Biomedical subjects

M E Nesbit

Publications and source records attributed to M E Nesbit.

At least 55 records · Page 3Linked to original sources

PubMed1989

Remission induction in children with acute non-lymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Childrens Cancer Study Group.

Four hundred ninety evaluable patients were treated on an induction regimen consisting of two to four courses of cytosine arabinoside plus an anthracycline. Overall, 78% of patients went into remission, 10% died during induction, and 12% were induction failures. For the first 152 patients, courses consisted of 7 days continuous infusion with cytosine arabinoside (Ara-C, 100 mg/m2) and 3 days of doxorubicin (30 mg/m2). Because of unacceptable toxicity, particularly for children less than 3 years of age, the anthracycline was changed to daunorubicin, and the doses of both induction drugs for children under 3 was reduced. For children aged 3 years and older the change in anthracycline was associated with a significant increase in induction failures (7% to 16%, P = .04) and a decrease in deaths (15% to 8%, P = .09). For younger children, for whom doses were also changed, the effect was greater; Mortality decreased from 29% to 1% (P less than .0001), and the remission induction rate increased from 66% to 88% (P = .005). The therapy modifications also influenced survival following remission induction: Daunorubicin-treated patients, aged 3 years and over, did significantly better than those given doxorubicin (P = .03), but the opposite was seen in younger children (P = .06). Gastrointestinal and skin toxicities and septicemia were significantly more common when doxorubicin was being used, but the extent of myelosuppression was similar for the two anthracyclines.

Age Factors↗

PubMed1988

Sequelae of thrombotic or hemorrhagic complications following L-asparaginase therapy for childhood lymphoblastic leukemia.

Thirty-four cases of childhood lymphoblastic leukemia that were complicated by CNS and peripheral thrombosis or hemorrhage associated with L-asparaginase (L-asp) therapy were reviewed to determine the effect of the events on the subsequent clinical status. There was no predilection for any site in the CNS cases; all but one of the peripheral events occurred in the lower extremities. The median time for 28 CNS and eight peripheral events from the beginning of L-asp therapy was 17 and 16 days, respectively. One patient died as a result of the CNS event. Twenty-six patients were surviving with a median follow-up of 27 months at the close of the study. Of the patients with peripheral thromboses, only the patient with a dorsal pedal artery occlusion had a significant problem (autoamputation of a toe). Although eight patients received L-asp subsequently without recurrence of the complication, two had transient neurological deterioration associated with the repeat administration of L-asp. Twenty-two patients received CNS prophylaxis consisting of intrathecal methotrexate, CNS radiation, or both, following the CNS event without deterioration. In general, clinical status was not compromised after thrombotic or hemorrhagic events. Although most patients had gross recovery of their neurological impairment, detailed neurological and neuropsychological testing is needed to elucidate possible defects.

Adolescent↗

PubMed1988

Kidney size at diagnosis of childhood acute lymphocytic leukemia: lack of prognostic significance for outcome.

The prognostic significance of kidney size at diagnosis of acute lymphoblastic leukemia (ALL) was assessed in a population of 142 children. Kidney size was determined using three different methodologies, and its significance was determined by univariate and multivariate life-table methods. Enlarged kidney size (as determined by any of the three methods used) was not associated with an overall poorer survival. These findings were consistent when kidney size at diagnosis was analyzed as a singled variable and when it was considered after adjustment for the known prognostic factors of age, sex, and initial WBC count. Assessment of renal size at the time of diagnosis of childhood ALL is not indicated for the purpose of predicting subsequent prognosis.

Age Factors↗

PubMed1988

Allogeneic bone marrow transplantation for acute leukaemia: comparative outcomes for adults and children.

Advances in both allogeneic marrow transplantation and conventional therapy for acute leukaemia have complicated the choice between bone marrow transplantation (BMT) and other remission treatment options. Because older patients may be more susceptible to BMT-related complications, this study analysed the effect of age on clinical outcome for 149 patients with acute leukaemia in remission receiving allogeneic BMT. Overall projected relapse-free survival at 3 years post-transplant is equivalent for 48 adults (18 years or older) and 101 children (less than 18) at 45.4% (31.1-59.6; 95% confidence interval) and 39.9% (30.1-49.7; 95% C.I.), respectively. Among 73 patients with acute lymphocytic leukaemia (ALL) 35.3% of adults and 30.1% of children survive relapse-free at 3 years. Cox multiple regression analysis demonstrated that higher diagnostic white count, but not pre-transplant extramedullary leukaemia, remission number, or age, was important as an independent adverse clinical prognostic factor for patients with ALL. Overall outcome was better for 76 patients with acute myeloid leukaemia (AML) with 51.6% of adults and 52.9% of children surviving relapse-free at 3 years post-transplant. Cox multivariate regression analysis identified first remission status and lower white cell count, but not patient age, as independent predictors of improved relapse-free survival for AML patients. Adults had greater transplant morbidity, predominantly related to a higher incidence of acute graft-versus-host disease (GVHD), resulting in longer hospital stay. Survival at 100 d, long-term survival and clinical performance status were similar in both age groups. These data suggest that results of allogeneic BMT for adults with acute leukaemia compare favourably with those found in children and are superior to most reports of conventional chemotherapy. Allogeneic BMT remains a reasonable option for remission acute leukaemia patients up to the age of 45.

Adolescent↗

PubMed1988

Allogeneic bone marrow transplantation for acute nonlymphocytic leukemia in first remission.

Seventy-three patients with acute nonlymphocytic leukemia in first complete remission (CR) have received allogeneic bone marrow transplantation (BMT) with non-T-lymphocyte-depleted marrow obtained from matched sibling donors. The first 36 patients received a preparative regimen consisting of cyclophosphamide, 60 mg/kg/d (days -6 and -5), and 750 cGy single-dose total-body irradiation (TBI) (day -1). Subsequently, 37 patients received cyclophosphamide 60 mg/kg/d (days -6 and -5), and 165 cGy fractionated TBI administered twice daily for a total dose of 1,320 cGy (days -4, -3, -2, and -1). Survivors have been followed from 9 to 124 months (median, 40 months). The 61% (95% confidence interval [CI], 45% to 77%) projected disease-free survival (DFS) of 41 children less than 18 years old does not differ significantly from the 62% (95% CI, 49% to 73%) projected DFS of 32 adults at 84 months (P = .89). Similarly, the 15% (95% CI, 1% to 29%) projected relapse rate seen in children does not differ from the 9% (95% CI, 0% to 21%) seen in adults (P = .69). Multivariate Cox regression analysis of presenting features demonstrates that a presenting WBC count greater than 20,000/m3 is associated with decreased DFS (P = .01). When compared with other French-American-British (FAB) subtypes, presentation with FAB M4 or M5 morphology is significantly associated with relapse in multivariate analysis (P = .014). Other presenting features such as preparation with single-dose or fractionated TBI, interval from diagnosis to CR or CR to BMT, donor or recipient sex, and donor or recipient cytomegalovirus serology do not correlate independently with either DFS or relapse. When included in the stepwise multivariate analysis of presenting patient features, two posttransplant events, development of grades 2 to 4 acute graft-v-host disease (GVHD) (P less than .03) and development of interstitial pneumonitis (P less than .001), also correlate independently with poor DFS. Allogeneic BMT provides equivalent, prolonged DFS in both children and young adults when performed in first CR and should be considered the therapy of choice for all first CR patients under 45 years of age with a suitable donor. Continued efforts to prevent and treat acute GVHD and pneumonitis as well as efforts designed to prevent relapse in patients presenting with FAB M4 and M5 morphology should further improve outcome.

Age Factors↗

PubMed1987

Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia.

Chemoradiotherapy and transplantation of bone marrow from matched sibling donors have been useful for the treatment of acute lymphoblastic leukemia in patients with a poor prognosis but are not available to some two thirds of patients who do not have a matched allogeneic donor. We undertook this study to compare autologous and allogeneic marrow transplantation in the treatment of such cases. We treated 91 patients with high-dose chemoradiotherapy and followed them for 1.4 to 5 years. Forty-six patients with an HLA-matched donor received allogeneic marrow, and 45 patients without a matched donor received their own marrow taken during remission and purged of leukemic cells with use of monoclonal antibodies. Bone marrow engraftment occurred earlier in patients who received autologous marrow. Recipients of autologous marrow had shorter hospital courses, with significantly fewer peritransplantation deaths than recipients of allogeneic marrow. Post-transplantation relapse of leukemia was the most frequent cause of treatment failure; relapses occurred in an estimated 37 percent of patients with allogeneic grafts in whom graft-versus-host disease developed, 75 percent of patients with allogeneic grafts in whom graft-versus-host disease did not develop, and 79 percent of patients who received autologous grafts. The interval before relapse was significantly shorter in the autologous-marrow group than in the allogeneic-marrow group. Recipients of autologous and allogeneic marrow whose first pretransplantation remissions were short (less than 18 months) had eventual outcomes similar to those whose first remissions were longer than 18 months. Patients with a first remission lasting less than 18 months had an outcome better than that expected with chemotherapy alone. The fractions of "cured" patients were estimated to be 20 percent in the autologous-marrow group and 27 percent in the allogeneic-marrow group--not a significant difference, but because of the limited statistical power of the study, the question of long-term disease-free survival must still be considered open.

Adolescent↗

PubMed1987

Intermittent central nervous system irradiation and intrathecal chemotherapy for central nervous system leukemia in children.

Between 1979 and 1985, nine children with recurrent CNS leukemia who had previous radiation of more than 1800 cGy to the brain were treated with intermittent central nervous system irradiation and intrathecal chemotherapy (IIIC). There was no isolated CNS recurrence. Three patients died; one from generalized recurrent disease, two from complications associated with bone marrow transplantation. Six patients are alive without evidence of disease between 9 years and 2 4/12 years from the diagnosis of recurrent CNS leukemia. This experience suggests that IIIC may be an effective treatment for preventing the recurrence of CNS leukemia with minimal side effects.

Adolescent↗

PubMed1987

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

Adolescent↗

PubMed1987

Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group has assessed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and pubertal development in 97 long-term female survivors of childhood acute lymphoblastic leukemia (ALL). All patients received identical induction and maintenance therapy with either 18 or 24 Gy of radiation therapy (RT) to one of the following fields: cranial, craniospinal, or craniospinal plus 12 Gy abdominal RT including the ovaries. Thirty-six percent (35 patients) were found to have above normal levels of FSH and/or LH. The percentages of elevated values for RT fields were 93% for craniospinal plus abdominal RT, 49% for craniospinal RT, and 9% for cranial RT (P less than .001). A dose-response relationship was observed between 18 Gy and 24 Gy in females receiving only craniospinal RT (P = .01). Craniospinal plus abdominal RT and abnormal FSH/LH levels were significantly associated with lack of pubertal development and delayed onset of menses. Duration of maintenance chemotherapy was not associated with abnormal gonadotropin levels or the development of secondary sexual characteristics. Additional follow-up of this cohort is needed to establish the ultimate pubertal development and fertility of these patients.

Adolescent↗

PubMed1987

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Actuarial Analysis↗

PubMed1987

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease.

Forty remission patients with high-risk acute lymphoblastic leukemia (ALL) underwent matched allogenic bone marrow transplantation (BMT) following preparation with cyclophosphamide and fractionated total body irradiation (TBI). As of March 1987, the median follow-up is more than 3 1/2 years. Thirteen patients are alive (11 relapse free) between 2 and 4 1/2 years post-BMT. Neither age, sex, remission number, prior extramedullary leukemia, nor WBC at diagnosis of ALL was statistically significant as a predictor of relapse-free survival. The development of acute graft-v-host disease (GVHD) in 17 patients was found, with time-dependent Cox regression analysis, to be associated with a significant reduction in post-BMT relapse risk (P = .04) and improved disease-free survival (P = .11). A prospective, randomized trial of maintenance chemotherapy with oral methotrexate and mercaptopurine did not demonstrate improvement in relapse risk or survival for those assigned maintenance chemotherapy (P = .7). These results suggest that allogeneic BMT can result in extended relapse-free survival for some patients with high-risk ALL. More effective preparative chemoradiotherapy and exploitation of the apparent graft-v-leukemia effect may be useful in future trials.

Acute Disease↗

PubMed1987

Bone marrow transplantation for acute non-lymphocytic leukemia: a report from the Childrens Cancer Study Group of sixty-seven children transplanted in first remission.

Sixty-seven children with acute non-lymphocytic leukemia (ANLL) in first remission underwent HLA-identical sibling bone marrow transplants as part of a cooperative study by the Childrens Cancer Study Group. Three patients died of sepsis before marrow recovery. Sixty-four patients recovered marrow function and have been followed for a median of greater than 1300 days. Two-year actuarial survival is 59% (95% confidence interval (CI): 47-71%). The risk of relapse by 2 years is 16% (95% CI: 6-26). All relapses occurred among patients with single-dose irradiation (p = 0.07), but these patients also experienced a diminished risk of acute graft-versus-host disease (AGVHD) (p = 0.12) compared to patients conditioned with fractionated irradiation. Radiation technique (single-dose vs fractionated) did not affect survival or the risk of development of interstitial pneumonia. Significant AGVHD (greater than or equal to grade II) occurred in 27 patients (40%). Patients with AGVHD were at increased risk of death due to sepsis or interstitial pneumonia during the first year after transplant, but disease-free survival was unaffected by AGVHD, because all 10 relapses occurred in patients without significant AGVHD. Neither survival nor relapse risk were affected by patient age, sex, white cell count at diagnosis, or FAB classification. This collaborative transplant study has resulted in survival data comparable to those of single institutions and the best reported outcomes of conventional chemotherapy.

Age Factors↗

PubMed1986

Priorities for the future for clinical research. Center perspective.

Clinical research has by and large been responsible for the success achieved in treating pediatric cancer during the last 20 years. An important milestone has recently been reached with the passing of the halfway mark in the goal of curing all childhood cancer. It is important to re-evaluate our priorities and set future goals. The large multi-institutional cooperative groups have been the mainstay of past successes and should as their major goal continue work towards improvements in survival, particularly for those malignancies which continue to have a poor prognosis. The second priority should be the identification of potential long-term effects of childhood cancer and the effects associated with therapy. Concomitant with improvements in the cure rate it is our responsibility to ensure that cured patients can have the opportunity to enjoy productive, useful and happy lives. The third priority is to foster research of pilot clinical research to serve as a source of ideas to be used for future Phase III clinical trials. Moreover, increased efforts should be directed towards aspects of preventive oncology which requires increased knowledge regarding the etiology of childhood cancers.

Child↗

PubMed1986

Cytogenetic studies of long-term survivors of childhood acute lymphoblastic leukemia: a follow-up report.

Previous series including our earlier study of survivors of childhood acute lymphoblastic leukemia have documented the presence of nonclonal chromosome abnormalities in peripheral blood lymphocytes. To investigate whether or not these abnormalities persist, we restudied nine patients, all of whom had received radiotherapy and a minimum of 3 years of systemic chemotherapy. Therapy had been discontinued a median of 3.9 years prior to study in our first report and a median of 7.2 years prior to study in this follow-up report. Thirty metaphases from short-term cultures of phytohemagglutinin-stimulated peripheral blood from each of nine patients and nine matched controls were analyzed using G-banding. Nonclonal chromosome abnormalities were present in cells from six of the nine patients and 3.0% of patients' cells overall, as compared to seven of ten patients and 3.5% of patients' cells in the earlier study. All patients studied twice had abnormalities on one or both occasions. No evidence for the development of cytogenetically abnormal clones was found. Combined data from the two evaluations indicate that all of the patients have a small population of long-lived lymphocytes with nonclonal chromosome abnormalities, the frequency of these cells appears to remain remarkably constant over time, and the proportion of cells with chromosome abnormalities is approximately threefold greater in patients than in controls. It has become apparent that survivors of acute lymphoblastic leukemia are at increased risk for development of second malignant neoplasms. The relationship between therapy-induced chromosome damage and the development of second malignant neoplasms is currently unknown. We speculate that some cells, possibly in tissues other than peripheral blood, are preneoplastic by virtue of therapy-induced chromosome rearrangements involving critical genes and, following a long latent period, may undergo subsequent genetic or cellular changes that result in malignant transformation. Unfortunately, however, estimation of genetic damage through cytogenetic studies of peripheral blood T-lymphocytes does not appear to be a useful method for prediction of second malignant neoplasms following acute lymphoblastic leukemia, since most or all of the patients have a low level of abnormal cells.

Acute Disease↗

PubMed1986

Home care for children dying of cancer.

The feasibility of home care as an alternative to hospitalization for children dying of cancer was studied. The home care system was defined as nurse-directed with a consultant physician and did not entail extensive participation by other health professionals. Of 58 children cared for at home during the 2-year project, 79% died at home and 21% died in the hospital or en route to it. The findings, as shown by interview data, suggest that home care at the end stage of life is a viable alternative for children dying of cancer and for their families.

Adolescent↗

PubMed1986

Acute megakaryoblastic leukaemia in children.

We report four children with acute megakaryoblastic leukaemia (AMKL) and compare their clinical course with 16 previously reported cases of AMKL in children. In adults, AMKL has been reported as a rapidly progressive disease characterized by pancytopenia associated with bone marrow fibrosis, absence of organomegaly, and unresponsiveness to therapy. Although some of the childhood cases present with these features, the clinical course can be quite variable, particularly in young children, with both organomegaly and leucocytosis occurring. Down syndrome, or other constitutional abnormalities of chromosome 21 were present in four of 20 reported cases. Two of the four cases reported herein were initially diagnosed cytologically as childhood acute lymphoblastic leukaemia (ALL). All four patients achieved a complete remission, and three remain in remission from 34 to 56 months from diagnosis. Greater recognition of AMKL in the future will help to clarify the disease characteristics, prognosis and optimal treatment of this unusual form of leukaemia.

Acute Disease↗

PubMed1986

Fungal pneumonias masquerading as thromboses during induction therapy of acute lymphoblastic leukemia.

Fatal fungal pneumonias developed in two children with ALL during remission induction. Pulmonary and central nervous system signs suggested the L-asparaginase-induced multiple-thromboses syndrome in both children. Fungal infection should be considered-whenever pneumonia develops in a neutropenic child already receiving broad-spectrum antibiotics or when multiple thromboses occur.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1986

Bone marrow transplantation for children with acute leukemia and Down syndrome.

Four children with acute leukemia and Down syndrome received high-dose cyclophosphamide therapy and total body irradiation in preparation for bone marrow transplantation. Skin and mucous membrane toxicity was pronounced. Furthermore, three children died during the immediate posttransplantation period of infectious and hemorrhagic pulmonary complications. One patient had hematologic recovery and is surviving disease-free 1 year following transplantation. These preliminary observations are in agreement with previous data suggesting that children with Down syndrome are at higher risk for toxicity, pneumonitis, and, possibly, death following administration of intensive therapy for leukemia in comparison with children without Down syndrome. Improvements in the management of these children in the future will depend upon a better understanding of the biologic and pathophysiologic aspects of Down syndrome and additional clinical experience.

Adolescent↗