Stuart Gold

Increased Age at Diagnosis Has a Significantly Negative Effect on Outcome in Children With Down Syndrome and Acute Myeloid Leukemia: A Report From the Children’s Cancer Group Study 2891

PURPOSE To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors. PATIENTS AND METHODS Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Childrens Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine. RESULTS Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P <.001), with more megakaryocytic leukemia (70% v 6%; P <.001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P <.001). Equivalent grade 3 to 4 toxicity (29% v 30%; P =.84) was seen, though children with DS had greater pulmonary toxicity (P <.01) during induction and mucositis during intensification (P =.12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P <.0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P =.006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P =.002). CONCLUSION Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

Prospective Study of 90 Children Requiring Treatment for Juvenile Myelomonocytic Leukemia or Myelodysplastic Syndrome: A Report From the Children’s Cancer Group

PURPOSE We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Childrens Cancer Group protocol 2891. PATIENTS AND METHODS Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. RESULTS Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and de novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. CONCLUSION Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.

Bone density in survivors of childhood malignancies

Purpose The purpose of this study was to assess bone mineralization in survivors of childhood malignancies. Patients and Methods Bone mineral density (BMD) of the lumbar spine was measured in 60 patients aged 5.5–20.1 years (mean. 12.4 years) who had no known disease 1.0–14.5 years (mean, 4.3 years) after completing treatment for a malignancy. The age-normalized BMD findings (Z scores) were correlated with multiple variables, including measures of growth and nutrition, type of malignancy, and various treatments, including use of steroids, methotrexate, or cranial irradiation. Results BMD was normal in most patients with a mean Z score of-0.28 + 0.14 (±SE). Only 8% of the patients were more than 2 SDs below age-matched normal BMD. Weight Z score was the major determinant of BMD Z score. Calcium intake and height Z score were also important variables. Conclusions Most survivors of childhood malignancies will not be left with a clinically significant deficit in BMD. Risk factors for diminished BMD include low-weight and low-height Z scores and low calcium intake. Therapeutic interventions are available to address these risk factors in those patients with significantly diminished BMD.

Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma.

Overexpression of the HER-2/neu oncogene appears to have prognostic significance in breast cancer. Recently, some have reported a relationship between increased immunohistochemical expression in osteosarcoma and poor clinical outcome. Despite limited data, a pilot trial of Herceptin, which targets the oncogene product, has been initiated for the therapy of some metastatic osteosarcomas (CCG-P9852). Archival formalin-fixed, paraffin-embedded tissue obtained from 41 patients diagnosed with osteosarcoma was examined immunohistochemically by 2 antibodies against the HER-2/neu oncogene product: CB-11 (monoclonal, 1/100) and Oncor (polyclonal, 1/200). All but one tumor (case of recurrent dedifferentiated parosteal osteosarcoma) represented primary tumor samples; when applicable, only prechemotherapy biopsies were analyzed. The study sample included the full spectrum of histologic subtypes and grades of osteosarcoma (25 conventional high grade; 3 telangiectatic; 1 small cell; 6 parosteal; 1 periosteal; and 5 low-grade intramedullary). A case of metastatic breast cancer with known overexpression of the HER-2/neu oncogene served as the positive control. Complete membranous positivity, considered prognostically significant in breast cancer, was not seen in any of our osteosarcoma cases. At least focal cytoplasmic positivity was documented in 40 (98%) tumors using the CB11 antibody and in 34 (83%) using the Oncor antibody. The intensity of the cytoplasmic staining (0, 1–3+) did not correlate with histologic subtype/grade, response to chemotherapy (<90% versus ≥90% necrosis), metastasis, or survival. Immunohistochemical overexpression of the HER-2/neu oncogene, defined as complete membranous positivity, is not present in our series of osteosarcomas. Cytoplasmic positivity is observed in most osteosarcomas, irrespective of histologic subtype/grade, and is not associated with response to preoperative chemotherapy or disease progression.

Longitudinal Evaluation of Bone Mineral Density in Children Receiving Chemotherapy

Purpose: Some children who survive a childhood malignancy have diminished bone mineral density (BMD). The purpose of this study is to assess when, and perhaps why, this problem develops. Patients and Methods: BMD was longitudinally monitored in 37 children for a minimum of 1 year (mean, 23.4 months; range, 12 to 41 months) during and, in some cases, after chemotherapy. Evaluations included serum analyses (vitamin D, calcium, and alkaline phosphatase), assessment of calcium intake, and measures of growth and nutrition (height, weight, and skinfolds). Results: BMD was already diminished at the start of treatment in some patients; 6 of 13 patients (46%) had a BMD score in the hip or spine of < - 1.0. However, only 1 patient (8%) was < - 2.0. Most patients did not have a significant drop in BMD z scores during chemotherapy, but one in four did decrease at least 0.5 standard deviations. Age greater than 10 years, a drop in height z score, and treatment with cranial irradiation correlated with a drop in BMD z scores during treatment. In the year immediately after completion of chemotherapy, no consistent “catch-up” was observed in BMD Z scores. Conclusions: In some patients, BMD Z scores are diminished at the time of diagnosis and a drop may occur during treatment in others. Multiple factors related to the disease process and treatment likely contribute to these observations. Cranial irradiation, perhaps by impacting on growth hormone homeostasis, is one such factor. Fortunately, most survivors of a childhood malignancy will not have large deficits in BMD later in life.

Risk factors for recurrent fever after the discontinuation of empiric antibiotic therapy for fever and neutropenia in pediatric patients with a malignancy or hematologic condition

We studied episodes of fever and neutropenia in children and adolescents without documented infections to determine the risk of recurrent fever after early discontinuation of empiric antibiotic therapy; 213 episodes occurred in 106 patients. All patients received empiric antibiotic therapy after cultures were obtained. Antibiotic therapy was discontinued if no infection was found, culture results were negative for 48 hours, and the patient was afebrile for 24 hours. In 83 episodes without documented infection, antibiotic therapy was stopped with absolute neutrophil counts < 0.5 x 10(9)/L (< 500/mm3); 50 episodes occurred in patients with solid tumors, leukemia in remission, and other hematologic conditions (group 1), and 33 in patients with active leukemia (group 2). Fever recurred before neutropenia resolved in 6% of group 1 and 45% of group 2 episodes; five patients in group 2 had documented infection. Recurrent fever risk correlated with absolute neutrophil count and monocyte count at the time antibiotic therapy was stopped, in both groups, as did increasing absolute neutrophil count and increasing leukocyte count in group 2. We conclude that discontinuing antibiotic therapy is safe in febrile episodes without documented infections before neutropenia resolves in patients with high potential for bone marrow recovery. The risk of recurrent fever and infection is significant for patients with neutropenia and poor marrow recovery potential.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

Magnetic resonance imaging of neuroblastoma using current techniques

We evaluated the ability of current magnetic resonance (MR) scanning techniques to detect and stage neuroblastoma in children, using surgical and histopathologic correlation. We prospectively and retrospectively reviewed 16 MR examinations from 14 patients with neuroblastoma (13 patients) or ganglioneuroblastoma (1 patient) and compared these to computed tomography (CT) (5 patients) and pathology (all patients). Sequences included: precontrast T1-weighted and T2-weighted images, and gadolinium-enhanced T1-weighted images. The study time for each MR exam was also calculated. Five primary tumors were intrathoracic paraspinous masses, eight were adrenal, and 1 was presacral. Neural foraminal invasion was demonstrated on MR in four of 14 patients. Three of the four patients had undergone CT and neural foraminal invasion was shown in one. Vascular encasement was demonstrated in five of 14 patients on MR images. Three of the five patients had undergone CT and vascular involvement was shown in two. All cases of neural foramina invasion and vascular encasement were proven at surgery. There were no false positive or false negative MR studies of neural foraminal invasion or vascular encasement. Bone marrow invasion was shown in two of 14 patients on MR images which were confirmed by bone marrow aspirate. No false negative cases of bone marrow invasion was shown. In one patient, CT considered one neuroblastoma to be adrenal in location which was correctly shown to be intrathoracic on MR. The mean study time for MR imaging was 49 min. Current MR techniques are accurate at detecting and staging neuroblastoma, and coverage of chest, abdomen, and pelvis can be performed in less than one hour.

β-Blockers for Infantile Hemangiomas: A Single-Institution Experience

Propranolol has become first-line therapy for the treatment of infantile hemangiomas in many centers. Of 302 children with hemangiomas seen at the University of North Carolina from 2008 through 2010, 15.6% were treated with oral propranolol alone, 5.6% with topical timolol (a propranolol derivative) alone, and 2.3% with both. The use of these agents increased over time from 7% of patients seen in 2008 to 54% of patients first seen in 2010. Starting doses of propranolol ranged from 0.25 to 1 mg/kg/d, with target doses of 1 to 4 mg/kg/d. Serious side effects, noted in 6/54 (10.9%) patients, included somnolence, bradycardia, hypotension, hypoglycemia, and mottling of extremities.The authors confirm the variation in use of propranolol for vascular lesions and extend experience with timolol. They suggest daily home monitoring of patients for the first 2 weeks of initiating or increasing doses. Frequent feeding of infants and young children on this drug is recommended.

Neuropsychologic functioning of human immunodeficiency virus-infected children with hemophilia.

Efforts to detect subtle but objective neuropsychologic deficits could clarify the early involvement of the central nervous system and the progression of human immunodeficiency virus (HIV) infection in older children and young adolescents. Baseline examinations of 63 children and adolescents with hemophilia were conducted by examiners unaware of HIV status or staging or of our studys major hypotheses. They measured six domains of neuropsychologic functioning (motor, language, memory, attention, visual processing, and problem solving), and no differences between groups of similar age, race, and socioeconomic status defined by HIV seropositivity (n = 25) and HIV seronegativity (n = 38) were revealed. A high incidence of subtle neuropsychologic deficits relative to (1) age norms and (2) individual cognitive potential was found on measures of motor performance, attention, and speeded visual processing within both infected and uninfected groups. On the basis of these baseline data, it seems premature to attribute early, subtle neuropsychologic deficits in seropositive children with hemophilia to the central nervous system effects of HIV infection.