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Biomedical subjects

R L Capizzi

Publications and source records attributed to R L Capizzi.

At least 91 records · Page 5Linked to original sources
PubMed1986

Peripheral neuropathy after high-dose cytosine arabinoside, daunorubicin, and asparaginase consolidation for acute nonlymphocytic leukemia.

Two patients with acute nonlymphocytic leukemia (ANLL) developed peripheral motor and sensory neuropathies after consolidation chemotherapy with high-dose cytosine arabinoside (ara-C), daunorubicin, and asparaginase. Evidence for ara-C and daunorubicin-induced peripheral neuropathies is reported. Despite the frequent use of these agents, only two cases of peripheral neuropathy after systemic therapy have been previously described; neurotoxic effects may be potentiated and become clinically important when the three drugs are used in combination.

Acute Disease↗
PubMed1985

Use of phytohemagglutinin response to determine the extent that somatic cell mutation accounts for 6-thioguanine resistance of human blood mononuclear cells.

We investigated the likelihood that human peripheral blood mononuclear cells which incorporate tritiated thymidine in the presence of 6-thioguanine (6-TG) are mutants by comparing findings for cells from the same blood specimen cultured in the presence or absence of phytohemagglutinin (PHA). After 42 h in culture, autoradiography revealed that about 0.1% of cells from healthy control donors and 1% of cells from patients receiving chemotherapy for breast cancer labeled in the absence of PHA. About 5% of this number labeled when 6-TG was added to the medium. This high frequency of cells labeling in the presence of 6-TG suggested that many cells were resistant to 6-TG for reasons other than mutation at the HGPRT locus. Despite a labeling index of about 30% in the presence of PHA alone, the addition of PHA to cells cultured with 6-TG did not increase the labeling index over that observed with 6-TG alone. Also, in the presence of 6-TG there was a significant correlation between labeling indices for cells from the same blood specimen cultured with or without PHA. These findings suggest that the two conditions measured the same population of non-mutant cells. These studies reinforce observations made by the developers of this technique and other laboratories which indicate that refinements will be required before the assay can be used to study somatic cell mutation in human populations. Such refinements are underway in several laboratories; although not definitive, the approach and procedures used in this report which investigated the original assay procedure provide methods and criteria to judge whether modifications of assay techniques improve the quantification of in vivo human somatic cell mutation.

Cells, Cultured↗
PubMed1985

Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia.

Pretreatment of L5178Y murine leukemia cells with uracil arabinoside (ara-U) enhances the cytotoxicity of cytosine arabinoside (ara-C). This effect is mediated by the cytostatic effect of ara-U, which causes a delay of cell progression through S-phase. Consequently, the specific activity of enzymes that peak during S-phase increases, and deoxycytidine kinase increases 3.6-fold over untreated controls. This allows enhanced anabolism of ara-C to nucleotides, as well as increased incorporation into DNA with ultimate synergistic cytotoxicity. It is postulated that the systemic metabolism of high-dose ara-C to sustained high levels of ara-U in patients with acute leukemia may enhance the activity of subsequent doses of ara-C, and thus contribute to a means for pharmacologic self-potentiation, contributing to the unique therapeutic activity of high-dose ara-C.

Animals↗
PubMed1985

Megestrol acetate v tamoxifen in advanced breast cancer: a phase III trial of the Piedmont Oncology Association (POA).

One hundred twenty-four patients with recurrent or metastatic breast cancer were randomized to receive megestrol acetate 40 mg orally, four times daily, or tamoxifen 10 mg orally twice daily. If therapy failed patients were crossed over to the alternate treatment. Eligibility required that either the estrogen or progesterone receptor be positive or that both values be unknown, and that patients be at least 2 years postspontaneous menopause or over 50 years of age. Pretreatment characteristics were similar for both groups. Three patients had had previous hormonal therapy while one third had had chemotherapy. Objective response for evaluable patients based on strict UICC criteria was 29% with megestrol acetate and 31% with tamoxifen. Responses in patients with bone and soft tissue disease were similar for both regimens; however, 7 of 19 (37%) patients with visceral disease responded to tamoxifen but none of 18 (0%) responded to megestrol acetate. Response did not correlate with amount of estrogen or progesterone receptor. Unadjusted analysis of time to progression and survival showed no significant differences between regimens. With adjustment for pretreatment characteristics, patients on tamoxifen had a statistically significant prolongation of both of these parameters. Crossover data show 3 of 24 patients responding to tamoxifen after failure on megestrol acetate and 1 of 24 responding to megestrol acetate after failure on tamoxifen. However, crossover data should be viewed cautiously, as patients who are currently responding to initial treatment are those who would be most likely to respond to crossover therapy.

Aged↗
PubMed1984

High-dose cyclophosphamide and 5-fluorouracil versus vincristine, doxorubicin, and cyclophosphamide in advanced carcinoma of the breast. A phase III study of the Piedmont Oncology Association (POA).

Forty-nine patients with advanced carcinoma of the breast who had received no prior chemotherapy were randomized to receive either high-dose cyclophosphamide (C) 1250 mg/M2 intravenously on day 1 and 5-fluorouracil (F) 600 mg/M2 intravenously on days 1 through 5 (CF), or vincristine (V) 1.5 mg/M2, doxorubicin (A) 50 mg/M2 and cyclophosphamide (C) 500 mg/M2 (VAC), all intravenously on day 1. Both regimens were repeated at 3-week intervals. Nine of 25 patients (36%) treated with CF and ten of 21 patients (48%) treated with VAC showed a complete or partial response as defined by the (UICC) guidelines. The estimated median time to progression for all patients was 3.5 months for CF and 6.0 months for VAC, with the median time to progression for responding patients being 8.5 months on CF and 6.3 months on VAC. Estimated survival is also similar for the two regimens. Ten of the patients treated with high-dose CF experienced septic episodes and four died. Toxicity on the CF arm necessitated premature closure of the study, and thus full statistical comparison of the efficacy of the two regimens cannot be made.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Differentiation versus cytoreduction during remission induction in acute nonlymphoblastic leukemia treated with sequential high-dose ara-C and asparaginase.

Patients with acute nonlymphoblastic leukemia (ANLL) treated with sequential high-dose ara-C and asparaginase (HiDAC----ASNase) have occasionally exhibited an unusual morphologic picture during induction therapy with a transition period in which large numbers of blasts coexist with returning mature hemopoietic elements. In 2 of 11 adult patients with ANLL treated during a 6-month period using a new protocol of HiDAC----ASNase, the hypoplastic phase typically seen after intense induction never developed. Serial marrow examinations performed 7 to 35 days after treatment showed equal admixtures of blasts and mature elements. Despite these findings, both patients subsequently entered complete remission with morphologically normal bone marrow examinations. The possibility for diagnostic error in interpreting these transition marrows as failed inductions is great and could lead to cessation of supportive therapy or to an unnecessary further course of cytotoxic therapy. This phenomenon raises the biological question, does remission represent leukemia killed or leukemia matured?

Acute Disease↗
PubMed1984

Detection of brain metastasis at diagnosis of small cell carcinoma of the lung.

As a part of the initial evaluation of previously untreated patients with small cell carcinoma of the lung, radionuclide and/or computerized tomographic (CT) scanning of the brain was performed. Evidence of metastatic brain disease was documented in 10 (9%) patients (9 by CT and 1 by radionuclide scanning). CT was abnormal in 2 patients who had no evidence of brain metastasis by radionuclide scan. The detection of brain metastasis resulted in upstaging of 6 neurologically asymptomatic patients who had no other extrathoracic disease. Evaluation of the brain with CT is recommended as part of the initial staging of patients with small cell carcinoma of the lung.

Brain Neoplasms↗
PubMed1984

Prospective evaluation of changes in computed cranial tomography in patients with small cell lung carcinoma treated with chemotherapy and prophylactic cranial irradiation.

Computed cranial tomographic scans were performed as part of the pretreatment evaluation and at six- to nine-month intervals posttreatment in 13 patients with small cell lung carcinoma. All patients received 3,000 rad of prophylactic cranial irradiation delivered over two weeks in ten treatment fractions in conjunction with multiagent chemotherapy. Posttreatment scans documented an extraordinarily high frequency of abnormalities including cerebral atrophy (100%), ventricular dilatation (70%), and decreased coefficient of absorption in the white matter (15%). Unexplained neurologic abnormalities developed in four of six patients living at least 15 months after institution of therapy. As the number of long-term survivors of this type of lung cancer increases, the need for prospective comprehensive neuropsychologic assessment to determine the clinical significance of these changes is needed.

Aged↗
PubMed1984

Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase.

Resistance of leukemia cells to cytosine arabinoside (ARA-C) may be due to any one or combination of biochemical processes, which in certain instances may be substantially reversed by an appropriate increase in ARA-C dosage. Based on these and other laboratory observations indicating pharmacologic synergy between sequential high-dose ARA-C and asparaginase (HiDAC----ASNase), a therapeutic program was developed for the treatment of patients with acute nonlymphocytic leukemia (ANLL) refractory to conventional doses of ARA-C, as well as patients with high risk ANLL and advanced acute lymphocytic leukemia (ALL). Treatment consisted of 3-hr intravenous infusions of 3 g/sq m of ARA-C given at 12-hr intervals for 4 doses, followed by 6,000 IU/sq m ASNase given i.m. at hour 42. The same schedule was repeated on day 8. In 32 induction attempts, only 4 patients proved to be truly refractory, i.e., failed to achieve substantial leukemia cell cytoreduction. Complete remissions were achieved with HiDAC---- ASNase in 9 of 13 patients with refractory ANLL, 6 of 9 patients with antecedent hematologic disorders, and 3 of 10 patients with advanced ALL. These include 9 of 14 patients who had either failed induction or who had relapsed on active ARA-C therapy and 6 of 8 patients who had had no prior exposure to ARA-C. The median duration of unmaintained remission in ANLL was 5 mo. In a patient with central nervous system (CNS) leukemia, there was clearance of cerebral spinal fluid (CSF) blasts without intrathecal therapy, suggesting a role for HiDAC in CNS prophylaxis. In general, toxicity was tolerable and reversible. These data suggest that HiDAC----ASNase is an exceptionally effective and well tolerated regimen in leukemic patients with antecedent hematologic disorders and in those refractory to conventional doses of ARA-C.

Acute Disease↗
PubMed1983

High-dose methotrexate in small cell lung cancer. Lack of efficacy in preventing CNS relapse.

Few studies have incorporated high-dose methotrexate (MTX) with leucovorin rescue in the treatment of small cell lung cancer (SCLC). Potentially therapeutic levels of MTX can be achieved in the central nervous system (CNS) by systemic administration of high doses of this drug. Utilizing a combination chemotherapy program of Adriamycin, vincristine, cyclophosphamide, and methotrexate, 31 patients were sequentially assigned to receive either low-dose MTX (40 mg/m2), or high-dose MTX (500 mg/m2) with leucovorin rescue. Radiation therapy to the primary site was also administered. At these dosage levels there were no statistically significant differences in response rate or survival between the two groups. High-dose MTX did not prevent the appearance of CNS disease; there being 2/15 and 3/15 CNS relapses in the HD MTX and LD MTX treated groups, respectively. The occurrence of CNS disease did not significantly affect overall survival as compared to patients not similarly affected.

Aged↗
PubMed1983

Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia.

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.

Acute Disease↗