ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeOriginally conceived as a means to replace or correct defective genes in patients with inherited disorders, gene transfer has shown broad potential for medical intervention in the hematopoietic cancers and for study of hematopoietic stem cell biology. The purpose of this article is to review emerging applications of gene therapy with special reference to hematopoietic neoplasia.ResultsGene transfer strategies now under investigation in the hematopoietic cancers focus on (a) repair of one or more genetic defects associated with the malignant process, (b) delivery of a prodrug-metabolizing enzyme that causes tumor cells to become sensitive to the corresponding anticancer drug, (c) modification of immune responses to the cancer, or (d) introduction of drug resistance genes to increase the therapeutic index of cytotoxic agents. Finally, by marking normal or malignant cells with readily detectable genes, one can monitor the efficacy of therapy or study the dynamics of stem cell behavior in vivo.ConclusionDespite their undisputed contributions to our knowledge of the hematopoietic cancers, gene transfer studies have been limited by the quality of vector technologies. As transduction efficiencies and gene regulatory mechanisms improve, gene transfer can be expected to evolve into a major therapeutic modality in its own right.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeWe present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B.Patients and MethodsTwelve hemophilia centrs from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes.ResultsAll 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor titers were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children.ConclusionPhysicians treating young children with hemophilia B should be aware of the potentially life-threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeCranial irradiation has been widely used in order to prevent central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) in childhood. Owing to the risk of late side effects, the Nordic Society for Pediatric Hematology and Oncology (NOPHO) replaced CNS irradiation with systemic high-dose methotrexate (HDMTX) in 1992. A prospective study of the effects of HDMTX and intrathecal MTX on CNS function is in progress at our center.Patients and MethodsSix ALL patients underwent99mTc-HMPAO single-photon emission computed tomography (SPECT) examination of regional cerebral blood flow (rCBF): three owing to neurological symptoms during treatment for ALL and the other three as part of the study.ResultsAll the patients had various degrees of disturbed rCBF, which was more pronounced in the patients with neurological symptoms. One patient had severe symptoms and impaired rCBF after three intrathecal injections of MTX but before administration of HDMTX.ConclusionsImpaired cerebral perfusion was found in patients with and without neurological symptoms during treatment for ALL. The impact of these findings is still unknown from both the long- and the short-term perspective. The possibility that intrathecal MTX alone or in combination with HDMTX may affect rCBF through vascular damage should be further investigated, in terms of both mechanisms and clinical significance.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeDespite improved event-free survival of older children with acute lymphocytic leukemia (ALL), infants <1 year of age continue to have a very poor prognosis. A new therapy designed specifically for infants with ALL was initiated.Patients and MethodsFrom 1984 until 1990, 82 eligible infants <1 year of age were entered on a Pediatric Oncology Group (POG) protocol 8493 for infant ALL. Compared to older patients, infants at diagnosis had more overt CNS leukemia (26%), higher initial WBC count (56%>50,000/μl), and a higher likelihood of CD-10 (CALLA) negative lymphoblasts (55%). A translocation involving chromosome 11 at band q23 was detected in 27 of 64 cytogenetically informative cases. Treatment was based upon two institutional pilot studies utilizing chemotherapy doses based upon body weight. Important components included remission induction with cyclophosphamide (Ctx), vincristine (Vcr), cytosine arabinoside (Ara-C), and prednisone (Pred) (COAP); consolidation therapy with teniposide (VM-26) and Ara-C; and continuation therapy with alternating pulses of COAP with VM-26/Ara-C separated by a methotrexate (Mtx) and 6-mercaptopurine (6-MP) backbone plus CNS therapy consisting of standard triple intrathecal therapy (TIT) (Mtx/hydrocortisone/Arc-C), which avoided the use of radiotherapy in this population.ResultsSeventy-six infants achieved a complete remission (93%). Fifty patients have relapsed: 35 isolated marrow relapses, five isolated CNS relapses, eight combined marrow and CNS relapses, and two other relapses. Actuarial event-free survival was 28% (SE=5%) at 4 years. Infants >274 days (9 months) at diagnosis had a better outcome than those <274 days.ConclusionsThis study represents a modest outcome improvement in comparison to previous experience with ALL for infants treated on POG trials. More effective therapy is still needed for infants with ALL.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeCytomegalovirus (CMV) infection can cause severe disease and mortality in recipients of allogeneic bone marrow transplants (alloBMT) when either the donor or recipient is CMV seropositive (high-risk alloBMT). We investigated the efficacy of preemptive therapy guided by detection of CMV antigenemia.MethodsIn 11 high-risk alloBMT recipients, high-dose ganciclovir (GCV) treatment was initiated at first positive antigenemia and was continued until antigenemia became negative.ResultsThe treatment strategy prevented CMV disease during the follow-up period of the study in 7 alloBMT recipients with positive CMV antigenemia. Three other patients who were shown to be CMV antigenemia negative but positive for CMV DNA in blood by the polymerase chain reaction (PCR) were not treated and did not develop CMV disease. The eleventh patient was negative for CMV by all tests for the duration of the study and did not develop CMV disease.ConclusionsWe have found antigenemia-guided preemptive GCV therapy to be an effective strategy for the prevention of CMV disease in high-risk alloBMT recipients.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeAlteration in the p53 tumor suppressor gene is the most common tumor specific genetic change identified in most major cancer types including rhabdomyosarcomas. To investigate the overexpression of p53 and its relation to clinical features and outcome in patients with rhabdomyosarcoma (RMS), an immunocytochemical study was performed.MethodsFormalin-fixed paraffin embedded tissue sections obtained from 42 cases of RMS were immunostained with a mouse monoclonal antibody p53-D07. Staining was assessed by evaluating the percentage of p53 immunopositive cancer cell nuclei.ResultsNuclear accumulation of p53 protein was detected in 8 of 42 (19%) samples. Clinical analyses of patients demonstrated no correlation between positive staining and age, sex, histological subtype, stage and overall survival. This analysis, however, was limited by the small number of patients who demonstrated p53 immunostaining. Nonetheless, a statistically significant association was observed between p53 expression and adverse outcome. Nuclear p53 expression was associated with disease progression or recurrence (p < 0.001) and with a worse event free survival (p = 0.0015).ConclusionThe nuclear p53 immunoreaction rate is low in RMS, but p53 expression appears to correlate with poor prognosis.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeThe purpose of this study was to investigate the role of bone marrow transplant (BMT) early in the course of disease for pediatric patients with high-risk leukemia using a preparatory regimen of fractionated total body irradiation (FTBI) and etoposide (VP-16).Patients and MethodsThose studied were 33 patients aged ≤18 years with either acute leukemia in first complete remission (CR) (n = 29) or chronic myelogenous leukemia (CML) in first chronic phase (n = 4) who received 1,320 cGy FTBI followed by highdose VP-16 (60 mg/kg) as a preparatory regimen for BMT from matched sibling donors. Patients with acute leukemia included 18 with acute nonlymphocytic leukemia (ANLL), one with biphenotypic acute leukemia (BAL), and 10 with selected “high-risk” acute lymphocytic leukemia (ALL). Patients with ALL were selected for a high risk for recurrence: those who failed standard remission induction chemotherapy, had a t(9;22) or t(4;11) chromosomal translocation, or had certain clinical high-risk features.ResultsAt the time of analysis, 28 patients are alive, all of them in continued complete remission for 1.1-7.8 years (median, 5.3 years; mean, 4.9 years). The Kaplan-Meier projected event-free survival (EFS) is 84.5% at 7 years, and the actuarial recurrence hazard is 6.5%. All surviving patients have a performance status of >80%.ConclusionThis result of early BMT in a two-institution study of pediatric patients with hematopoietic malignancies suggests that (a) matched sibling allogeneic BMT after conditioning with FTBI and high-dose VP-16 is an excellent treatment for pediatric patients with high-risk leukemia, and (b) children may have a better prognosis than adults treated with allogeneic BMT. Larger multiinstitutional cooperative trials for pediatric patients are needed to confirm this result.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

PurposeThe purpose of this study was to evaluate the efficacy and toxicity of three different salvage regimens (Rx) in children with recurrent or refractory neuroblastoma.Patients and MethodsForty-six children with recurrent or refractory neuroblastoma received treatment according to one of three regimens: Rx 1 (five patients), high-dose cisplatin (HDP) (200 mg/m2) with concurrent sodium thiosulfate (STS) (9.9 g/m2) as a nephroprotectant and etoposide (VP-16) (200 mg/m2/day for 3 days); Rx 2 (22 patients), high-dose carboplatin (HD-CBDCA) (500 mg/m2/day for 2 days) and VP-16 (100 mg/m2/day for 3 days); Rx 3 (19 patients), ifosfamide (1.5 g/m2/day for 3 days) followed by CBDCA (400 mg/m2) on day 4. Chemotherapy was administered every 3-4 weeks. Responses were assessed following four courses with or without surgery. Patients achieving less than a partial response (PR) on their primary treatment were crossed over to the next regimen (i.e., Rx 1 → Rx 2 ← Rx 3).ResultsRx 1 was ended early owing to grade 4 nephrotoxicity in two patients following their first course. Ten of 22 evaluated patients (45%) primarily (n = 19) or secondarily (n = 3) treated by Rx 2 responded [five complete response (CR) and five PRs]. Nine of the 23 evaluated patients (39%) on Rx 3 as primary (n = 18) or secondary (n = 5) treatment responded (one CR and eight PRs). Grades 3-4 neutropenia and thrombocytopenia occurred after 80% and 50% of courses administered on Rx 2 and Rx 3, respectively. Central venous line infections were the most commonly documented infections on these regimens.ConclusionsRx 2 and Rx 3 are active combinations in patients with recurrent or refractory neuroblastoma and are associated with manageable toxicity. HDP administered as a short i.v. infusion with concurrent STS infusion cannot be safely given to children with neuroblastoma pretreated with cisplatin.

ISSN:1077-4114    

出版商:OVID    

年代:1997

数据来源: OVID