Active microwave pulse compressor using an electron-beam triggered switch.

A high-power active microwave pulse compressor is described that operates by modulating the quality factor of an energy storage cavity by means of mode conversion controlled by a triggered electron-beam discharge across a switch cavity. This Letter describes the principle of operation, the design of the switch cavity, the configuration used for the tests, and the experimental results. The pulse compressor produced output pulses with 140-165 MW peak power, record peak power gains of 16∶1-20∶1, and FWHM pulse duration of 16-20 ns at a frequency of 11.43 GHz.

Observation of multipactor in an alumina-based dielectric-loaded accelerating structure.

We report a new regime of single-surface multipactor that was observed during high-power testing of an 11.424-GHz alumina-based dielectric-loaded accelerating structure. Previous experimental observations of single-surface multipactor on a dielectric occurred in cases for which the rf electric field was tangential and the rf power flow was normal to the dielectric surface (such as on rf windows) and found that the fraction of power absorbed at saturation is approximately 1%, independent of the incident power. In this new regime, in which strong normal and tangential rf electric fields are present and the power flow is parallel to the surface, the fraction of power absorbed at saturation is an increasing function of the incident power, and more than half of the incident power can be absorbed. A simple model is presented to explain the experimental results.

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 > or = 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.

Off-label use of recombinant factor VIIa in patients following bone marrow transplantation.

Recombinant factor VIIa (rFVIIa, NovoSeven) is FDA-approved for the treatment of bleeding in patients with hemophilia A/B with inhibitors. A growing literature suggests that there may be expanded indications for the use of NovoSeven in patients with significant bleeding who do not have a known factor deficiency. Severe bleeding refractory to standard hematologic or hemostatic support is common in patients undergoing bone marrow transplantation (BMT). We review our experience with rFVIIa in three patients (8 years 8 months to 19 years, median 13 years) treated for pulmonary hemorrhage (n = 1), hemorrhagic cystitis (n = 3), and gastrointestinal bleeding (n = 2). Boluses of 90-270 microg/kg rVIIa with subsequent doses of 90 microg/kg every 4-24 h for 3-14 days were given, concurrent with maintaining platelet counts >50,000/mm(3). Transient clinical responses in gross hematuria (two patients) and in pulmonary hemorrhage were noted within several days of starting rFVIIa, but bleeding in a new site in two patients and renewed bleeding of the initial site in the third resulted in discontinuation of the drug. No toxicity or adverse events were observed while the patients were on rFVIIa treatment. Because of the substantial cost of this product, the lack of adequate monitoring methodology, and the variability of current dose and dosing intervals, large randomized studies are needed before definitive off-label use in the setting of BMT can be recommended.

The role of fine needle aspiration biopsy in the diagnosis and management of osteosarcoma.

We retrospectively reviewed our experience with fine needle aspiration biopsy (FNAB) in the diagnosis and management of skeletal osteosarcoma. The bi-institutional study sample involved 30 consecutive aspirates from 29 patients (28 primary tumors, 1 pulmonary metastasis, 1 local recurrence). There were 17 children and 12 adults. Two aspirates were unsatisfactory for diagnosis. Of the adequate primary osteosarcoma cases analyzed by FNAB, 24 of 26 were diagnosed as osteosarcoma. All pediatric cases were correctly interpreted as osteosarcoma and treated appropriately. There were 2 incomplete diagnoses. A secondary osteosarcoma arising within an otherwise clinically, radiologically, and histologically typical giant cell tumor (malignant giant cell tumor) was not diagnosed preoperatively on FNAB due to nonrepresentative sampling. Chronologically, the first patient with osteosarcoma analyzed by FNAB was diagnosed simply as "spindle cell neoplasm." No complications resulted from the procedure. With adequate clinical and radiologic correlation, FNAB represents a technically, easily performed, cost-effective, and accurate procedure for establishing the diagnosis of skeletal osteosarcoma. Immediate interpretation of aspirated material allows for therapy planning and oncologic consultation at the initial clinic visit.

Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients.

We reviewed the clinicopathologic features of 145 consecutive fine-needle aspiration biopsy (FNAB) specimens from 140 patients without a previous diagnosis of sarcoma. Among 138 adequate specimens, 42 bone sarcomas and 80 soft tissue sarcomas were recognized as sarcomas; histologic subtyping was easier in bone than in soft tissue sarcomas and in pediatric than in adult cases. There was no correlation in accuracy of subtyping in low- vs high-grade sarcomas. FNAB was most accurate for subtyping of skeletal osteosarcoma, pediatric small round cell bone/soft tissue sarcomas, synovial sarcoma, skeletal chondrosarcoma, and adult myxoid soft tissue sarcomas. Although almost always recognized as sarcoma, subtyping of adult pleomorphic soft tissue sarcomas generally was not possible but did not influence therapy; all were considered high-grade sarcomas for treatment purposes. There were 4 misinterpretations of subtype in soft tissue sarcomas; none resulted in a change in therapy. Cytogenetic analysis on aspirated material confirmed t(11;22) in 2 Ewing and t(X;18) in 3 synovial sarcomas. No procedure-related complications occurred. Among bone and soft tissue sarcomas, FNAB was sufficient for initiation of definitive therapy in 87% and 83% of patients, respectively. Most FNAB specimens from bone and soft tissue sarcomas are recognized easily as sarcoma, but subtyping seems more accurate in bone sarcomas. Although histologic subtyping of adult soft tissue sarcomas is often impossible, no influence on initial therapy is usually observed. In contrast, subtyping of pediatric sarcomas by FNAB seems highly accurate and is necessary for appropriate therapy.

Social skills and psychological adjustment of child and adolescent cancer survivors.

Social skills and psychological adjustment for survivors of childhood cancer were investigated. Cancer survivors included 42 children and adolescents ranging in age at evaluation from 6 to 18 years with a mean age of 13.1 years. Measures included teacher and parent ratings of social skills and adjustment and parent ratings of family functioning. The findings showed that social skills and psychological adjustment as rated by both parents and teachers were primarily associated with academic functioning. In addition, family cohesiveness was found to account for nearly one third of the variance in survivors' adjustment when rated by teachers, and length of time off treatment accounted for a significant percentage of the variance in children's adjustment when rated by parents. The findings underscore the importance of a multi-informant approach to the assessment of psychological adjustment of pediatric cancer survivors and demonstrate the role of learning difficulties and family functioning in influencing social skills and adjustment for these children and adolescents.

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 z 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.

HIV-infected children with hemophilia: one- and two-year follow-up of neuropsychological functioning.

This report describes the absence of neuropsychologic change observed over a 2-year period for 25 HIV-seropositive (HIV+) children and adolescents with hemophilia and 33 HIV-seronegative (HIV-) controls. Efforts were made to match the groups on the basis of chronological age, race, and hemophilia severity. The baseline evaluation included blinded neuropsychologic measurement of motor, attention, language, visual processing, memory, and general intelligence. HIV+ and HIV-group means did not differ at baseline on any neuropsychologic domain, and this trend continued at the 2-year follow-up. Mixed models analyses did not indicate that the HIV+ group performed more poorly than the HIV- group on any of the neuropsychological domains, nor did they show different patterns of change over time on these variables for the HIV+ group. Consistent with emergent findings, it continues to be premature to attribute subtle neuropsychologic deficits in seropositive children with hemophilia directly to the central nervous system (CNS) effects of HIV infection.

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.

Health insurance access to young adult survivors of childhood cancer in North Carolina.

Historically, there has been evidence to support the hypothesis that survivors of childhood cancer have been discriminated against in the private health insurance market in some areas of the United States. Results of previous studies have been inconsistent and have generally focused on a limited number of outcome variables. A retrospective cohort study of young adult survivors of childhood cancer and their siblings was performed to determine the risk of health insurance access problems of childhood cancer survivors in North Carolina. Mailed questionnaires were completed by 182 cancer survivors from three institutions who were diagnosed between 1976 and 1988, and by 101 of their siblings for a response of 62.1%. Using logistic regression in SAS, cancer survivors were found to be more likely to be denied health insurance than their siblings, with an adjusted odds ratio of 15.1. Childhood cancer survivors also had health insurance policies that excluded care for pre-existing medical conditions more often than their siblings (OR = 5.5). In addition, cancer survivors reported problems obtaining health insurance coverage more frequently than their siblings with an adjusted odds ratio of 22.8. In general, survivors of childhood cancer who were diagnosed in North Carolina have had decreased access to health insurance coverage when compared to their siblings of similar age. North Carolina health insurance regulations permit health insurance firms to discriminate against cancer survivors because of their history of illness, often decreasing their access to needed follow-up care.

Symptomatic cataplexy in pontomedullary lesions.

Cataplexy is a cardinal manifestation of the narcolepsy syndrome. Although symptomatic narcolepsy is well described, isolated cataplexy is extremely rare. We reviewed clinical and radiologic data in two patients with isolated symptomatic cataplexy and associated CNS disease. In an HLA-DR2-positive patient with chronic progressive MS, we confirmed cataplexy by observation of reported spells. MRI revealed diffuse white-matter lesions involving the medial medulla, pons, and subcortical white matter; protriptyline provided symptomatic relief. A second patient with a pontomedullary pilocytic astrocytoma developed infrequent but recurrent cataplectic attacks in association with sleep fragmentation due to nocturnal cough and nausea. MRI revealed an enhancing lesion involving the dorsal pons and medulla. Genetic predisposition and sleep fragmentation may precipitate symptomatic cataplexy in patients with structural pontomedullary lesions.

Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.

The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.

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.

Cytosine arabinoside and mitoxantrone treatment of relapsed or refractory childhood leukemia: initial response and relationship to multidrug resistance gene 1.

The objective of this study was to determine the response rate and toxicity of high-dose cytosine arabinoside (AC) and mitoxantrone (M) in relapsed or refractory childhood acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) and to correlate response with the expression of the multidrug resistance gene 1 (mdr1). Twenty-nine patients were treated with AC 1.0 g/m2 infused over 2 h every 12 h for eight doses (days 1-4) and M 12 mg/m2 infused over 1 h (days 3-6). Mdr1 expression was determined by a polymerase chain reaction (pcr) assay. Ten of 15 patients (67%) with AML obtained a complete remission (CR) of 3 to 30+ months duration. Eight of 14 (57%) ALL patients obtained a CR of 1 to 23+ months duration. The major toxicities were hematopoietic and infectious. Seventy-nine per cent of patients developed a documented infection during induction. Mdr1 did not correlate with a lower induction rate. This AC/M regimen is active in childhood AML and ALL.

Radiologic staging of thoracoabdominal tumors in childhood.

Thoracoabdominal tumors of childhood include a pathologically diverse spectrum of neoplasms. Improved survival for many of these once lethal malignancies reflects current multimodality approaches to treatment based on the combined experience of specific tumor study groups. The choice of surgery, chemotherapy, and/or radiation depend on accurate clinical and radiologic staging based on determination of tumor extent and the feasibility of surgical resection. Advanced cross-sectional and scintigraphic imaging techniques have enhanced the accuracy of radiologic assessment and staging. Established pathologic patterns of local extension and more distant dissemination, as well as the relative sensitivity and specificity of applicable imaging modalities determine radiologic approaches to radiologic staging of specific neoplasms.

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 study's 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.

The coagulopathy of childhood leukemia. Thrombin activation or primary fibrinolysis?

Little information is available on the prevalence and etiology of the coagulopathy present in some children with acute leukemia at disease presentation. We studied 102 children with newly diagnosed acute leukemia (50 retrospective: Group A; and 52 prospective: Group B) with prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), fibrinogen (FIB), and fibrin degradation products (FDP). All patients in Group B also had assessment of thrombin activation by measurement of the crosslinked fibrin fragment, D-dimer, and of primary fibrinolysis with the B beta 1-42 peptide. Additionally, ten patients from Group B had Factors II, V, VII, and X measured, and eight of these patients had measurement of tissue factor from sonicated bone marrow cells. Thirty-two percent of Group A and 40% of Group B had totally normal coagulation studies, whereas 20% of Group A and 10% of Group B had a severe coagulopathy on disease presentation. A high percentage of both groups had elevated PT (Group A, 52%; Group B, 27%) and increased FDP (Group A, 39%; Group B, 25%). In Group B, 38% of the patients had a positive D-dimer, whereas only 4% of this prospective group had an elevated B beta 1-42 peptide (P less than 0.00001). Nine of ten patients with a positive D-dimer had low levels of one or more of the extrinsic pathway factors. Three of four patients with the highest tissue factor levels were of monocytoid leukemia cell type. These data indicate that the coagulopathy associated with acute leukemia of childhood is usually mediated by thrombin activation.