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Biomedical subjects

G L Rosner

Publications and source records attributed to G L Rosner.

51 records · Page 3Linked to original sources
PubMed1991

The therapeutic impact of dipyridamole: chemopotentiation of the cytotoxic combination 5-fluorouracil/cisplatin in an animal model of human bladder cancer.

Using an in vivo assay of tumor cytotoxicity (the subrenal capsule assay in nude mice), two therapeutic strategies for the treatment of advanced human transitional cell carcinoma have been evaluated: 1) the use of 5-fluorouracil in combination with cisplatin and 2) the ability of the chemosensitizer dipyridamole to augment the cytotoxicity of CDDP and 5FU. A moderate cytotoxic response of human TCC line DU-4284 to single agent CDDP was seen; it was dose dependent at minimally toxic doses [maximal cytotoxicity--27% tumor survival (%TS) relative to control]. Efficacy was further significantly enhanced by the addition of DP [11%TS (p = .008)]. 5FU at minimally toxic doses (100 and 150 mg./kg.) also demonstrated moderate dose-dependent cytotoxic activity (35 and 31%TS, respectively) which was further enhanced by DP [21%TS (p = .03) and 18%TS (p = .05)]. A constant dose ratio of CDDP/5FU when diluted showed dose-dependent cytotoxicity; at the highest dose dilution studied, substantial cytotoxic efficacy (17%TS) was attained. The cytotoxicity of 5FU/CDDP was order independent (p = .95). The addition of DP to this combination (5FU/CDDP) further enhanced efficacy; host toxicity was not substantially enhanced. A multiple regression analysis confirmed a statistically significant effect of DP with both CDDP and 5FU (p = .001 and 0.0001, respectively); tests for trend showed no significant interaction (p = 0.33 for all models). It is concluded that, in this preclinical in vivo model of human bladder cancer, 1) CDDP and 5FU show substantial enhanced efficacy when combined, and 2) DP serves as an in vivo chemosensitizer of both CDDP and 5FU; DP further augments the efficacy of this binary combination. These data would indicate the potential of this ternary (5FU/CDDP/DP) drug therapeutic regimen for clinical trial to treat advanced bladder cancer.

Animals↗
PubMed1991

4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial.

We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS), using 4-hydroperoxycyclophosphamide (4-HC), an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs), as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate (Duke AFM) regimen, followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients), 40 micrograms/mL (four patients), 60 micrograms/mL (nine patients), or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide, cisplatin, and carmustine, followed by infusion of the purged marrow. The study end point was marrow engraftment, defined as WBC count greater than 1,000 cells per microliter. At the first three dose levels (20, 40, and 60 micrograms/mL 4-HC), there was no significant delay in time to engraftment (19, 20, and 23 days, respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL, engraftment was significantly delayed compared with the lower concentrations (P = .027), and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay, we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program, 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.

Adult↗
PubMed1989

The impact that group sequential tests would have made on ECOG clinical trials.

Using designs that several authors proposed, we reanalysed a large number of completed phase III clinical trials of the Eastern Cooperative Oncology Group as if each had been designed with group sequential stopping rules. With survival the primary endpoint of the large multicentre trials, we discuss the relative merits of each design, as well as the feasibility of group sequential designs in general.

Clinical Trials as Topic↗
PubMed1989

Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation.

During the course of differentiation of early human myeloid cells toward monocytes and granulocytes, cell surface expression of the cell adhesion molecule, CD11b/CD18 (Mo1) increases dramatically and expression of myeloperoxidase (MPO), a bacteriocidal enzyme, decreases markedly. Using the inducible promyelocytic cell line HL-60 as a model, we studied the mRNA expression of these genes. Differentiation of these cells along both a monocytic and a granulocytic pathway demonstrated that the mRNA levels of the two subunits of CD11b/CD18 increased in a pattern temporally and quantitatively similar to the increase in cell surface expression of this heterodimer. In contrast, the expression of MPO mRNA decreased in a temporal and quantitative pattern similar to the known decrease in MPO protein during differentiation, suggesting that regulation of these myeloid-specific proteins may occur at the level of mRNA expression. These findings have important implications with regard to the nature of the block in differentiation in acute nonlymphocytic leukemia and the regulation of myeloid gene expression.

Antigens, Differentiation↗
PubMed1988

Translocation and rearrangement of myeloperoxidase gene in acute promyelocytic leukemia.

Acute promyelocytic leukemia (subtype M3) is characterized by malignant promyelocytes exhibiting an abundance of abnormally large or aberrant primary granules. Myeloperoxidase (MPO) activity of these azurophilic granules, as assessed by cytochemical staining, is unusually intense. In addition, M3 is universally associated with a chromosomal translocation, t(15;17)(q22;q11.2). In this report, the MPO gene was localized to human chromosome 17 (q12-q21), the region of the breakpoint on chromosome 17 in the t(15;17), by somatic cell hybrid analysis and in situ chromosomal hybridization. By means of MPO complementary DNA clones for in situ hybridization and Southern blot analysis, the effect of this specific translocation on the MPO gene was examined. In all cases of M3 examined, MPO is translocated to chromosome 15. Genomic blot analyses indicate rearrangement of MPO in leukemia cells of two of four cases examined. These findings suggest that MPO may be pivotal in the pathogenesis of acute promyelocytic leukemia.

Bone Marrow↗
PubMed1987

cDNA cloning of human myeloperoxidase: decrease in myeloperoxidase mRNA upon induction of HL-60 cells.

Myeloperoxidase (MPO), the most abundant neutrophil protein, is a bacteriocidal component of the primary granules and a critical marker in distinguishing acute myelogenous leukemia from acute lymphoid leukemia. A cDNA clone for human MPO was isolated by immunologic screening of human hematopoietic lambda gt11 expression vector libraries with specific anti-MPO antibody. The identity of the cDNA clone was confirmed by finding that epitope-selected antibody against this clone recognizes purified MPO and MPO in human promyelocytic (HL-60) cell lysates by immunoblot analysis, and that hybrid selection of HL-60 mRNA with this cDNA clone and translation in vitro results in the synthesis of an 80-kDa protein recognized by the anti-MPO antiserum. RNA blot analysis with this MPO cDNA clone detects hybridization to two polyadenylylated transcripts of approximately 3.6 and approximately 2.9 kilobases in HL-60 cells. No hybridization is detected to human placenta mRNA. Upon induction of HL-60 cells to differentiate by incubation for 4 days with dimethyl sulfoxide, a drastic decrease in the hybridization intensity of these two bands is seen. This is consistent with previous data suggesting a decrease in MPO synthesis upon such induction of these cells. The MPO cDNA should be useful for further molecular and genetic characterization of MPO and its expression and biosynthesis in normal and leukemic granulocytic differentiation.

Cell Line↗
PubMed1984

Exact confidence intervals following a group sequential test.

A numerical method is used to compute confidence intervals, which have exact coverage probabilities, for the mean of a normal distribution following a group sequential test. This method, which uses an ordering of the sample space similar to that employed by Siegmund (1978, Biometrika 65, 341-349), is contrasted with the usual confidence interval for the mean.

Biometry↗
PubMedDate not supplied

Using units of CEM 43 degrees C T90, local hyperthermia thermal dose can be delivered as prescribed.

A randomized study was designed in dogs with spontaneous soft tissue sarcomas to gain information about the relationship between hyperthermia dose and outcome. The study compared two levels of thermal dose applied to dogs with heatable tumours, so it was necessary to deliver either a low (2-5 CEM 43 degrees C T90) or high (20-50 CEM 43 degrees C T90) thermal dose as precisely as possible. It was also desirable to have similar numbers of hyperthermia treatments in each thermal dose group. Identification of heatable tumours and randomization to high or low heat dose group was done during the first hyperthermia treatment. This was readily accomplished using mapping of temperatures in thermometry catheters, manual recording of thermal data, and visual inspection of raw thermal data with subsequent adjustment of the duration of the hyperthermia treatment. An analysis of precision of thermal dose delivery was conducted after approximately 50% of projected accrual had been met in a randomized phase III assessment of thermal dose effect. Fifty-four dogs were eligible for randomization; in 48 dogs the tumour was deemed heatable according to predetermined temperature criteria applied during the first heat treatment. Twenty-four dogs were randomized to the high heat dose group, and 24 to the low heat dose group. Median (range) total thermal dose for dogs in the high dose group was 43.5 CEM 43 degrees C T90 (16.4-66.6) compared to 3.2 CEM 43 degrees C T90 (2.1-4.6) for dogs in the low dose group. There was no overlap of thermal doses between groups. Thus, thermal dose could be delivered accurately, being within the predetermined range in 47 of the 48 dogs. Thermal dose quantified as CEM 43 degrees C T50, however, did overlap between groups and the clinical significance of this finding will not be known until outcome data are analysed. Most dogs in both groups received five hyperthermia treatments. Median (range) treatment duration for dogs in the high dose group was 300 min (147-692) compared to III min (51-381) for dogs in the low dose group. Relatively simple but accurate methods of delivering prescribed thermal dose as described herein will aid the translation of clinical hyperthermia from the research setting into more general practice once the characteristics of the relationship between hyperthermia dose and outcome are understood.

Animals↗
PubMedDate not supplied

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

Adult↗
PubMedDate not supplied

Phase III evaluation of doxorubicin and whole-body hyperthermia in dogs with lymphoma.

Sixty-one dogs with histologically confirmed, untreated, high-grade lymphoma were evaluated and treated with doxorubicin (DOX, 30 mg/m2) alone. Forty-seven dogs (77%) achieved a complete response. Forty-six of the 47 dogs were randomized to receive five additional treatments with doxorubicin +/- whole-body hyperthermia (WBH). Median disease-free survival for the group treated with DOX alone (n = 22) was 189 days and for the DOX plus WBH (n = 24) was 239 days (p = 0.17). After the analysis was adjusted for stratification variables (i.e. institution, weight, stage), the effect of heat on disease-free survival remained statistically insignificant (p = 0.10), but suggested a tendency towards increased disease-free survival in hyperthermic dogs. Intact male dogs had significantly shorter disease-free survival than neutered males and neutered females (178 days vs 266 days, respectively; p = 0.013). No intact females were treated. Body weight, when evaluated as a continuous variable, was found to be a negative prognostic factor (p = 0.036). Tumour volume, stage and institution were not significant. Clinical incidence of cardiac dysfunction was not increased in dogs receiving DOX and WBH; however, post-mortem histological analysis of cardiac tissue suggested that the combined therapy of DOX and WBH was associated with greater myocyte degeneration (p = 0.012) and a tendency for increased cardiac fibrosis (p = 0.08). We concluded that continued refinement of DOX-WBH protocols is warranted, and may ultimately result in significant therapeutic improvement.

Animals↗
PubMedDate not supplied

Estimation of cell survival in tumours heated to nonuniform temperature distributions.

UNLABELLED: A stochastic model describing the probability of cell survival as a function of thermal exposure was developed and fit to data arising from studies of CHO cell survival under hyperthermic conditions. This model characterizes the separate risks of temperature-induced cell death and induction of thermotolerance during heating. Tumour cells are assumed to be affected independently of each other by hyperthermia. Tumour geometry, perfusion and power deposition affect hyperthermia-induced temperature distributions in tumours, producing nonuniform temperatures. Two tumours may respond to hyperthermia slightly differently because of differences in tumour geometry, perfusion, power deposition, or by chance alone and the approach presented here incorporates chance and these other factors explicitly. THE RESULTS: (1) the time-temperature history is important for estimating tumour cell survival; (2) tumour temperature heterogeneity leaves more surviving cells at a given T90 temperature than would be expected if the entire tumour were uniformly heated to that same temperature; and (3) changes in the shape of the temperature distribution because of tumour geometry and perfusion distribution greatly influence cell survival between tumours, even when the standard temperature descriptors, such as T90, are fixed. The simulations also showed a modest effect on cell kill attributable to varying the lengths of the warm-up and the cool-down periods. These simulations indicate that these types of sensitivity studies can be used to investigate relationships between various modifiers of temperature distributions achieved when treating tumours with hyperthermia and to assess their potential therapeutic impact in clinical trials.

Animals↗
PubMedDate not supplied

The pharmacologic effects of recombinant, human colony-stimulating factors and their modulation by theophylline.

STUDY OBJECTIVES: To investigate the effect of colony-stimulating factors (CSFs) on drug metabolism using theophylline as a substrate (phase I), and to evaluate the influence of theophylline on endogenous serum cytokine concentrations (phase II). DESIGN: Open-label, prospective study. SETTING: The bone marrow transplant unit of a tertiary university teaching hospital. PATIENTS: Thirty-seven women with breast cancer (28 phase I, 9 phase II). INTERVENTIONS: Patients received aminophylline 0.58 mg/kg either as a 30-minute intravenous infusion before receiving recombinant CSFs or after several days of CSF therapy, just before high-dose chemotherapy (phase I) or as a continuous intravenous infusion after bone marrow transplantation (phase II). MEASUREMENTS AND MAIN RESULTS: Clearance of theophylline was significantly higher after CSF administration (0.76 vs 0.99 ml/min/kg, p = 0.019). Continuous infusion of aminophylline resulted in elevations of serum macrophage-CSF and interleukin 6. CONCLUSIONS: Administration of CSFs before autologous bone marrow transplantation for priming progenitor cells may alter drug metabolism. Studies should be conducted to evaluate the potential effects of CSFs on the disposition of chemotherapeutic agents.

Adult↗