Biomedical subjects

K McCredie

Publications and source records attributed to K McCredie.

At least 19 recordsLinked to original sources

PubMed1991

Mitoxantrone and high-dose etoposide for patients with relapsed or refractory acute leukemia.

Among 35 patients with relapsed or refractory acute myelogenous leukemia (AML) who received salvage chemotherapy, 28 were treated with mitoxantrone (7.5 mg/m2/d intravenously [IV] over 1 hour for 5 days) and etoposide (VP-16) (2 g/m2 over 4 days either as a daily infusion or as two daily doses). Seven patients received mitoxantrone (6 mg/m2/d for 5 days) and VP-16 (1500 mg/m2 over 3 days). The median duration of the initial complete remission (CR) was 6 months and 83% of the patients had initial CR that lasted 12 months or less. Forty-six percent of the patients were undergoing a second or subsequent salvage attempt. Eight patients (23%) achieved CR; seven of these CR were obtained after one course of therapy. Twelve patients (33%) died and 15 patients (42%) had disease that was resistant to treatment. Patients undergoing a first salvage attempt had a higher incidence rate of CR than those undergoing a second or subsequent salvage attempt (37% versus 6%; P = 0.03). CR rates were also higher in patients with a favorable (translocation 8;21 or 15;17) or diploid karyotype compared with other patients (32% versus 8%; P = 0.10). The median survival time was 2 months for all patients and 8 months for patients achieving CR. Mucositis occurred in 74% of the patients and was severe in 32%. Diarrhea and rash occurred in less than 33% of the patients. Fever was noticed in all but 1 of the patients and documented infections occurred in 65% of the patients. Six patients had pancytopenia or thrombocytopenia that lasted more than 42 days from the initiation of treatment. Although mitoxantrone and high-dose VP-16 is an effective antileukemic regimen, it is associated with a high incidence of mucositis. Strategies that are used to limit mucosal damage may improve the tolerance of this combination.

Adult↗

PubMed1991

Generation of cytotoxic NK cells in peripheral blood and bone marrow of patients with acute myelogenous leukemia after continuous infusion with recombinant interleukin-2.

We have studied the cytotoxic profile and distribution of lymphocyte subsets of patients with acute myelogenous leukemia in second remission, after continuous infusion with recombinant interleukin-2 (IL-2). The patients received repetitive cycles of 1-1.25 x 10(6) U/m2/day of IL-2, given as 4 days continuous intravenous infusion followed by a 3-day treatment-free interval for the first 4 weeks. Patients receiving greater than 4 cycles were treated with the same dose of IL-2 continuously for 4 days, followed by a 10-day treatment-free interval. These studies showed that IL-2 treatment resulted in the generation of peripheral blood cytotoxic activity against both NK-susceptible, K-562, and NK-resistant Daudi cell lines. In most patients, enhancement of lytic activity increased with the number of IL-2 infusions. The cytotoxicity in some patients increased as much as 700-fold and 830-fold against K-562 and Daudi cells, respectively. It is of importance that oncolytic activity was also induced in bone marrow compartment (up to 182-fold against K-562). Some decline in cytotoxicity was observed within 14 days after initiation of IL-2 infusion in peripheral blood, but high levels of lytic activity persisted at this time in bone marrow. It is of interest to note that the cytotoxicity of in vivo IL-2 primed lymphocytes was further potentiated by IL-2 in vitro. Importantly, the cytotoxic cells induced in vitro displayed lytic activity against fresh leukemic blasts. Phenotypic analysis demonstrated that CD3-, CD56+ NK cells were significantly increased by in vivo IL-2 treatment (34 to 47-fold in absolute numbers), while CD3-, CD56+ T-cell subset remained low. Characterization of cytotoxic cells using the complement-dependent assay and monoclonal antibodies indicated that both the in vivo-induced and ex vivo-potentiated lytic function was mediated by CD3-, CD56+, CD16- -NK cells.

Adult↗

PubMed1990

High-dose chemotherapy and unpurged autologous bone marrow transplantation for acute leukemia in second or subsequent remission.

The authors administered high-dose chemotherapy with cyclophosphamide, BCNU (carmustine) and VP-16 (etoposide) plus autologous bone marrow transplantation (ABMT) to 22 adult patients with relapsed acute leukemia in second or subsequent remission. The marrow was not treated ex vivo. The long-term, disease-free survival rate was 14%. Comparison of results with other treatments can be difficult because of patient selection biases. The concept of inversion (achievement of a longer remission with salvage therapy than with prior treatments) is proposed to compare treatment results. Three patients remain in complete remission beyond 4 years, with inversions. More intensive cytoreductive regimens will be needed to improve results.

Adult↗

PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Adult↗

PubMed1988

Brown Sequard syndrome secondary to soft tissue infection in a patient with acute lymphocyte leukemia.

A 42-year-old Latin American female with acute lymphocytic leukemia in second relapse developed a small ecthymic lesion around the entrance site of a left subclavian line. This was followed by development of left-sided hemiparesis with contralateral loss of pain and temperature sensation. CT of the neck revealed a diffuse inflammatory process with soft tissue involvement and several bubbles of air in the anterior paraspinal muscles and within the spinal canal in the epidural location.

Adult↗

PubMed1988

Cytogenetic association and prognostic significance of bone marrow blast cell terminal transferase in patients with acute myeloblastic leukemia.

One hundred ninety-two patients with previously untreated AML had TdT studies performed on their presenting BM aspirate specimens. Thirty-seven patients (19%) had greater than 5% TdT-positive (TdT+) blasts in their BM, as determined by an indirect immunofluorescence technique. CR rates were similar in both groups of patients (20/37 vs. 97/155, p = not significant) as were remission durations and median survivals. In the subset of patients younger than 60 years, patients with TdT+ blasts had an increased median survival (110 vs. 54 weeks, p = 0.1) compared with those having TdT- blasts. Six of 37 patients with TdT+ findings had t(8;21) translocations compared to 5 of 155 with TdT- findings (16% vs. 3%, p less than 0.01). Patients with more than 50% BM blast cells showing TdT positivity at diagnosis tended to be younger than those with TdT- (mean age 30.5 years and 50.3 years, p = 0.04). The presence of TdT+ blast cells in the initial marrow in patients with AML may be associated with specific cytogenetic abnormalities and may identify subsets of patients who have improved prognoses.

Bone Marrow↗

PubMed1987

Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes.

The myelodysplastic syndromes are characterized by ineffective hematopoiesis and refractory cytopenias. In an attempt to improve hematopoiesis, we administered recombinant human granulocyte--macrophage colony-stimulating factor (GM-CSF) to eight patients with myelodysplastic syndrome, as part of a Phase I trial. The GM-CSF was given by continuous intravenous infusion daily for two weeks and then again after a two-week rest period. Over the entire dose range tested (30 to 500 micrograms per square meter of body-surface area), treatment was associated with marked increases in peripheral-blood leukocytes (5- to 70-fold), including granulocytes (5- to 373-fold), in all eight patients. The absolute number of monocytes, eosinophils, and lymphocytes increased in all patients. Three of eight patients also had 2- to 10-fold increases in platelet counts and improvement in erythropoiesis, with the result that two of three patients who had required red-cell and platelet transfusions no longer needed them (at 20 to 27 weeks of follow-up). Treatment was also associated with increased marrow cellularity and a decreased percentage of blasts in the bone marrow of patients with excess blasts, resulting in an increase in the ratio of differentiated myeloid cells to immature myeloid cells. We observed relatively few side effects, but bone pain was dose-limiting when it was associated with high white-cell counts. Our results showed that GM-CSF is a potent stimulator of hematopoiesis in vivo and may produce hematologic improvement in the short term (8 to 32 weeks of observation) in patients with myelodysplastic syndrome. More experience, with longer follow-up periods, will be necessary to assess the long-term safety and efficacy of this new treatment.

Adult↗

PubMed1987

Therapy of chronic myelogenous leukemia.

While the demonstrated antiviral, antiproliferative, and immunomodulatory properties of interferons have led to a number of theories regarding their potential use in treating individuals with chronic myelogenous leukemia (CML), their limited availability has prevented thorough clinical investigation. However, in 1980, successful cloning of the mature human alpha-A interferon led to the production of large quantities of bacterially synthesized human alpha-A interferon, now designated interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ). This abundance of alfa-2a made possible clinical studies of alpha interferon's capacity to suppress CML Philadelphia (Ph1) clones as well as restore the cells with normal karyotype. The data resulting from these clinical trials indicate that interferon alfa-2a is effective in inducing hematologic remissions in the majority of minimally treated, benign-phase CML, Ph1-positive patients. In some of the patients, treatment resulted in Ph1 chromosome suppression in the bone marrow and in the emergence of cells with a normal karyotype.

Antineoplastic Agents↗

PubMed1987

Clinical and prognostic features of patients with Philadelphia chromosome-positive chronic myelogenous leukemia and extramedullary disease.

Twenty-four patients who developed extramedullary disease during the course of Philadelphia chromosome-positive chronic myelogenous leukemia are described. The most frequent sites of extramedullary disease were lymph nodes (54%), bone (37%), and skin and soft tissue (29%). The appearance of extramedullary disease was associated with a high incidence of other features of accelerated disease (37%) and with cytogenetic clonal evolution (62.5%). The median time from extramedullary disease to blastic crisis was 4 months, and the median survival was 5 months. At the time of analysis, 23 patients have died, 16 after evolving into blastic crisis, and 7 from progressive disease without satisfying the criteria of medullary blastic crisis. This study confirms the importance of extramedullary disease as a sign of poor prognosis in chronic myelogenous leukemia, and the need for alternate therapies when such an event develops.

Bone Neoplasms↗

PubMed1987

The localization of the human myeloperoxidase gene is in close proximity to the translocation breakpoint in acute promyelocytic leukemia.

The human myeloperoxidase (MPO) gene has recently been cloned in our laboratory. Southern blot hybridization of our MPO cDNA to DNA from a somatic cell hybrid clone panel revealed that the MPO cosegregated with human chromosome 17. In situ hybridization mapped the MPO gene to chromosome 17q22-24. Although this location is close to the translocation breakpoint which occurs in acute promyelocytic leukemia (APL), t(15;17)(q22;q21-22), Southern blot hybridization with different restriction-digested genomic DNA samples from four APL patients did not reveal MPO gene rearrangement. However, RNA dot-blot hybridization showed that APL patients with the translocation expressed high levels of MPO mRNA. This observation raises the possibility that the high levels of MPO gene expression in APL could be due to the arrest of leukemic cells at a specific stage of differentiation or a consequence of the translocation.

Chromosome Mapping↗

PubMed1987

Diversity of the effect of recombinant tumor necrosis factors alpha and beta on human myelogenous leukemia cell lines.

In vitro characteristics of response to recombinant tumor necrosis factors alpha (rTNF-alpha) and beta (rTNF-beta) were studied in six human myelogenous leukemia cell lines. Heterogeneity of the response to rTNF was observed, and one line (K562) was resistant. No enhancement of cell growth was noted in any cell line. The dose-response curves for rTNF-alpha were characteristically sigmoid, the maximum inhibitory effect occurring between 25 and 200 ng/mL. Nonresponsiveness within this range indicated resistance that could not be overcome, even with very high doses of rTNF alpha. A similar response of sensitive and resistant lines occurred after exposure to rTNF-beta. The clonogenic cells were more sensitive than the overall population to the action of rTNF alpha, and prolonged exposure was necessary for manifestation of the effect. Concomitant exposure to recombinant interferon-alpha (rIFN-alpha) increased the response of two cell lines to rTNF-alpha, but no clear synergistic action could be demonstrated. The addition of rIFN-gamma was without effect. Variations in the rTNF-alpha-induced proliferative response could not be explained by differences in the number of binding sites per cell or their affinity for rTNF-alpha. That the clonogenic cells showed a higher sensitivity than the whole population might indicate a preferential effect on more primitive, actively proliferating cells with high growth potential.

Cell Division↗

PubMed1987

Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia.

The cytotoxic effect of cytosine arabinoside (ara-C) is presumably mediated by cytosine arabinoside 5'-triphosphate (ara-CTP). We tested for a correlation between intracellular ara-CTP pharmacokinetics and clinical response among 51 patients who received high dose ara-C (3 g/m2 at 12-hr intervals) as therapy for refractory acute leukemia. After accounting for pretreatment clinical variables that correlated with response, measurement of ara-CTP pharmacokinetics added significant prognostic information. This provides a rationale for manipulation of schedules of high dose ara-C administration in those patients whose pharmacokinetic characteristics are inconsistent with response to an every 12-hr schedule.

Acute Disease↗

PubMed1986

Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia.

We treated 17 patients who had Philadelphia-chromosome-positive chronic myelogenous leukemia (4 of whom had not received therapy and 13 of whom had been treated with hydroxyurea or busulfan for less than six months) with recombinant human interferon alpha A (Roferon-A). The interferon was given as 5 X 10(6) units per square meter of body-surface area per day intramuscularly during induction therapy. Fourteen patients responded to the treatment, of whom 13 had a hematologic remission and 1 had a partial hematologic remission. The median number of white cells in those patients declined from 60.9 X 10(3) to 3.4 X 10(3) per microliter, and the median number of platelets decreased from 476 X 10(3) to 231 X 10(3) per microliter. Among the five responding patients who had splenomegaly before treatment, the spleen size returned to normal in four and decreased by 75 percent in one, although it remained enlarged. Bone marrow cellularity declined from a median of 92.5 percent to a median of 57.5 percent. In six of the patients with hematologic remission, complete suppression of Philadelphia cells was observed on at least one examination. Of the 14 patients who responded, 11 have received the interferon therapy for 9 to 15 months. One patient relapsed during the treatment, and the treatment has been temporarily interrupted in two patients because of toxicity. These data are preliminary and will need further confirmation, but they suggest that recombinant human interferon alpha A is effective in inducing hematologic remission in most patients with benign-phase chronic myelogenous leukemia and in suppressing the Philadelphia chromosome in some of these patients.

Adolescent↗

PubMed1986

Rearrangement and enhanced expression of c-myc oncogene in fresh tumor cells obtained from a patient with acute lymphoblastic leukemia.

Both enhanced and altered expressions of cellular oncogenes have recently been implicated in specific forms of human malignancy (for review: [2, 8]). The fact that certain human tumors have characteristic chromosomal translocations has led to the hypothesis that specific cellular oncogenes may be 'activated' in these genetic recombinations. In a number of human undifferentiated B-cell lymphoma (UBL) cell lines carrying the t(8:14) translocation it has been shown that the human c-myc gene is located on the region of chromosome 8 (8q24), which is translocated to the immunoglobulin heavy-chain (IHC) locus on chromosome 14 [7, 24]. We report here the molecular cloning of the recombination site between c-myc and IHC in fresh uncultured cells obtained from a patient with rapidly progressive and fatal acute lymphoblastic leukemia. The translocation was associated with an enhanced c-myc expression in the tumor cells of this patient.

Base Sequence↗

PubMed1986

Chronic myelogenous leukaemia: haematological remissions with alpha interferon.

Twenty-seven consecutive patients with previously untreated, or minimally treated benign phase Philadelphia-chromosome-positive, chronic myelogenous leukaemia (CML) were treated with partially purified human leucocyte (alpha) interferon; 24 of the 27 patients responded to therapy achieving either haematological remission (20 patients) or partial haematological remission (four patients). In the responding patients the peripheral white blood cells declined from a median of 89.6 X 10 X 10(9)/l to 4.5 X 10 X 10(9)/l. The serum lactate dehydrogenase declined from a mean of 8.36 Katal/l (492 mu/ml) to 2.8 Katal/l (165 mu/ml), and the vitamin B12 levels declined from 1492 pg/ml to 838 pg/ml. Fifteen patients had splenomegaly. The spleen size normalized in four and decreased by a median of 30% in 10 additional patients. The bone marrow cellularity fell from a median of 100% to a median of 62%. In seven of the 24 responding patients, followed for greater than or equal to 6 months, the percentage of Ph1-positive cells in the bone marrow declined to a median of 70% (range 5-75%). Alpha interferon was found to be an effective therapeutic agent for controlling the myeloid proliferation in CML, and in partially restoring the nonclonal haematopoietic cells in some of the patients.

Adult↗

PubMed1985

Evaluation of silicone elastomer catheters for long-term intravenous chemotherapy.

We evaluated the efficacy and the complications of 65 silicone elastomer catheters inserted percutaneously for long-term venous access for administration of chemotherapy, antibiotics, and blood products in patients with metastatic cancer. Treatments were administered either in the hospital or in the outpatient clinic, using a portable infusion pump. The median indwelling time of catheters was 238 days (range, two to 521). The projected duration of catheter function, when the electively removed catheters were censured, was 310 days. Twenty-three catheters were removed because of malfunction, while the remaining either were discontinued electively (20) or were functioning at the conclusion of the study (22). The problems necessitating removal of 23 catheters were inadvertent dislodgement from loose sutures (eight), mechanical damage to the catheters (four), sepsis (four), phlebitis (four), intraluminal blockage with a clot (two), and cellulitis (one). We conclude that silicone elastomer catheters are safe and reliable for extended venous access for cancer chemotherapy. They are easy to insert and remove and can be replaced with a guide wire without requiring surgical intervention.

Antineoplastic Agents↗

PubMed1984

Piperacillin plus vancomycin in the therapy of febrile episodes in cancer patients.

Piperacillin and vancomycin were used as initial empirical therapy for 211 febrile episodes in cancer patients. The response rate in 95 episodes of documented infection was 72%. The response of bacteremias, soft tissue infections, and pneumonias was 78, 71, and 38%, respectively. The response in infections caused by gram-negative organisms was 73%. Only 6 of 10 Pseudomonas aeruginosa infections responded to therapy, although the organisms were sensitive in vitro to piperacillin. Of 14 infections caused by gram-positive organisms, 12 responded to this combination. No major side effects were observed with this regimen. Although the overall response rate with this antibiotic combination was comparable with other regimens used for neutropenic patients, superior results might be obtained by combining piperacillin with an extended-spectrum cephalosporin or an aminoglycoside.

Bacterial Infections↗

PubMed1984

Oncogene expression in human leukemia.

The transforming genes of retroviruses (v-onc) are derived from normal cellular genes referred to as proto-oncogenes. These cellular genes have the capacity for conversion to oncogenes (c-onc) that are capable of inducing or maintaining the transformed state when they are overly expressed or altered by mutation or rearrangement. To study the possible involvement of these genes in human leukemia, we have analyzed their expression in a variety of fresh samples. We found that a number of oncogenes are expressed in different leukemic types and that although the transcript size did not vary for each gene, the copy number did. The myc gene (2.4 kb transcript) and the rasHa gene (1.5 kb transcript) were universally expressed. But in contrast to rasHa, the myc signal intensity varied. Myb (4.5 kb transcript) was expressed in all samples except B cell diseases. We detected low levels of abl expression (multiple mRNA species) in all leukemic types analyzed. Sis gene (4.2 kb transcript) expression was restricted to one patient sample with chronic myelogenous leukemia in blast transformation.

Acute Disease↗