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Biomedical subjects

D L Glaubiger

Publications and source records attributed to D L Glaubiger.

At least 19 recordsLinked to original sources
PubMed1991

Chondrosarcoma of the larynx after radiation treatment for vocal cord cancer.

The case of a 57-year-old man with chondrosarcoma of the laryngeal cartilage is presented, occurring 16 years after radiation treatment for squamous cell carcinoma of the right true vocal cord. Chondrosarcoma of the larynx is an uncommon tumor. The location, grade, and time elapsed from initial treatment make it probably that this patient's chondrosarcoma is associated with his prior radiation treatment. However, it is a rare occurrence, this being the second case reported in the literature.

Adult↗
PubMed1989

Treatment of sarcomas of the chest wall using intensive combined modality therapy.

As part of two sequential protocols using intensive combined modality treatment in pediatric and adolescent sarcomas, 31 consecutive patients with primary chest wall tumors were treated between November 1977 and March 1986. This group included 13 patients with peripheral neuroepithelioma (Askin's tumor), 11 patients with Ewing's sarcoma, 3 patients with rhabdomyosarcoma, and 4 patients with undifferentiated sarcomas. Following complete work-up, 17 patients presented with localized disease and 14 patients presented with metastases. Patients received intensive combined modality treatment with combination chemotherapy (vincristine, cyclophosphamide, Adriamycin, +/- actinomycin-D and DTIC) and high-dose conventionally fractionated radiation therapy to the primary (55-60 Gy) and non-pulmonary metastases (45-50 Gy). Radiation techniques used for the primary chest wall tumor varied with the clinical presentation. Patients achieving a complete response received either low-dose fractionated TBI (1.5 Gy/0.15 Gy fx/5 weeks) or high-dose TBI (8 Gy/4 Gy fx/2 days) and an intensive cycle of chemotherapy followed by autologous bone marrow transplantation. Twenty-five of 31 patients were judged to have a complete response (including 1 patient with complete resection). With minimum follow-up of 6 months and median follow-up of 36 months from completion of treatment, 14 patients remain disease-free with 2 additional patients alive in second remission after relapse. Patients with localized disease at presentation have improved disease-free survival and overall survival compared to patients with metastases at presentation. All 17 localized patients achieved a CR and 11 are NED compared to 8 of 14 metastatic patients achieving a CR and only 3 are NED. There have been 5 loco-regional recurrences with 3 "in-field" failures and 2 failures in the regional pleura. There were no treatment-related deaths and no clinically significant cases of pneumonitis. To date, 2 patients have significant treatment related morbidity, including 1 patient with scoliosis requiring surgery and 1 patient with acute leukemia developing 42 months after the start of therapy (presently in remission). We conclude that this intensive combined modality therapy results in a high CR rate and good local control with acceptable morbidity. Patients with metastatic disease at presentation remain a therapeutic challenge.

Adolescent↗
PubMed1986

Phase I study of ICRF-187 in pediatric cancer patients and comparison of its pharmacokinetics in children and adults.

A phase I study of ICRF-187 as a 2-hour iv infusion daily for 3 days was conducted in 46 evaluable pediatric patients. The maximum tolerated dose was 3500 mg/m2/day X 3 based on changes in hepatic function and coagulation abnormalities encountered when larger dosages were administered. One patient with acute lymphocytic leukemia achieved a complete remission and four cleared the blood of lymphoblasts. No other objective responses were seen. Pharmacokinetic analysis showed that the children had a larger volume of distribution per kilogram of body weight in the central compartment and total body and a more rapid total-body clearance than adults. These parameters can explain only part of the increased tolerance of children to ICRF-187.

Adolescent↗
PubMed1985

Phase I trial of mitoxantrone in children.

Mitoxantrone was administered as a single iv injection once every 3 weeks to 84 children with advanced acute leukemia and solid tumors in a phase I trial. Dose-limiting granulocytopenia occurred at dosages greater than 18 mg/m2 in children with solid tumors, while hospitalization for febrile episodes occurred in nine of 12 patients with acute leukemia receiving dosages greater than 24 mg/m2. Six children developed evidence of cardiac dysfunction, including three instances of congestive heart failure. No other significant toxicity was noted. Complete responses were seen in one child with neuroblastoma metastatic to bone, one with acute lymphoblastic leukemia, and four with acute nonlymphoblastic leukemia.

Acute Disease↗
PubMed1984

Probenecid inhibition of methotrexate cytotoxicity in mouse L1210 leukemia cells.

The effect of probenecid on methotrexate cytotoxicity has been measured using mouse L1210 leukemia cells in vitro. Cytotoxic effects were measured using a soft agar cloning technique. Cell exposure to varying concentrations of methotrexate at fixed concentrations of probenecid resulted in increased cell survival when compared with exposure to methotrexate alone. Cell exposure to a fixed concentration of methotrexate and varying concentrations of probenecid showed this effect to be dependent on the concentration of probenecid. Intracellular methotrexate concentrations were unchanged by the presence of probenecid. However, there was an effect of probenecid on progression of cells through the cell cycle which would tend to decrease the number of cells susceptible to the cytotoxic effects of methotrexate.

Animals↗
PubMed1982

Phase II study of 5-azacytidine in sarcomas of bone.

Eight patients with osteogenic sarcoma and seven patients with Ewing's sarcoma, all with advanced metastatic disease refractory to conventional therapy, were treated with 5-azacytidine (NSC-102816) intravenously at a dosage of 150 mg/m2 in three divided doses daily X 5 days. The courses were repeated q 4 weeks and the dosage was escalated to 200 mg/m2/day, as tolerated. Fourteen patients were evaluable for response. Major toxicities wee hematologic and gastrointestinal. 5-azacytidine had no demonstrable antitumor activity.

Adolescent↗
PubMed1982

The radiographic follow-up of patients with Ewing sarcoma: a demonstration of a general method.

An analysis of the patterns of detectable tumor recurrence using the concepts of hazard rate, predictive value, and cumulative probability was undertaken to assess the appearance of metastases in Ewing sarcoma. This study comprises 107 patients who were seen between 1964 and 1977. The distribution of the sites of metastases indicates that repeated examinations of both lungs and bones are necessary for the effective surveillance of both truncal and extremity primary lesions. The hazard rates for metastases suggest that these serial examinations should be concentrated early in the follow-up period for truncal primaries and more uniformly distributed for extremity primaries. The method used is general and is applicable to any disease for which the surveillance for recurrence or a complication is of major concern. The results of the analysis may be used in the selection and scheduling of follow-up examinations for patients with Ewing sarcoma, and in advising the patient of the prognosis for continued remission.

Bone Neoplasms↗
PubMed1982

Controlled clinical trials of nutritional intervention as an adjunct to chemotherapy, with a comment on nutrition and drug resistance.

Nutritional intervention in the cancer patient [e.g., total parenteral nutrition (TPN)] might improve durable survival because of increased tolerance to aggressive tumor therapy. To determine whether this assumption is correct, 42 patients with diffuse histiocytic lymphoma were induced with prednisone, high-dose methotrexate, Adriamycin, cyclophosphamide, and VP-16 (ProMACE). Nitrogen mustard-vincristine-procarbazine-prednisone (MOPP) consolidation was then used, followed by late intensification with ProMACE. Patients were selected randomly to receive adjuvant TPN or a standard diet during ProMACE-MOPP treatment. While TPN patients had a greater median weight gain than did control patients, lean body mass and degree of myelosuppression did not improved as a consequence of TPN. There was no significant difference in tumor response or survival between TPN and control patients, whether or not the patients were initially malnourished. In a second trial, 32 young patients with metastatic or other poor-prognosis sarcomas were randomly allocated to receive TP or a standard diet as an adjunct to one very intensive course of combination chemotherapy or chemotherapy plus total body irradiation; autologous marrow transplantation was used with gain than did controls but remained in a negative nitrogen balance. Response rates and median durable survival did not differ between the two groups. In both trials, the maximum nutritional support permitted by currently available technology was offered. Thus, the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy. In in vitro studies of the possible influence of nutrition on cancer treatment, we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin. The difference in drug sensitivity correlated with differences in lipid composition, with more intracellular lipid, and with greater membrane rigidity in the resistant cells. Resistant cells have a relatively poor transport of drug into the cell; moreover, intracellular Adriamycin is sequestered in lipid depots away from DNA. These results suggest one possible relationship between nutritional phenomena and drug sensitivity.

Animals↗
PubMed1982

Influence of tetrahydrouridine on the pharmacokinetics of intrathecally administered 1-beta-D-arabinofuranosylcytosine.

Tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase, has been shown to increase the antitumor activity of 1-beta-D-arabinofuranosylcytosine (ara-C) both in vitro and in vivo. In initial studies, which examined the cerebrospinal fluid (CSF) pharmacokinetics of intrathecally (i.t.) administered THU, the drug was found to be slowly cleared from the CSF with alpha and beta half-lives of 1 and 8 hr, respectively. In subsequent experiments, both i.v. pretreatment with THU and concomitant i.t. injection of THU were found to retard the disappearance of i.t. ara-C from the CSF, although the effect of i.t. THU was more profound. ara-C given alone was cleared from CSF with alpha and beta half-lives of 27.5 +/- 6.7 and 115.6 +/- 0.4 (S.D.) min, respectively. Pretreatment with i.v. THU resulted in alpha and beta half-lives of 10.4 +/- 1.5 and 85.7 +/- 11.1, respectively, whereas concomitant administration of i.t. THU resulted in a single half-life of 96 +/- 0.7. The mean calculated clearance rates for ara-C alone, ara-C plus i.v. THU, and ara-C plus i.t. THU were 7.5, 6.2, and 4.2 ml/hr, respectively. This effect appeared to be primarily due to THU inhibition of ara-C deamination, since a decrease in formation of 1-beta-D-arabinofuranosyluracil in the CSF was observed when ara-C was given in the presence of THU (either i.t. or i.v.). No acute neurotoxicity was noted after administration of either i.t. THU alone or i.t. THU with ara-C. The ability of THU to alter CSF ara-C pharmacokinetics may have potential therapeutic value.

Animals↗
PubMed1982

Assessment of in vitro drug sensitivity of human tumor cells using [3H]thymidine incorporation in a modified human tumor stem cell assay.

We have developed a method for performing in vitro drug testing on primary human tumor explants which is a variant of the human tumor stem cell assay (HTSCA) described previously by Salmon et al. (N. Engl. J. Med. 298: 1321, 1978). The method utilizes a cell-containing liquid top layer and a soft-agar bottom layer. Tumor growth is measured by [3H]thymidine incorporation into material precipitable by 5% trichloroacetate. Results show linear correlations with number of cells plated and with a number of colonies per plate measured using the HTSCA, when cell aliquots from one sample are used. In vitro drug sensitivity, as determined by inhibition of [3H]thymidine incorporation, correlates with HTSCA results in 54 of 61 determinations (89%). Of 22 experiments in which drug sensitivity curves were compared, 21 (95%) were similar in both systems. The [3H]thymidine method yields results more quickly (5 days after samples are plated) and with smaller variances than those measurements obtained using the HTSCA. Normal human skin muscle, lung, and colon tissue and a human fibroblast cell line do not incorporate significant amounts of [3H]thymidine into trichloroacetic acid-precipitable material. Thus, normal cell components plated in tumor samples do not interfere with assay results. Standard scintillation counting is used; optical counting, either visual or automated, is not required. Therefore, the measurement of in vitro drug sensitivity by inhibition of incorporation of radiolabeled precursors deserves further evaluation as a predictor of in vitro response.

Antineoplastic Agents↗
PubMed1981

Leg function after radiotherapy for Ewing's sarcoma.

Twenty-nine patients with Ewing's sarcoma of the lower extremity who survived for two or more years following therapy (5000 rad locally and systemic chemotherapy) were studied to assess functional status of the affected leg. Twenty-two of twenty-nine were alive and were reexamined; the deceased patients were evaluated by record review. Twenty-two of the twenty-nine had serial radiographs, which were reviewed to assess growth change induced by radiation. The living patients were divided on the basis of clinical examination into four functional groups with Group I comprising patients with minor functional limitations and leg length discrepancy 1.5 cm or less. Group II patients had moderate functional limitations with 2.5-cm leg-length discrepancy or less. Group III patients had severe functional limitations with up to 4-cm leg length discrepancy. Group IV patients had severe complications, sufficient enough to warrant amputation. Thirteen of twenty-two patients were classified as functional Group I, five as Group II, three as Group III, and one as Group IV. Radiographic changes in growing bone did not correlate with functional results. Although a femoral fracture and an age less than 16 years at diagnosis were found to be less favorable prognostic factors for the functional treatment result, these results show that neither femoral location nor young age justify primary amputation for Ewing's sarcoma of the lower leg extremity.

Adolescent↗
PubMed1981

DNA crosslinking and cell survival in human lymphoid cells treated with 8-methoxypsoralen and long wavelength ultraviolet radiation.

8-Methoxypsoralen (8-MOP) when irradiated with long wavelength ultraviolet radiation (UV-A) inhibits DNA synthesis in lymphocytes in vitro and in vivo. 8-MOP binds reversibly to DNA in the dark; when exposed to UV-A, covalent monoadducts and cross-links are formed with the DNA. The present study correlates the cytotoxic effects of 8-MOP plus UV-A with DNA crosslinking. E-B virus transformed human lymphoblastoid cells were suspended in a colorless salt solution containing 8-MOP and exposed to UV-A from fluorescent lamps filtered to remove radiation below 320 nm (22.5 J/m2-sec). Cells were then returned to complete medium and assayed for survival (by daily counts of viable cells and by cloning in microtiter wells) and for DNA crosslinking by alkaline elution. 8-MOP alone or UV-A alone resulted in minimal to no alterations in survival or in DNA crosslinking. DNA crosslinking was found to be linearly dependent on 8-MOP concentration (in the range of 0.01-1.0 microgram/ml) for 3 different UV-A doses (3000-15 000 J/m2). The surviving fraction declined exponentially as a function of the relative number of DNA crosslinks. These results suggest that the cytotoxic effects of photoactivated 8-MOP in human lymphoblastoid cells may depend on DNA interstrand crosslinks.

Cells, Cultured↗
PubMed1981

L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans.

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.

Animals↗
PubMed1981

Phase I study of 2'-deoxycoformycin in acute lymphoblastic leukemia.

2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Adenosine Deaminase Inhibitors↗
PubMed1981

Influence of prognostic factors on survival in Ewing's sarcoma.

We have analyzed the survival data for 117 patients with Ewing's sarcoma treated at the National Cancer Institute since 1964. Treatment consisted of local irradiation to the primary site and a series of increasingly intensive systemic chemotherapy regimens. Four protocols were used with varying numbers of patients in each treatment group. When survival results were compared by treatment group, an overall difference in favor of the most recent treatment regimens was demonstrated (P less than 0.03). When results were evaluated by treatment group according to the site of primary disease, a significant difference was found only for patients who presented with primary lesions of the central axis and without metastases (P less than 0.001). However, we noted a statistically significant correlation of survival with 1) site of primary disease (P less than 0.001), 2) serum lactate dehydrogenase (LDH) level at presentation (P less than 0.0001), and 3) metastatic status at presentation (P less than 0.0001), irrespective of treatment protocol. When the results were reassessed after adjustment for these factors, no significant difference in survival remained. We concluded that further studies, in which stratification for site of primary disease and LDH levels would be used, are necessary to clarify the role of intensive adjuvant chemotherapy in Ewing's sarcoma.

Antineoplastic Agents↗