Cerebrovascular disease in symptomatic and asymptomatic patients with sickle cell anemia: screening with duplex transcranial Doppler US--correlation with MR imaging and MR angiography.

PURPOSE: The authors evaluated the role of transcranial Doppler ultrasonography (US) in patients with sickle cell disease (SCD) and cerebrovascular disease. MATERIALS AND METHODS: Twenty-one patients with SCD and stroke (aged 3-22 years; mean age at stroke, 9 years) were evaluated with magnetic resonance (MR) imaging and duplex transcranial Doppler US with a 2-MHz transducer. Nineteen patients also underwent MR angiography. Forty-six asymptomatic patients with SCD were also evaluated with Doppler US, MR imaging, and MR angiography. RESULTS: The following transcranial Doppler US findings were correlated with cerebrovascular disease in patients with SCD: (a) maximum velocity in the ophthalmic artery (OA) of more than 35 cm/sec; (b) mean velocity in the middle cerebral artery (MCA) of more than 170 cm/sec; (c) resistive index in the OA of less than 50; (d) velocity in the OA greater than that of the ipsilateral MCA; and (e) maximum velocity in the posterior cerebral, vertebral, or basilar arteries greater than the maximum velocity in the MCA. CONCLUSION: Transcranial Doppler US scanning has great potential as an inexpensive, easily performed screening procedure for cerebrovascular disease in patients with SCD.

A comparison of neuropsychological and psychosocial functioning after prophylactic treatment for childhood leukemia in monozygotic twins.

Outcome findings based on a comprehensive battery of neuropsychological and psychosocial measurements were compared for a set of monozygotic twins. One twin had been diagnosed with acute lymphoblastic leukemia and given prophylactic treatment involving intrathecal methotrexate. Her twin sibling, who developed no signs of the disease, served as a unique control. Remarkably similar profiles were noted for the twins on tests of nonverbal intelligence, visual memory, visual attention, psychomotor speed, and mental flexibility. All performances were in the average to high average range. Significant differences were found on tasks measuring verbal abstract reasoning skills. These differences were postulated to result from prophylactic treatment, leukemia itself, or disruption in normal psychosocial development. As in previous studies, problems with auditory attention were found. However, both children displayed attentional difficulties regardless of treatment status. Emotional assessment indicated that both twins were experiencing a clinically significant level of anxiety that was postulated to play a role in reduced attention skills. Findings argue for the continued need for monitoring the neuropsychological functioning of children given prophylactic treatment and demonstrate the importance of measuring emotional factors in assessment with these children.

Single institution experience with high-dose cyclophosphamide, continuous infusion vincristine, escalating doses of VP-16-213, and total body irradiation with unpurged bone marrow rescue in children with neuroblastoma.

Seven consecutive autologous bone marrow transplants were performed in children with neuroblastoma with very good partial remission (VGPR). A combination of cyclophosphamide, escalating doses of VP-16-213, continuous infusion vincristine, and total body irradiation followed by infusion with unpurged bone marrow was used. The dose-limiting toxicity in this regimen was mucositis which occurred when the total dose of VP-16-213 was 2,400 mg/m2. The response rate to this regimen was 4/7 (-CR 48+, 21+, 21+, 35+ mo) 3/7 had a CP/PR post transplant with progressive disease between 1 and 4 months later (mean 2.6 mo). We conclude that this regimen is well tolerated when the maximum dose of VP-16-213 does not exceed 1,800 mg/m2. Further evaluation will be necessary with this regimen to determine its therapeutic value in a larger number of patients with neuroblastoma.

Long-term results in the treatment of acute nonlymphocytic leukemia: a Pediatric Oncology Group Study.

Complete remission (CR), 5-year remission duration (RD), and overall 5-year survival rates are 74%, 28% and 25%, respectively, for previously untreated children with acute nonlymphocytic leukemia diagnosed between 1977 and 1981, following induction therapy with vincristine, doxorubicin and prednisone (VAP), consolidation therapy with 6-thioguanine, cytosine arabinoside (TA) and cyclophosphamide/vincristine/cytosine arabinoside/prednisone (COAP), and maintenance therapy of alternating TA and COAP with or without VAP pulses. Approximately 20% are free of their disease for more than 5 years. High white blood cell counts (WBC) at diagnosis and M3 and M6 morphology were associated with lower CR rates, while M5 morphology was associated with higher CR rates. Patients with M1 morphology had shorter remission duration as compared to those with M4 or M5 morphology. Low WBC and age between 2 and 10 years at diagnosis were associated with longer remission durations and survival. Patients with M4 morphology also survived longer. The observed CR rates are comparable to other studies initiated at the same time as this study but survival is less than those reported more recently. Low WBC at diagnosis and M4/M5 morphology may identify relatively favorable prognostic groups.

Clinical trial of etoposide (VP-16) in children with recurrent malignant solid tumors. A phase II study from the Pediatric Oncology Group.

Etoposide (VP-16), 150 mg/M2, given intravenously daily for 3 days every 3 weeks resulted in 3 complete responses and 6 partial responses in 154 patients with a spectrum of recurrent malignant solid tumors. There was evidence of disease control in an additional 37 patients (27 mixed responses and 10 stable disease). These responses occurred primarily in patients with Ewing's sarcoma, Hodgkin's disease, neuroblastoma and rhabdomyosarcoma. Most of the patients had every extensive prior therapy; however prior therapy with teniposide (VM-26), the congener of VP-16, did not seem to preclude responses to the latter drug. Myelosuppression was the principal form of toxicity. Neutropenia characterized by absolute neutrophil counts of 0.5 to 0.9 x 10(9)/L occurred in one-half of the patients, and thrombopenia with platelet counts of less than 25 to 49 x 10(9)/L in one-fourth. These results demonstrate a favorable therapeutic index for VP-16 in several recurrent childhood solid tumors, supporting its use as a component of primary therapy for these diseases.

Prognostic factors for healing of bone lesions in histiocytosis X.

Healing characteristics and rates of resolution were retrospectively reviewed in 38 bone lesions in 18 patients with histiocytosis X. Signs which tended to indicate future healing were a change from a nontrabecular pattern to a trabecular pattern by 10 weeks, a nonsclerotic lesion to one with sclerosis by 13 weeks, and loss of distinct margins by 24 weeks. Complete healing then occurred within 36 to 40 weeks after development of these favorable signs. The earliest occurrence of a favorable sign was 6 weeks. A trabecular pattern was found in 90% of the lesions, outside the skull, which eventually healed. Fifty-eight percent (22 of 38) of the lesions completely healed in an average of 13.6 months. Five months was the most rapid occurrence of healing in any of our cases.

Neuropsychological effects of irradiation and chemotherapy treatments upon children with acute lymphoblastic leukemia: a case study of monozygotic twins.

Numerous attempts have been made to determine the effects of irradiation and chemotherapy upon cognitive functioning when used for treatment of acute lymphoblastic leukemia (ALL). While many studies have demonstrated a deleterious effect, others have found no significant changes in neuropsychological functioning. The uncertainty regarding the cognitive effects of these treatments is exemplified via a presentation of monozygotic twins who were evaluated via neuropsychological tests. The children received similar induction-consolidation therapy which included intrathecal methotrexate and cranial irradiation. Neuropsychological tests yielded almost identical I.Q. patterns, however, subtle differences were noted between the children when abstract reasoning abilities, achievement tests scores, motor speed, grip strength, performance on complex tasks requiring haptic sensitivity, and fingertip sensitivity were observed. This discussion also summarizes the previous findings related to cognitive function after chemotherapy and radiation therapy and some of the confounding factors which have been noted.

An experience with an implanted port system in 66 children with cancer.

Totally implanted port catheter systems have a lower incidence of infection and are more easily used in home care that external catheters in adult cancer patients. Experience with this method in children has been limited. During the past 2 years, we have implanted 71 ports in 66 children with cancer. Our experience demonstrates an infection rate (0.15 episodes of bacteremia per 100 patient days) slightly lower than that reported for children with Broviac or Hickman catheters, but not as low as that seen in adults with implanted systems. Patients and families have been extremely satisfied with the devices. Our experience supports further use of implanted systems in children with cancer.

Thrombotic thrombocytopenic purpura in an asplenic patient with hereditary spherocytosis: failure of plasmapheresis, antiplatelet therapy, and corticosteroids.

Thrombotic thrombocytopenic purpura (TTP) is a severe multisystem disorder characterized by microangiopathic hemolysis, central nervous system and renal dysfunction, and a very poor prognosis. Recently, however, plasma exchange or infusion therapy has proven effective in the majority of patients with TTP. We report a patient who developed TTP several years after splenectomy for hereditary spherocytosis. Despite aggressive therapy with plasmapheresis (PP), plasma infusion, antiplatelet drugs, and corticosteroids, the patient had progression of TTP that eventually resulted in his death. The occurrence of TTP in an asplenic patient with an intrinsic red cell disorder, a previously unreported association, may predict a poor prognosis.

Paroxysmal nocturnal hemoglobinuria presenting as recurrent hemolytic uremic syndrome.

Paroxysmal nocturnal hemoglobinuria (PNH) may present with acute anemia, thrombocytopenia and, if hemoglobin nephropathy or dehydration is present, azotemia. Thus PNH may be confused with the hemolytic uremic syndrome (HUS). Recurrent episodes, though common in PNH, are unusual in HUS. A positive acid hemolysis test can be used to differentiate between the two diseases.

Natural history of histiocytosis-X.

Histiocytosis-X can involve many organs and tissues in all age groups and in both sexes and occurs most often in caucasians. The signs and symptoms observed in the patient are directly related to the infiltration of Langerhans histiocytes, which compress or displace normal tissues and cause destruction of the tissues and organs involved. The disease tends to be benign and self-limiting when the involvement is limited to only one site. When more than one site is involved, the disease course can be chronic or acute. The chronic course tends to smolder for years, causing significant morbidity and disability but not death. The acute form tends to cause significant morbidity and early mortality.

Chromosome abnormalities in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHLH) is an uncommon disorder characterized by multiorgan infiltration with phagocytic histiocytes/macrophages. It may be inherited as an autosomal recessive trait, but specific associated cytogenetic abnormalities have not been documented. The authors describe a 10-week-old white female without prior family history of FHLH, who fulfilled the histologic and clinical criteria for the diagnosis. In addition, cytogenetic abnormalities, including the presence of double minute chromosomes and occasional loss of chromosomes 7 and 12, were documented in unstimulated peripheral blood cells. These karyotypic findings are usually associated with dyserythropoietic and leukemic states, and have not been described previously in the context of FHLH. It may be useful to do chromosome analyses on unstimulated peripheral blood cultures from FHLH patients before treatment to examine the karyotype of proliferating cells, which may represent the infiltrative histiocytes seen in the disorder.

Natural history of histiocytosis X: a Pediatric Oncology Group Study.

The best therapy for patients with histiocytosis X with disease involvement other than isolated bone lesions but without organ dysfunction is unclear. This retrospective study was undertaken to define the natural history of this group of patients. In 25 of the 92 studied patients, there was no progression of the disease after diagnosis. In 53 surviving patients, the disease either continuously progressed (40) or recurred intermittently (13). The onset of last disease activity was 24 months or less for 55% of these children. A fatal outcome occurred in 14 children. All of these children developed organ dysfunction and 11/14 died during or before the second year of disease. These three different outcomes could not be predicted from the parameters evaluated; however, the disease that never abated but was continuously active was associated with a suboptimal outcome, and the development of organ dysfunction was a grave prognostic sign.

Conversion to resectability by intra-arterial infusion chemotherapy after failure of systemic chemotherapy.

A 17 cm hepatoblastoma was unresectable at initial exploration. Multiagent chemotherapy (ADR, CTX, VCR, 5FU, BLEO) incurred minimal response at 5 months. Infuse-A-Ports were placed in each hepatic artery and FUDR infused intermittently but there was no response at 6 weeks. Adriamycin and vincristine were then begun via the Infuse-A-Port, with prompt regression of the tumor mass. The intra-arterial course was continued 3 months. Repeat arteriography showed vascular distortion but exploration revealed no gross tumor. A persistent alpha-feto-protein elevation prompted repeat arteriography 4 months afterward. A 3 cm calcific tumor was removed via an extended left lobectomy. Selective hepatic arterial infusion appeared to potentiate chemotherapy after systemic chemotherapy had failed to produce sufficient cytoreduction to allow safe surgical excision. The intra-arterial chemotherapy for unresectable hepatoblastoma warrants further investigation.

Comparison of maintenance treatment regimens for first central nervous system relapse in children with acute lymphocytic leukemia. A Pediatric Oncology Group study.

Eighty-seven children with central nervous system (CNS) leukemia were randomized to receive either induction intrathecal chemotherapy (ITC) and cranial irradiation (CRT) plus maintenance ITC, or induction ITC and craniospinal irradiation (CSpRT) with no maintenance ITC. ITC consisted of six weekly injections of methotrexate, hydrocortisone, and arabinosylcytosine. Also, intensification of systemic induction and maintenance chemotherapy was given. CRT + ITC was given as CRT, 2400 rad in 12 fractions followed by ITC maintenance bimonthly for 2 years. Craniospinal irradiation consisted of CRT + 1400 rad in ten fractions to the spine. Randomization was stratified according to whether CNS leukemia occurred at initial diagnosis of acute lymphocytic leukemia (ALL) (Stratum I, 15 patients), during first bone marrow (BM) remission (Stratum II, 49 patients), simultaneous with first BM relapse (Stratum III, 12 patients), or during second BM remission (Stratum IV, 11 patients). The median follow-up for patients who remain at risk is 15 + months. Eight children (seven on CRT + ITC, one on CSpRT) developed presumed therapy related encephalopathy. In Stratum II, 16 of 29 (55%) patients receiving CRT + ITC experienced adverse events: 3 deaths during continuous complete remission (CCR) and 13 relapses (2 CNS, 1 CNS + BM, 1 BM + testes, and 2 testes) as compared with only 5 relapses in 20 (25%) patients on CSpRT (1 CNS, 1 CNS + BM, 1 BM, and 2 testes). The children on both regimens were comparable for sex, race, age at initial ALL diagnosis, time from ALL diagnosis to first episode of CNS leukemia, systemic therapy both before and after CNS relapse, and number of blasts in the spinal fluid at diagnosis of CNS leukemia. The conclusion is that children with isolated CNS leukemia can achieve prolonged survival with aggressive therapy, and that CSpRT is possibly less toxic and more likely than is CRT + ITC to prevent subsequent BM and testicular relapse (P less than 0.02), but not subsequent CNS relapse (P = 0.7). A possible systemic therapy effect of spinal irradiation is postulated to explain the superiority of CSpRT.