Biomedical subjects

J N Lukens

Publications and source records attributed to J N Lukens.

At least 19 recordsLinked to original sources

PubMed1991

Epipodophyllotoxin-related leukemia. Identification of a new subset of secondary leukemia.

Thirty-seven children and adults who developed acute nonlymphocytic leukemia after the administration of chemotherapy that included etoposide or teniposide for a variety of hematologic and solid malignancies were identified. The secondary leukemia that occurred in these patients could be distinguished from the secondary leukemia that occurs after treatment with alkylating agents by the following: a shorter latency period; a predominance of monocytic or myelomonocytic features; and frequent cytogenetic abnormalities involving 11q23. Patients receiving an epipodophyllotoxin are at risk for developing secondary leukemia that has features distinct from the syndrome of secondary leukemia associated with alkylating agents.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Open-wedge testicular biopsy in childhood acute lymphoblastic leukemia after two years of maintenance therapy: diagnostic accuracy and influence on outcome--a report from Children's Cancer Study Group.

Bilateral testicular biopsies were performed on 708 males with acute lymphoblastic leukemia completing 24 to 30 months of maintenance chemotherapy in continuous remission. The 73 patients (10.3%) with occult testicular leukemia (TL) had a significantly increased risk of subsequent relapse (P = .0001) and death (P less than .0001) when compared with patients with negative biopsies. Protocol-specified therapy for occult TL included reinduction therapy with concurrent bilateral testicular radiation, and 2 years of maintenance therapy. Four-year event-free survival for patients with negative biopsies was 78.2% +/- 4% versus 65% +/- 14% for patients with occult TL who received protocol-specified therapy (P = .05). This study suggests that (1) occult TL occurs in 10% of males completing 2 years of maintenance therapy; (2) occult TL significantly increases risk for subsequent relapse and death; (3) treatment results for occult TL and isolated overt off therapy TL (no previous biopsy) are similar; and (4) given current therapy, documentation of occult TL after 2 years of therapy does not improve disease-free survival.

Antineoplastic Agents↗

PubMed1989

Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1988

Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum.

Twenty-two patients with aplastic anemia were treated with antilymphocyte serum or antithymocyte globulin at Vanderbilt University and affiliated hospitals from 1980 to 1986. The median age was 42 (eight to 73 years); the male:female ratio was 8:14. Nineteen patients had severe aplastic anemia, and three had moderate disease. Twenty patients received antilymphocyte serum initially while two patients received antithymocyte globulin. Fifteen patients received fluoxymesterone 10 mg by mouth three times a day with antilymphocyte serum, and all received prednisone during the course of antilymphocyte serum or antithymocyte globulin. There were seven responses (31.8 percent) to the first course with four complete responses and three partial responses. Six of 15 patients who received fluoxymesterone showed a response, compared with zero of five treated without androgens (p less than 0.05). Eight patients with no initial response and a patient who experienced a relapse after a complete response were re-treated with either antithymocyte globulin (six) or antilymphocyte serum (three), with four of nine patients (44 percent) having a response (three complete responses, one partial response). Overall, 10 of 22 patients (45 percent) had a response (six complete responses, four partial responses). Median survival for those without a response is six months. Median survival for those with a response has not been reached, with follow-up ranging from 18 to 70 months. This study shows the benefit of a second cycle of antilymphocyte serum or antithymocyte globulin and a possible role for concomitant androgens in this treatment of aplastic anemia.

Adult↗

PubMed1986

Modulation of neutrophil oxidative responses to soluble stimuli by platelet-activating factor.

The role of platelet activating factor (PAF) as a regulator of human neutrophil superoxide (O2-) generation in response to soluble and particulate stimuli was examined. At concentrations greater than 10(-7) mol/L, PAF alone induced a brief burst of O2- production. When cells were exposed to PAF and either the chemotactic peptide n-formyl-methionyl-leucyl-phenylalanine (FMLP 10(-7) mol/L) or the tumor promoter phorbol myristate acetate (PMA 10 ng/mL), a marked synergistic augmentation of O2- release was noted when compared to control cells stimulated with FMLP or PMA alone. Mean percentage of enhancement by 10(-5) mol/L of PAF was 297% +/- 35% (n = 9) of control responses to FMLP and 185% +/- 16% (n = 3) of control responses to PMA. Consistent enhancement occurred with PAF concentrations of as low as 10(-9) mol/L. Enhancement could be demonstrated when neutrophils were exposed to PAF either at the same time as, or up to 60 minutes prior to, the second stimulus, and was neither reversed by removal of PAF from the medium prior to addition of FMLP or PMA nor dependent on the presence of extracellular divalent cations. Continuous recordings revealed that the enhancement was due to an increased maximal rate of O2- production. In contrast, PAF concentrations up to 10(-5) mol/L had only a minimal effect on the response to neutrophils to opsonized zymosan. Analysis of the enhancing properties of lipids structurally related to PAF revealed that the critical moiety was the saturated fatty acid at position 1. These results indicate the presence of a PAF-mediated positive feedback loop whereby the oxidative burst induced by some soluble stimuli is augmented. Modulation of neutrophil O2- production by PAF may serve to amplify neutrophil oxidative responses at sites of inflammation.

Adult↗

PubMed1985

Investigations of the biological activity of leukotriene A4 in human polymorphonuclear leukocytes.

An investigation was undertaken to compare the responses of human neutrophils to the epoxide leukotriene A4 with those elicited by its stable product leukotriene B4 under identical IN VITRO conditions. LTA4 evokes neutrophil responses similar in nature to those induced by LTB4 but at much higher concentrations. Evidence suggests that LTA4 is important primarily for its role as an intermediate rather than for inherent activity.

Arachidonic Acids↗

PubMed1985

Systemic metastases in primary intracranial germinoma. Case report and literature review.

Systemic metastases from central nervous system germinomas are exceedingly rare, and when they occur lead to fatal outcomes. The authors report the case of a 10-year-old girl who presented with metastatic involvement of the rib and pelvis 2.5 years after surgical resection and radiation therapy for a suprasellar dysgerminoma. After combination chemotherapy, the patient remains disease-free 30 months after relapse. This case provides evidence that chemotherapy can be an effective therapeutic alternative to the use of radiation in the treatment of children with extracranial germinomas.

Bone Neoplasms↗

PubMed1985

Stimulation of neutrophil oxidative metabolism by indomethacin.

Human neutrophils exposed to indomethacin demonstrate an enhanced capacity for superoxide ion (O2-) generation when stimulated with opsonized zymosan. Enhancement is not seen with indomethacin-treated cells exposed to soluble oxidative stimuli. To further investigate this phenomenon, O2- generation, chemiluminescence, and phagocytosis were assessed in human neutrophils preincubated with indomethacin. Zymosan-stimulated O2- release was increased from 150 to 300% of controls in neutrophils exposed to 400 micrograms/ml indomethacin. Enhancement was not reversed by removal of indomethacin from the medium prior to addition of the stimulus and was dose-dependent at drug concentrations of 5 to 400 micrograms/ml. Neutrophils exposed to methacin alone also generated more O2- than control cells, although this increment was not sufficient to account for the degree of enhancement seen when indomethacin-treated cells were exposed to zymosan. Neutrophil chemiluminescence induced by zymosan was also increased by exposure to indomethacin, and at a drug concentration of 400 micrograms/ml (1.1 mM) enhancement ranged from 253 to 333% of controls. As was observed with O2- generation, chemiluminescence of neutrophils was increased in the presence of indomethacin alone, although, to a degree far less than was seen when drug-treated cells were stimulated with zymosan. Phagocytosis of radiolabeled S. aureus by neutrophils incubated with indomethacin was increased 13 +/- 5% over controls (P less than 0.01, n = 5), but was unaltered by incubation of cells with the buffer used to solubilize the drug. The modest degree of enhancement of phagocytosis suggests that increased particle uptake is not the sole mechanism of oxidative enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Synergism↗

PubMed1985

Differential effects of lipoxygenase products on FMLP and LTB4 evoked neutrophil aggregation.

There is evidence that the endogenous biosynthesis of LTB4 is involved in the aggregation of human neutrophils induced by the chemotactic peptide f-met-leu-phe (FMLP). If LTB4 mediates this aggregatory response, then agents which desensitize neutrophils to LTB4 should inhibit the cellular response to FMLP. Since many lipoxygenase products modulate other neutrophil responses to LTB4 and FMLP, we have investigated the effects of lipoxygenase products on LTB4- and FMLP-initiated aggregation. Prior exposure to low concentrations of LTB4 (0.5-10 nM) inhibited subsequent aggregation to the same agent (50 nM), but it did not influence the response to FMLP (10(-7) M). Relatively high concentrations of 5-HETE (5-50 microM) inhibited aggregation initiated by either stimulus. Although the hydroperoxy derivative 5-HPETE also inhibited the response to LTB4, in the relatively narrow concentration range of 1-4 microM it stimulated FMLP-induced aggregation. This latter effect was confirmed using 12 cell preparations from six separate donors; it (the activity of 5-HPETE) was not mimicked by other 5-lipoxygenase products, including LTB4, nor the dihydroperoxide 8,15-DiHPETE. Our results indicate that neutrophil aggregation in response to LTB4 or FMLP can be selectively potentiated or inhibited. On the basis of these data we conclude that the endogenous synthesis of LTB4 is not directly involved in the neutrophil aggregatory response to FMLP, although the hydroperoxy intermediate 5-HPETE may act to enhance the cellular response.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1985

Stimulation by lipoxygenase products of superoxide anion production in FMLP-treated neutrophils.

Our recent observation that leukotriene B4 (10(-9)M) is a potent enhancer of FMLP-initiated neutrophil superoxide anion formation prompted an evaluation of the ability of other lipoxygenase products and related compounds to modulate this response. The results indicate that FMLP-evoked O-2 may be enhanced by 10(-8)-10(-7)M levels of a number of lipids, in addition to LTB4, including 5-HPETE, 5-HETE, 5,15-DiHPETE and by higher levels of other 15-series lipoxygenase products and arachidonic acid. It is of interest that the relative potency of these agents in potentiating the superoxide response to FMLP approximately parallels their reported ability to induce chemotactic activity in leukocytes.

Adult↗

PubMed1985

Prognostic implications of blast cell morphology in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) has evaluated French-American-British (FAB) morphology in newly diagnosed children with acute lymphoblastic leukemia (ALL) since 1975. A modification of the FAB system was used in which individual lymphoblast cells were scored and designated as either L1 or L2 on the basis of distinctive morphologic characteristics. L1 ALL was defined as less than 10% L2 cells and greater than 90% L1 cells; L2 ALL was defined as greater than or equal to 10% L2 cells and less than 90% L1 cells. FAB morphology was an independent predictor of overall survival (P = 0.02) in CCSG-141 and a highly significant predictor of successful induction of complete remission and event-free survival in the CCSG-160 series (P = 0.00001). These studies involved nearly 3900 patients. Two concordance studies have been performed. In the first (1981) study, overall concordance between the FAB reference laboratory and member institutions was 76% using a two-category system (L1, non-L1), 86% for L1 cases, and 47% for non-L1 cases. In the second (1984) concordance study, the use of more stringent, semiquantitative definitions of L1 and L2 lymphoblasts did not improve overall (75%), L1 (89%), or non-L1 (46%) concordance. The results of reference laboratory classification more powerfully predicted event-free survival than did member institutions (P = 0.016 vs P = 0.125). Quality control factors (slide preparation, cellularity, staining quality, and discipline of the reviewer) did not influence concordance. These results justify the continued assignment of patients to protocols of the CCSG-100 series on the basis of the modified FAB classification. The biological significance of the FAB morphologic variants remains to be determined.

Child↗

PubMed1979

Angiography of the hemophilic joint.

Angiography in the hemophilic patient is a safe and reliable procedure for recognition of surgically treatable vascular abnormalities. When untreated, these abnormalities can cause repeated bleeding and progressive joint destruction.

Adolescent↗

PubMed1979