Lewis C. Strauss

Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: a multivariate analysis of risk factors.

We evaluated the courses of 115 consecutive cases of pediatric acute leukemia treated with induction chemotherapy. Seventy-two patients developed fever associated with neutropenia; 15 developed systemic fungal infections. We reviewed multiple demographic and treatment characteristics of these patients in an attempt to identify potential risk factors for the development of invasive fungal disease (IFD). Risk factors identified in a univariate analysis included duration of neutropenia after first fever (P less than .0001), diagnosis of acute nonlymphocytic leukemia (ANLL) (P = .003), onset of fever and neutropenia within 5 days of starting induction chemotherapy (P = .009), and multiple (greater than one) surveillance culture sites positive for fungal organisms (P = .02). In a multiple logistic regression analysis, duration of neutropenia (P less than .001) remained a significant risk factor. The study group of patients had a significantly higher risk of fungal infections than a matched group of leukemia pa...

Two-phase [11C]l-methionine PET in childhood brain tumors

Thirteen children (1.8-15.8 years of age) with brain tumors were studied with [11C]L-methionine positron emission tomography (METPET). Patients were injected intravenously with tracer before a baseline PET scan was obtained. To assess the sensitivity of [11C]L-methionine uptake to competitive inhibition, 10 patients received oral L-phenylalanine (100 mg/kg); 1 hour later, a second METPET was obtained. Subjective assessment of [11C]L-methionine uptake closely paralleled results of quantitative examination (r = 0.81). [11C]L-methionine uptake in tumor-containing brain was increased in 11 patients (mean ratio of [11C] radioactivity in tumor to normal brain: 1.5 +/- 0.57; range: 1.13-2.98). Increased tracer uptake occurred in ependymomas (3), medulloblastoma (1), and astrocytomas (5), but was less intense in low-grade tumors. L-phenylalanine reduced L-methionine uptake (25-69%) in 70% of studies. L-methionine uptake was not sensitive to competitive inhibition in brain radiation injury. Two-phase METPET is of potential value in difficult clinical situations evident in children with brain tumors, including the differential diagnosis of tumor recurrence and cerebral radiation injury.

Selection of normal human hematopoietic stem cells for bone marrow transplantation using immunomagnetic microspheres and CD34 antibody

Complete yet nontoxic removal of tumor cells from autologous marrow grafts has proved difficult. New methods for separating normal stem cells from tumor cells are needed. The CD34+ cells in bone marrow, 1–2% of the low-density leukocytes, include precursors of all lymphohematopoietic lineages and probably also the primitive cells responsible for engraftment. A nontoxic, inexpensive, reproducible, and clinically applicable method for positive selection of CD34+ cells was developed. Paramagnetic microspheres coated with goat anti-mouse IgG, are used to partition the cells; brief incubation with chymopapain is used to release them from the beads. Chymopapain exposure does not injure colony-forming cells or delay engraftment in rodents. Clinical volumes of bone marrow can be processed rapidly. In pilot experiments, the resulting grafts have a purity of 85–99% CD34+ cells and 40% median recovery of the assayable colony-forming cells. These studies form the background for a Phase I trial of autologous BMT using CD34+ stem cells.

Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a pediatric oncology phase II study.

Purpose To assess the efficacy and define the toxicity of paclitaxel given at a dosage of 350 mg/m 2 every 3 weeks as a 24-hour continuous infusion to children with recurrent or progressive primary brain tumors. Patients and Methods Seventy-three eligible patients, ages 4 months to 19 years, with progressive or recurrent primary brain tumors were treated according to a Pediatric Oncology Group (POG) phase II protocol with paclitaxel (POG 9330). Tumor histologic strata included: astrocytoma (n = 4), malignant glioma (n = 13), medulloblastoma (n = 16), brain stem glioma (n = 15), ependymoma (n = 13), and miscellaneous histologies (n = 12). All patients had previous histologic confirmation of a primary intracranial or spinal cord tumor with magnetic resonance imaging or computed tomography documentation of unequivocally measurable progressive or recurrent disease. All patients had received previous therapy including surgery, radiation therapy, and/or chemotherapy, but no patient had been previously treated on more than one phase II trial. Paclitaxel was administered as a 24-hour intravenous infusion at a dosage of 350 mg/m 2 every 3 weeks. Neurologic and neuroradiologic reevaluations were performed after every second course. Patients were allowed to continue therapy for a total of 18 cycles in the absence of progressive disease or unacceptable toxicity. Results Seventy-five patients were enrolled onto the POG 9330 protocol; two ineligible patients were removed from the study before receiving any therapy. Of the 73 eligible patients, 72 were evaluable for toxicity and 70 were either fully or partially evaluable for disease response. There was one complete response and three partial responses (5.7%). Twenty patients had stable disease for more than 2 months. Toxicities included mild nausea, central nervous system toxicity, myelosuppression, and febrile neutropenia, including one septic death. One grade 2 and two grade 3 allergic reactions occurred. No cardiac toxicities or arthralgias were reported. Conclusion Paclitaxel is well tolerated in children with recurrent or progressive brain tumors at this dosage and schedule and may result in short-term disease stabilization in this patient population. The lack of a significant number of patients with measurable disease regression, however, precludes it from being identified as an active agent when administered as a single agent by 24-hour continuous infusion.

Development of a simplified counterflow centrifugation elutriation procedure for depletion of lymphocytes from human bone marrow

Graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow (BM) transplantation. Techniques that effectively purge BM of mature T lymphocytes should reduce the incidence of GVHD and improve survival. We have developed a simplified, two-flow rate, fixed rotor speed counterflow centrifugation-elutriation (CCE) procedure that reproducibly depletes 99% of lymphocytes from Ficoll-Hypaque (F/H)-separated BM or BM buffy-coat. Two predetermined flow rates (24 and 28 ml/min) were used to purge small and intermediate-to-large lymphocytes, respectively, whereas faster sedimenting cells were recovered at the termination of the run. Lymphocyte depletion was substantiated by pan-T monoclonal antibody analysis as well as by complete loss of responsiveness of alloantigens and mitogens. Despite the lack of mature T cells, the depleted marrow fraction retained lymphoid colony-forming ability. Lymphocyte-purged marrow was obtained in high yield (72%), and retained high viability (>97%) and hematopoietic colony-forming ability (>99%). The ratio of total myeloid/erythroid colony-forming cells to T lymphocytes was 73-fold higher in the lymphocyte-depleted fraction than in unseparated BM. We concluded that a two-step CCE procedure can be used to rapidly deplete lymphocytes from both F/H-separated and buffy-coat BM inocula without altering hematopoietic capacity as measured by the in vitro clonogenic assays. It may be possible to adapt this procedure to the separation of the large number of marrow cells required for human BM transplantation.

Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium

PURPOSE Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.

Cisplatin, ara-C and etoposide (PAE) in the treatment of recurrent childhood brain tumors

Sixteen patients with recurrent childhood brain tumors were treated with intravenous cisplatin, cytosine arabinoside and etoposide (PAE), daily for three days every three to four weeks. Objective responses were observed in 6 of 15 evaluable patients and an additional six patients had stable disease for > 6 months. The tumor-specific response rate for astrocytoma/glioma was 3 of 7 and for medulloblastoma was 2 of 4. The mean progression-free interval was 11.0 months and the hazard rate for progression was 0.085 per patient-month of observation. The most common toxicities were neutropenia and thrombocytopenia. Clinically significant ototoxicity wasidentified in 7 patients. The activity of PAE chemotherapy for recurrent childhood brain tumors warrants further investigation.

Response of a recurrent choroid plexus tumor to combination chemotherapy.

SummaryChoroid Plexus tumors are rare. Surgery and biopsy is diagnostic, and radiotherapy has been used as the treatment of choice for choroid plexus carcinoma (CPC) and recurrent choroid plexus papilloma (CPP). We report the first case of CPP responding to combination chemotherapy consisting of cisplatin, bleomycin and vinblastine (CBV). This chemotherapy regimen should be considered for future trials in patients with choroid plexus tumors and recurrence after surgery and/ or radiotherapy.

Analysis of histiocytosis X infiltrates with monoclonal antibodies directed against cells of histiocytic, lymphoid, and myeloid lineage

Surface markers expressed on histiocytosis X (HX) cells were studied using 18 monoclonal antibodies (McAbs) and an in situ indirect immunoperoxidase technique. Specimens of skin (five biopsies from three cases) and lymph node (one case) were studied. Our study confirmed previous findings of an OKT6+ HLA DR+ Leu 3a+ phenotype of HX cells in skin and indicated that lymph node HX cells can also have this phenotype. A mixture of cells expressing T markers/T subset, monocyte/macrophage, and killer/natural killer (K/NK) markers was also present in two cases. However, one case with an aggressive course showed no detectable HNK 1+ (K/NK) or Leu 2A (suppressor) cells in the cutaneous infiltrates and no detectable HNK 1+ lymphocytes in an affected lymph node. The significance of these findings in relation to prognosis and therapy is discussed.

Two primary brain tumors in one child

We studied a 4-year-old boy with symptoms and signs of a posterior fossa tumor. CT showed two separate intracranial tumors: a fourth ventricle choroid plexus papilloma and a frontal subependymal giant-cell astro-cytoma. This case emphasizes that, even in the absence of special genetic predisposition to CNS tumors, two separate intracranial masses may not represent CSF metastasis of a single primary tumor.