mentioned.

High dose chemotherapy with autologous bone marrow rescue for children with diffuse pontine brain stem tumors. Children's Cancer Group.

PURPOSE: Diffuse pontine tumors are highly lethal, and there are few long-term survivors with the standard treatment of external beam irradiation. We investigated the effectiveness of high-dose thiotepa and etoposide-based chemotherapy regimens with autologous bone marrow rescue (ABMR) in children with pontine tumors. PATIENTS AND METHODS: Sixteen children with diffuse pontine tumors were treated. Ten had resistant or recurrent tumors. All ten had previously received irradiation; five had also received chemotherapy and one, beta-interferon. Three high-dose chemotherapy regimens were employed. Six patients received three days of thiotepa (300 mg/m2/day) and etoposide (250-500 mg/m2/day) (TE); two received three days of carmustine (BCNU) (200 mg/m2/day divided every 12 hours) followed by TE (BTE); and two received three days of carboplatin (500 mg/m2/day) followed by TE (CTE). Six other patients had newly-diagnosed tumors and had not received any prior treatment. They all received the BTE regimen and subsequently were treated with hyperfractionated irradiation (7200-7800 cGy) beginning approximately six weeks post-ABMR. RESULTS: There were two toxic deaths (13%), both in previously treated patients, due to multiorgan system failure and Candida septicemia in one case each. Median survival of the patients with resistant or recurrent disease was 4.7 months (range 0.1-18.7) from time of ABMR. Median survival of the newly-diagnosed patients was 11.4 months (range 7.6-17.1) from the time of ABMR. CONCLUSION: High-dose chemotherapy utilizing these regimens followed by ABMR did not appear to prolong survival compared to conventional therapy in these children with pontine tumors. Alternative strategies need to be developed for this highly lethal disease.

Comparison of the cellularity and presence of residual leukemia in bone marrow aspirate and biopsy specimens in pediatric patients with acute lymphoblastic leukemia (ALL) at day 7-14 of chemotherapy.

BACKGROUND: Many pediatric chemotherapy protocols for treatment of ALL require a bone marrow examination at day 7 or day 14 after initiation of therapy. The usefulness of a bone marrow biopsy, in addition to an aspirate, has been a frequently asked question. PROCEDURE: This study addresses the evaluation of bone marrow cellularity and presence of residual leukemia in both aspirate and biopsy specimens in 45 consecutive pediatric patients (ages 1-19 years, 19 females, and 26 males) with ALL 7-14 days after initiation of therapy. DISCUSSION: 20/45 patients showed evidence of residual leukemia by bone marrow biopsy; 16/20 (80%) of these had evidence of residual leukemia in the aspirate specimen. Of the 4 aspirate specimens that did not demonstrate residual leukemia, 2 had <5% blasts and 2 had too few cells in the aspirate for evaluation. Of the 25/45 bone marrow biopsy specimens with no detectable residual leukemia, 14 of the aspirates had <5% blasts, and 11 had too few cells in the aspirate for evaluation. 13/45 (29%) of the aspirates had too few cells for a differential count. The bone marrow cellularity judged from the aspirate specimen was considered to be low (0-1+) in 34/45 patients. Of these 34 patients, the bone marrow biopsy showed hypocellularity (<20% cellularity) in 12/34, moderate cellularity (20-79% cellularity) in 14/34, and hypercellularity (>79% cellularity) in 8/34. CONCLUSIONS: We conclude that both the bone marrow aspirate and biopsy specimens provide important information in evaluating the response to chemotherapy in pediatric patients with ALL at day 7-14 of induction chemotherapy. The aspirate alone may be misleading in terms of cellularity in many patients and may not provide evidence of residual leukemia.

A phase II study of carboplatin as a treatment for children with acute leukemia recurring in bone marrow: a report of the Children's Cancer Group.

BACKGROUND: Carboplatin is an analogue of cisplatin with less nonhematologic toxicity and a similar spectrum of antineoplastic activity. Although cisplatin has not been found to be an active agent against leukemia, carboplatin-induced complete remissions have been observed in adults with acute myelogenous leukemia (AML), and antileukemic activity has been observed in a Phase I trial involving children with acute lymphoblastic leukemia (ALL) and AML. Therefore, a pediatric Phase II study was undertaken to determine the degree of activity of carboplatin in childhood ALL and AML. METHODS: Between October 1991 and November 1994, the Children's Cancer Group conducted a Phase II study of carboplatin given by 5-day continuous intravenous infusion to children with acute leukemia recurring in bone marrow. RESULTS: Minimal antileukemic activity was demonstrated in patients with ALL and AML. One of 21 eligible patients with ALL achieved a partial response. Of 23 eligible patients with AML, including 1 patient with chronic myelogenous leukemia in blast crisis, 1 had hypocellular M1 bone marrow with a platelet count of 15,000/mm3, and 2 achieved partial responses. Nonhematologic toxicities, which were infrequent, included mild hepatic and renal dysfunction. CONCLUSIONS: In this pediatric Phase II trial of carboplatin as a treatment for acute leukemia, minimal activity was demonstrated in patients with ALL and AML recurring in bone marrow. Further evaluation of carboplatin as a treatment for childhood leukemia, using the dose schedule of 216 mg/m2/day given by 5-day continuous intravenous infusion, does not appear warranted.

A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children's Cancer Group.

BACKGROUND: The murine monoclonal antibody (MoAb) 14.G2a recognizes GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and facilitates antibody dependent cellular cytotoxicity (ADCC) in vitro. When given in vivo, interleukin-2 (IL-2) can increase ADCC by enhancing the activity and number of circulating lymphocytes. METHODS: Thirty-three pediatric patients with GD2 positive malignancies, ranging in age from 2 to 17 years (median, 9.9 years), received IL-2 and 14.G2a in this Phase I/IB study of the Children's Cancer Group (CCG) and were monitored for toxicities and response to therapy. Seven of these patients also received granulocyte-macrophage-colony stimulating factor. RESULTS: The maximum tolerated dose (MTD) of 14.G2a with IL-2 was 15 mg/m2/day. The most prevalent Grade 3-4 toxicities were generalized pain (n = 14 [42%]) and fever without documented infection (n = 17 [52%]). IL-2 was thought to be the causative agent in most cases of fever. Toxicities attributed to 14.G2a included pain, allergic or anaphylactic reactions, and rash. Human antimouse antibodies were demonstrated in 9 of 21 evaluated patients. One patient with neuroblastoma had a partial response, and one patient with osteosarcoma had a complete response. Immunocytology demonstrated that the number of neuroblastoma cells in bone marrow decreased in three patients. CONCLUSIONS: The murine MoAb 14.G2a was well tolerated at the MTD and appeared to have some antitumor activity. Further development of this approach will involve additional engineered forms of the antibody as well as testing in the adjuvant and minimal residual disease setting.

Nephrotic syndrome associated with hypocomplementemia in a 4-year-old boy with hemophilia B.

PURPOSE: The case of a 4-year-old boy with hemophilia B with inhibitor who developed nephrotic syndrome is described. The possible association between factor IX therapy and nephrotic syndrome in patients with hemophilia B is discussed. PATIENT AND METHODS: A chart review of a 4-year-old boy with hemophilia B and an inhibitor who developed nephrotic syndrome with transient hypocomplementemia was performed. In addition, a literature search was undertaken to determine the prevalence of this association and possible etiologic factors. RESULTS: Although the nephrotic syndrome was resistant to steroid therapy and Bebulin (Osterreichisches Institut für Haemoderivate Ges.M.B.H., Subsidiary of Immuno AG, Vienna, Austria) infusions were continued, the edema resolved and proteinuria decreased. Seven month later, proteinuria, accompanied by transient hypocomplementemia, increased again. A rise in factor IX inhibitor level was observed. The patient received no immunosuppressive therapy, and exhibited a continuous decrease in urinary protein excretion over the following months. DISCUSSION: A discussion about possible differential diagnoses and a review of the literature are presented.

Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.

We report the results of intravenous anti-D (WinRho, WinRho SD) therapy in 261 non-splenectomized patients treated at the New York Hospital-Cornell Medical Center over the period from 1987 to 1994. Children (n = 124) and adult patients (n = 137) with classic immune thrombocytopenic purpura (ITP; n = 156) or human immunodeficiency virus (HIV) related thrombocytopenia (n = 105) and acute (n = 75) or chronic (n = 186) disease at the time of the initial anti-D treatment were studied. In addition, 11 previously splenectomized patients were treated as a separate group. Our objectives were to evaluate the following. (1) Efficacy of anti-D: The response after the initial infusion was analyzed according to clinical parameters, such as patient's age, HIV status, gender, disease duration, pretreatment platelet count, and hemoglobin value, as well as treatment-related factors, including the dose of anti-D, the solvent detergent treatment of the preparation, and the type of administration. (2) Use of anti-D as maintenance therapy: The duration of response after the initial infusion and the results of subsequent treatments were evaluated. (3) Safety/toxicity of anti-D: Postinfusion reactions and hemoglobin decrease after treatment were studied. Anti-D is a safe treatment providing a hemostatic platelet increase in greater than 70% of the Rh+ non-splenectomized patients. The group with the best results is HIV- children, but all patient groups respond and the effect lasts more than 21 days in 50% of the responders. Duration of response is not influenced by HIV status; furthermore, HIV+ patients show no adverse effects on hemoglobin decrease or HIV disease progression. Patients with chronic ITP after splenectomy have minimal or no response to intravenous anti-D.

Pharmacokinetics of intravenous recombinant human granulocyte colony-stimulating factor (rhG-CSF) in children receiving myelosuppressive cancer chemotherapy: clearance increases in relation to absolute neutrophil count with repeated dosing.

Limited evidence suggests increased efficacy of rhG-CSF by subcutaneous (SQ) compared with intravenous (IV) administration. To examine the possibility that rapid elimination of IV rhG-CSF could substantially shorten the duration of systemic exposure and could explain a difference in pharmacodynamics, we characterized the pharmacokinetic profile of IV rhG-CSF for comparison to that previously reported for SQ administration. Twelve children were randomly assigned to receive 10 or more days of IV rhG-CSF at dosages of 5 or 10 microg/kg a day beginning 24 hr after chemotherapy. Enzyme-linked immunosorbent assay (ELISA) was used to measure rhG-CSF concentrations in timed serum samples on days 1 and 10. Pharmacokinetic parameters were estimated by nonlinear, least squares regression. All serum concentration-time profiles were best described by a two-compartment model of elimination. Mean t1/2beta values ranged from 3.68 +/- 0.86 to 22.4 +/- 12.0 hr. ANC was correlated with log CLT (r = 0.72, P < 0.05), and inversely with log dose-adjusted AUC (r = 0.75, P < 0.05) and log dose-adjusted Cmax (r = -0.65, P < 0.05). Estimated duration of serum rhG-CSF concentrations above 1 ng/ml exceeded 24 hr for all but the 5 microg/kg cohort on day 1. Pharmacokinetic parameters of IV rhG-CSF are similar to those previously reported for SQ administration in children treated with myelosuppressive cancer chemotherapy. Daily IV administration should be a suitable alternative route of administration in this patient population.

Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group.

PURPOSE: The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival. PATIENTS AND METHODS: Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP). RESULTS: The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not. CONCLUSION: EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

Acute lymphoblastic leukaemia: a guide to asparaginase and pegaspargase therapy.

The cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion. The 2 native forms of L-asparaginase are derived from Escherichia coli and Erwinia chrysanthemi. The half-lives (t((1/2))) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t((1/2)), pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t((1/2)) of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t((1/2)). Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t((1/2)) of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase. So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.

The effect of ABO and Rh blood type on the response to intravenous immune globulin (IVIG) in children with immune thrombocytopenic purpura (ITP).

PURPOSE: Immune thrombocytopenic purpura (ITP) is a common childhood illness characterized by thrombocytopenia secondary to shortened platelet survival. Medical therapy includes corticosteroids, intravenous immune globulin (IVIG), and IV Rho (D) immunoglobulin (anti-D). Individuals with Rh-negative blood generally do not respond to treatment with anti-D, but little information is currently available regarding the potential relationship between blood type and response to IVIG. This study was designed to characterize the relationship between ABO and Rh blood type and the response to IVIG in children and adolescents with newly diagnosed ITP. PATIENTS AND METHODS: A retrospective chart review was performed for 52 children and adolescents with newly diagnosed ITP initially treated with IVIG by the Division of Pediatric Hematology-Oncology at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. RESULTS: There were no significant differences in response rate or clinical outcome by ABO blood group or Rh type in children with ITP who received IVIG monotherapy as their initial treatment. CONCLUSIONS: ABO blood group and Rh type do not appear to be prognostic factors when IVIG monotherapy is the initial treatment for childhood ITP.

Successful treatment of a primary cardiac leiomyosarcoma with ifosfamide and etoposide.

PURPOSE: Primary cardiac leiomyosarcoma is a rare malignant tumor in childhood. Patients with unresectable or partially resected cardiac leiomyosarcoma typically have a poor prognosis. The role of chemotherapy in the treatment of these patients has not been well defined. PATIENT AND METHODS: A 6-week-old infant with an incompletely resected cardiac leiomyosarcoma was treated postoperatively with ifosfamide and etoposide. RESULTS: The patient is disease-free and without apparent late effects 5 years following the completion of therapy. CONCLUSION: The combination of ifosfamide and etoposide warrants further evaluation in patients with leiomyosarcoma.

An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia (ALL) in children for almost 30 years. Because L-asparaginase is a foreign protein, the potential exists for severe, dose-limiting hypersensitivity reactions. To reduce this toxicity, L-asparaginase has been linked with polyethylene glycol (PEG). METHODS: Patients with ALL in relapse were entered in a Phase II, open-label clinical trial (ASP-201A) to evaluate the toxicity and efficacy of PEG-L-asparaginase. PEG-L-asparaginase has demonstrated potential low immunogenicity and a prolonged plasma half-life relative to native enzyme. PEG-L-asparaginase (2000 IU/m2 every 2 weeks) was used as single-agent induction therapy during an initial 14-day investigational window. Thereafter, the regimen consisted of PEG-L-asparaginase, vincristine, and prednisone. Patients also were allowed to receive doxorubicin and intrathecal chemotherapy beginning on day 14. All patients had been treated previously with one or more courses of native L-asparaginase; one of these patients was hypersensitive to L-asparaginase at enrollment. RESULTS: During the 14-day investigational window with PEG-L-asparaginase monotherapy, 22% of patients examined achieved a complete or partial remission. By completion of the 35-day induction period, 78% (or 14 of 18) of evaluated patients achieved complete or partial remission. Anaphylaxis did not occur during treatment. Mild urticaria and mild local allergic reactions occurred in five patients but did not cause discontinuation of treatment. The incidence of hyperglycemia and pancreatitis was less than expected from historic data published for previous studies with native L-asparaginase. CONCLUSIONS: As administered in this study, PEG-L-asparaginase can be given safely with a spectrum of toxicity similar to that of native L-asparaginase. Single-agent activity was documented in patients with ALL in bone marrow relapse.