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Biomedical subjects

R K Dodge

Publications and source records attributed to R K Dodge.

At least 91 records · Page 5Linked to original sources
PubMed1989

Prognostic importance of structural chromosomal abnormalities in children with hyperdiploid (greater than 50 chromosomes) acute lymphoblastic leukemia.

Approximately one fourth of children with newly diagnosed acute lymphoblastic leukemia (ALL) have hyperdiploid (greater than 50 chromosomes) blasts and a relatively favorable prognosis. Nonetheless, a substantial proportion of these patients fail therapy. We studied 138 children (70 male, 68 female) with hyperdiploid greater than 50 ALL to assess initial clinical and cytogenetic features that might predict treatment failure. In 85 of these cases (62%), structural chromosomal abnormalities were also present; clinical and laboratory features in this group did not differ from those of the 53 cases with only numeric abnormalities. However, of the 28 failures seen at a median follow-up of 4 years, 22 occurred in cases with structural chromosomal abnormalities (P = .03 by Breslow test). In a multivariate analysis, only the presence of structural chromosomal abnormalities and male gender were independently associated with treatment failure. Structural chromosomal abnormalities in cases of ALL with greater than 50 chromosomes may define a biologically different form of leukemia characterized by increased likelihood of drug resistance.

Adolescent↗
PubMed1989

Lorazepam pharmacodynamics and pharmacokinetics in children.

We evaluated the effects of low doses of lorazepam on episodic versus long-term memory, attention, and somatic and affective symptoms, as well as its pharmacokinetics, in a group of 16 children aged 2.8 to 14.2 years. Psychologic assessments of each child were performed twice before intravenous administration of lorazepam (0.03 mg/kg), and 1 1/2 hours and 24 hours after lorazepam; there were no significant changes in long-term memory, attention, or somatic symptoms. There was a significant decrease in affective symptoms at 1 1/2 hours (p = 0.011), with a trend toward decreased anxiety at 1 1/2 and 24 hours after lorazepam (p = 0.026 and 0.028, respectively). There was also a selective anterograde amnestic effect in 5 of 16 children after lorazepam (p = 0.06). Mean (+/- SD) lorazepam systemic clearance was 1.3 +/- 0.4 ml/min/kg, with a terminal half-life of 10.5 +/- 2.9 hours and an unbound clearance of 15.9 +/- 5.2 ml/min/kg. A group of healthy adult volunteers who were given lorazepam had a mean systemic clearance of 1.0 +/- 0.4 ml/min/kg, somewhat less than that of the children (p = 0.069). There were no significant differences in any lorazepam pharmacokinetic parameter between those children who did versus those who did not have changes in affective symptoms or amnesia. These data should be helpful in establishing the dose of lorazepam in children, as the drug becomes more widely used as an antiemetic, premedicant, and anticonvulsant agent.

Adolescent↗
PubMed1989

Increased serum CD8 antigen level in childhood Hodgkin's disease relates to advanced stage and poor treatment outcome.

Measurement of the soluble form of CD8 antigen, a surface membrane component of suppressor/cytotoxic T cells, has yielded useful information relevant to prognosis in the lymphoid malignancies of childhood. We therefore determined pretreatment levels of serum CD8 antigen in 90 children with newly diagnosed Hodgkin's disease. The findings ranged widely, from 220 to 2,585 U/mL (median, 556 U/mL). In patients with advanced disease (stage III or IV), the median serum CD8 level was significantly higher than in those with less disease extension (stage I or II): 675 v 477 U/mL, P = .003. It was also higher in children with B symptoms compared with all others: 622 v 494 U/mL, P = .005. Cases with a histologic classification of mixed cellularity had a significantly higher median level of the antigen than did those classified as nodular sclerosis: 847 v 509 U/mL, P = .005. Finally, higher serum CD8 levels (greater than 430 U/mL) were significantly associated with an increased probability of treatment failure (P = .02). In a multivariate analysis, serum CD8 level retained its impact on treatment outcome after adjustment for other potentially useful prognostic factors, including disease stage, presence of B symptoms, histology, erythrocyte sedimentation rate, sex, age, and race. The prognostic strength shown by soluble CD8 in this analysis suggests that the antigen has clinical value. We postulate that increased CD8 levels in serum indicate enhanced suppressor T-cell activity, which may compromise the host's antitumor immunity, leading to unusually aggressive disease.

Adolescent↗
PubMed1989

Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features.

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more "lymphomatous" disease characteristics (including presence of a mediastinal mass in 15%. T-cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21-22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Child↗
PubMed1989

High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin's disease.

To improve the biologic evaluation of Hodgkin's disease, we determined serum interleukin-2 receptor (IL2R) levels in 88 children with this tumor. In patients with stage III or IV disease, the median receptor level was significantly higher than in patients with lower stages (3195 vs. 1087 U/ml, p = 0.0001). Similarly, the median level for children with stage B disease was 3262 U/ml, compared with 999 U/ml for those lacking constitutional symptoms (p = 0.0001). Patients with very high soluble IL2R levels (greater than or equal to 5000 U/ml) were significantly more likely to fail treatment (p = 0.01), even when the analysis was restricted to groups with advanced disease: stages III and IV (p = 0.0001). When entered in the Cox-proportional hazards model with other potentially useful prognostic factors, soluble IL2R level was found to be an independent predictor of treatment outcome. The relationship of high serum IL2R levels to an adverse clinical outcome in Hodgkin's disease may be explained by a model in which the soluble receptor competes for the ligand with the cellular receptor on normal lymphocytes, thus blocking antitumor immunity dependent on interleukin-2. Alternatively, high serum levels of IL2R may simply reflect increased release of the receptor from activated malignant cells in patients with advanced disease or an otherwise poor prognosis.

Adolescent↗
PubMed1988

Carcinomas in children. Clinical and demographic characteristics.

Carcinomas occur rarely in children and adolescents. Despite their rarity, these tumors present a unique opportunity to assess theories of origin because the interval from birth to tumor onset is relatively short compared with that seen in adults. We describe the clinical and demographic characteristics of 151 patients younger than 20 years of age with carcinomas who were treated at a pediatric cancer center having a large referral area. Incidence data for the major types of carcinomas in children, based on unpublished data provided by the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER), also are reported.

Adolescent↗
PubMed1988

Cyclic combination chemotherapy for acute lymphoblastic leukemia recurring after elective cessation of therapy.

Cyclic combination chemotherapy was administered to 26 patients with acute lymphoblastic leukemia who had relapsed in the bone marrow greater than or equal to 6 months after elective cessation of therapy. Each patient had been in initial continuous complete remission for 36-111 months (median, 47 months). Prednisone, vincristine, and doxorubicin induced second complete remissions in all patients within 1 month. Continuation therapy consisted of alternating 6-week courses of 6-mercaptopurine/methotrexate and vincristine/cyclophosphamide with intervening reinforcement courses of prednisone/doxorubicin, for a total of 18 months. All patients received 4 weeks of late intensification therapy with the same agents used for remission reinduction. Periodic intrathecal methotrexate was given as reprophylaxis for subclinical central nervous system leukemia. The estimated rate of continuous failure-free survival at 5 years is 31% +/- 17% (2 SE). Eight patients remain free of leukemia for 42 + to 65+ months after completing therapy a second time. Adverse second events included 11 hematologic, 1 testicular, and 3 meningeal relapses. Patients who relapsed at more than 12 months after the completion of initial treatment have had significantly longer second remissions than patients whose first remissions were shorter (p = .04). None of the other six factors we analyzed showed predictive strength. These end results indicate that intensive cyclic continuation chemotherapy, as described here, will secure durable second remissions in approximately one-third of the children with late bone marrow relapses.

Adolescent↗
PubMed1988

Efficacy of oral sucralfate suspension in prevention and treatment of chemotherapy-induced mucositis.

The efficacy of orally administered sucralfate suspension in preventing and treating chemotherapy-induced mucositis was evaluated in a double-blind trial. Forty-eight children and adolescents with newly diagnosed acute nonlymphocytic leukemia were randomized to receive suspensions of either sucralfate or placebo orally every 6 hours during the first 10 weeks of intensive remission-induction chemotherapy. Patients given sucralfate suspension were less likely than subjects receiving placebo to acquire colonization with potentially pathogenic microorganisms: 14 (58%) of 24 versus 22 (92%) of 24, respectively (p = 0.008). However, no effect on preexisting colonization was noted. Subjective reporting of discomfort, objective scoring of the severity of mucositis, and the maximal percent of body weight lost during therapy were similar; 58% of patients receiving sucralfate reported no oral pain compared with 25% receiving placebo (p = 0.06). Ten episodes of gastrointestinal bleeding, 25 documented infections, and 886 days with fever were also equally distributed between sucralfate and placebo groups. We conclude that sucralfate suspension is of limited, if any efficacy, in the prevention and treatment of chemotherapy-induced mucositis. Sucralfate administration can, however, reduce acquisition of alimentary colonization with potential pathogens, perhaps by interfering with adherence to mucosal membranes.

Administration, Oral↗
PubMed1988

Serum levels of CD8 antigen in childhood lymphoid malignancies: a possible indicator of increased suppressor cell activity in poor-risk patients.

Serum concentrations of CD8 antigen were measured at diagnosis with an enzyme-linked immunoassay in children with acute lymphoblastic leukemia (n = 344) or non-Hodgkin's lymphoma (n = 65). All patients had detectable levels of the serum antigen, which in its soluble nonreduced form appeared to be a 52-Kd homodimer as compared with the 66-Kd surface membrane component on most thymocytes and on a subset of functionally distinct T cells (suppressor/cytotoxic). Increased serum levels of CD8 in leukemia patients were significantly related to recognized high-risk prognostic features: high leukocyte count, large liver and spleen size, high serum lactic dehydrogenase level, T-cell immunophenotype, presence of a mediastinal mass, pseudodiploid karyotype, DNA index less than 1.16, and chromosomal translocation. Children with serum CD8 levels greater than or equal to 450 U/mL were more likely to fail treatment than were those with lower levels (P = .002), even in the group with non-T-cell leukemia (P = .003). In a multivariate analysis, serum CD8 antigen contributed independent prognostic information beyond that conveyed by age, leukocyte count, and race (P = .02). High serum CD8 antigen levels also correlated with advanced stages of disease in children with non-Hodgkin's lymphoma or B-cell leukemia. Children with higher serum CD8 antigen levels (greater than or equal to 700 U/mL) had a poorer treatment outcome (P = .003), even after results were adjusted for disease stage and serum lactic dehydrogenase level (P = .05). Measurement of serum levels of CD8 antigen not only has important prognostic value in childhood lymphoid malignancies but also could be useful in assessing the immunoregulatory role of T cells in patients with cancer.

Adolescent↗
PubMed1988

Serum interleukin 2 receptor levels in childhood acute lymphoblastic leukemia.

The clinical significance of interleukin 2 receptor (IL2R) concentrations in serum was determined for 344 children with newly diagnosed acute lymphoblastic leukemia (ALL). Serum levels of IL2R in patients (267 to 80,000 U/mL, median 2,007 U/mL) were significantly higher than normal control values (170 to 738 U/mL, median 347 U/mL) (P less than .0001). Measurements in cases of T cell ALL were lower than in the non-T, non-B cases (P = .02). Among the 264 patients with non-T, non-B ALL, but not in those with T cell disease, higher serum IL2R levels (greater than 2,000 U/mL) were associated with a poorer treatment outcome (P = .04). In a multivariate analysis, serum IL2R level contributed independent prognostic information beyond that conveyed by leukocyte count, race, and age (P = .04). One explanation for these results is that soluble IL2R competes with normal lymphocyte-integrated IL2R for the ligand and thus could suppress host antitumor immunity.

Adolescent↗
PubMed1987

Potentiation of ifosfamide neurotoxicity, hematotoxicity, and tubular nephrotoxicity by prior cis-diamminedichloroplatinum(II) therapy.

We investigated the relationship between prior therapy and three distinct forms of toxicity that developed during ifosfamide administration (1.6 g/m2/day for 5 days) in 36 children with malignant solid tumors. Of ten therapies that were studied by multiple regression techniques, only the number of doses of cisplatin that patients had received was significantly related to neurotoxicity, hematotoxicity, and tubular nephrotoxicity, with the more severe cases occurring after three or more doses (P less than 0.05). Increased urinary concentrations of the renal tubular enzyme N-acetyl-beta-D-glucosaminidase, measured before each course of ifosfamide, were predictive of neurotoxicity (P = 0.02) and hematotoxicity (P = 0.01). We suggest that cisplatin-induced renal tubular damage, leading to the impaired clearance of ifosfamide metabolites, may account for this added toxicity.

Acetylglucosaminidase↗
PubMed1987

Relationship between binding affinity, retention and sensitivity of human rhabdomyosarcoma xenografts to Vinca alkaloids.

Xenografts of human rhabdomyosarcoma (RMS) have been derived that differ in their degree of sensitivity to Vinca alkaloids. Lines Rh12 and Rh18 demonstrated, respectively, high and moderate sensitivity to vincristine (VCR), but showed little responsiveness to vinblastine (VLB) in vivo. Rh18/VCR-3, a subline of Rh18 selected for resistance to VCR under in situ conditions, was insensitive to further challenge with VCR. Resistance was associated with elimination of the agent in a biphasic manner, whereas sensitivity to VCR corresponded to very prolonged drug retention in sensitive neoplastic tissues. The initial half-times for drug retention in tumors in vivo (t1/2 alpha) correlated with the degree of sensitivity of tumors to Vinca alkaloids, decreasing t1/2 alpha being associated with decreased sensitivity. A single binding species was observed when membrane-free supernatant fractions were incubated at 37 degrees for 15 min with 10.4 nM [3H]VCR and analyzed by gel filtration HPLC. The protein eluted with a retention time of 57 min and corresponded to a molecular weight (Mr) of approximately 113,000 daltons, agreeing very closely with the Mr of dimeric tubulin (approximately equal to 110,000 daltons). Two fractions were collected and eluted on a one-dimensional denaturing gel. Proteins were transferred subsequently to nitrocellulose and probed with an 125I-labeled monoclonal antibody specific for beta-tubulins. Only the fraction containing bound [3H]VCR contained tubulin. Estimates for the dissociation constants (Kd) for the binding affinity of VCR and VLB in crude, membrane-free supernatant fractions from RMS xenografts were obtained by computer curve fitting using a mathematical binding model. Data fitted a two-site binding model, with Kd values for the high-affinity site ranging from 61 to 160 nM, and for the low-affinity site, from 42 to 94 microM. At physiologically achievable drug concentrations, the relationship between binding affinity, drug retention and tumor sensitivity was examined further. A close relationship was apparent between the Kd values for VCR in Rh12, Rh18 and Rh18/VCR-3 tumor supernatant fractions and VLB in Rh12 preparations, and t1/2 alpha values for drug retention. Prolonged drug retention correlated with a low binding constant. As t1/2 alpha decreased, binding affinity also decreased, as demonstrated by an increase in the Kd value. Consequently, the tightness of drug binding in tumors also correlated with the degree of sensitivity of the xenografts to Vinca alkaloids.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Carboplatin (CBDCA), iproplatin (CHIP), and high dose cisplatin in hypertonic saline evaluated for tubular nephrotoxicity.

We compared the acute tubular nephrotoxicity of three platinum compounds in children and adults with solid tumors by monitoring the urinary excretion of alanine aminopeptidase, N-acetyl-beta-D-glucosaminidase, and total protein. Cisplatin (100 mg/m2) was administered with mannitol, or at a twofold larger total dosage (50 mg/m2 per day for 4 days) in a 3% saline infusion. Carboplatin (300 mg/m2) was administered in combination with 5-fluorouracil, and iproplatin was administered in dosages ranging from 216 to 388 mg/m2. Enzymuria and proteinuria induced by cisplatin at a total dosage of 200 mg/m2 on a divided schedule did not significantly differ from that observed for the single 100 mg/m2 dose. Enzymuria and proteinuria induced by carboplatin and iproplatin were significantly less than that for cisplatin; however, one patient developed chronic tubular damage after three courses of carboplatin, and the acute tubular toxicity of iproplatin in one of 15 patients was exceptional. Our findings support the value of administering cisplatin in hypertonic saline on a divided schedule as a strategy to reduce acute tubular damage. Although carboplatin and iproplatin are less nephrotoxic than cisplatin, occasionally patients experience subclinical acute or chronic tubular damage that may lead to overt nephrotoxicity with continued therapy.

Acetylglucosaminidase↗
PubMed1987

Height at diagnosis of malignancies.

Studies of the presenting height of children with malignancies have produced conflicting results, from an excess of taller patients to an excess of shorter patients. The problems of measurement bias, inadequate comparison populations, small numbers of patients, subgroup analyses, and overreliance on simple significance tests are all possible reasons for the variation in results. To clarify this issue, we studied heights at diagnosis of 3657 children and adolescents aged under 18 years. Their malignancies included acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, acute non-lymphoblastic leukaemia, osteosarcoma, retinoblastoma, neuroblastoma, Wilms' tumour, rhabdomyosarcoma, and Ewing's sarcoma. Compared with published standards for the heights of children in control populations, no significant deviation from population norms was found for patients in any of the 10 disease categories after proper adjustment for multiple significance testing.

Age Factors↗
PubMed1987

Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L.

Childhood acute lymphoblastic leukemia with an initial leukocyte count greater than or equal to 100 X 10(9)/L responds poorly to conventional chemotherapy. To extend event-free survival (EFS) in this disease, we devised a protocol that specifies intensive 2-week courses of teniposide (VM-26, 165 mg/m2) plus cytarabine (ara-C, 300 mg/m2), before and immediately after standard 4-week remission induction therapy with prednisone, vincristine, and L-asparaginase. The VM-26 and ara-C combination was also administered intermittently for the first year of continuation treatment with oral 6-mercaptopurine and methotrexate. CNS prophylaxis consisted of periodic intrathecal (IT) injections of methotrexate and delayed cranial irradiation. At a median follow-up of 4 years, the estimated EFS rate for 57 consecutive patients with leukocyte counts of 100 to 1,000 X 10(9)/L was 44%, compared with 10% for matched controls (P less than .001). Remission induction rates in the two groups were similar (82% v 72%, P = .16). Twenty-five patients in the VM-26/ara-C group have survived without adverse events for 2.7 to 6.8 years, whereas only nine of the controls achieved more than a year of EFS. The most common complications during early treatment were acute hyperkalemia from rapid tumor cell lysis and infections due to prolonged marrow aplasia. Continuation chemotherapy was well tolerated. We conclude that VM-26 plus ara-C, added to each phase of an otherwise basic regimen of chemotherapy, will substantially improve prognosis in this high-risk form of childhood leukemia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

High serum interleukin-2 receptor levels are related to advanced disease and a poor outcome in childhood non-Hodgkin's lymphoma.

The clinical usefulness of serum interleukin-2 receptor (IL2R) measurements was determined in 59 children with non-Hodgkin's lymphoma (NHL) and six with B cell acute lymphoblastic leukemia (B-ALL). Levels of the receptor showed a clear relationship to disease stage, as follows: B-ALL greater than stage III or IV diffuse small noncleaved-cell NHL greater than stage III or IV lymphoblastic NHL greater than stage I or II NHL. Soluble IL2R levels were also closely correlated with serum lactic dehydrogenase levels (r = 0.7, P = .0001), a recognized indicator of tumor cell burden. Children with higher soluble IL2R levels (greater than 1,000 U/mL) were significantly more likely to fail treatment (P = .001), even when the analysis was limited to those with more advanced disease: stages III and IV NHL and B-ALL (P = .02). In a multivariate analysis, soluble IL2R level was found to have greater predictive strength than either serum lactic dehydrogenase level or disease stage. Thus, the measurement of soluble IL2R in children with NHL could be expected to improve existing methods of risk assignment in this disease.

Acute Disease↗
PubMed1987

Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

Acute Disease↗