Release of tumor cells from bone marrow.
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Blood Component Removal↗
Biomedical subjects
R B Jones
Publications and source records attributed to R B Jones.
Future strategies for the treatment of advanced epithelial ovarian cancer using high-dose chemotherapy and autologous bone marrow support.
The response and long-term disease-free survival rates with standard-dose salvage chemotherapy for advanced ovarian cancer are commonly reported to be less than 20 and 10%, respectively. More than 200 women with advanced, refractory, ovarian cancer have received high-dose chemotherapy regimens with autologous bone marrow support (ABMS) for their disease. A feature of the vast majority of the studies is the strikingly high response rates of 70-82% achieved when marrow-supported intensive therapy is administered to women with refractory ovarian cancer. Applying such high-dose therapy earlier in the disease course when the tumors are less resistant will likely produce durable antitumor effects. To further evaluate the effectiveness of high-dose therapy, the Southwest Oncology Group (SWOG) has initiated a phase II study for stage III/IV ovarian cancer with residual disease (microscopic up to 3 cm) following one cisplatin- or carboplatin-based induction regimen (SWOG 9106). Patients will be randomized to receive one of two high-dose regimens with ABMS: cyclophosphamide, cisplatin, and thiotepa or cyclophosphamide, carboplatin, and mitoxantrone. This initial trial is a feasibility study to evaluate whether such high-dose regimens can be given in a cooperative group setting to the ovarian cancer patient population. If the trial is successfully completed, one of the two regimens will be chosen (based on lesser toxicity) to use in a phase III randomized trial of high-dose therapy and ABMS versus standard therapy for high-risk ovarian cancer patients.
Antineoplastic Agents↗
Cyclophosphamide, cisplatin, and carmustine: pharmacokinetics of carmustine following multiple alkylating-agent interactions.
Cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) constitute a combination alkylating-agent regimen commonly used with autologous marrow support. Its therapeutic effectiveness is accompanied by sporadic life-threatening and fatal toxicities, the most common of which is acute lung injury. We have previously shown that variation in the BCNU AUC can be correlated to the risk of pulmonary injury in patients receiving CPA/cDDP/BCNU. In an attempt to understand further the role of interpatient variation in drug pharmacokinetics (PK) with respect to pharmacodynamic outcomes, we evaluated the effect of pretreatment with CPA, cDDP, or both on BCNU PK in male Sprague-Dawley rats. The drug-administration pattern was designed to mimic that of the CPA/cDDP/BCNU regimen in patients. Each pretreatment increased both the absolute value of and the variation in BCNU AUC relative to the control values. These findings are consistent with an important rate-limiting elimination pathway for BCNU in rats and may explain the wide interpatient variability of BCNU AUC and the sporadic pulmonary toxicity seen in patients receiving CPA/cDDP/BCNU.
Animals↗
Fear of humans in Japanese quail selected for low or high adrenocortical response.
Behavioral reactions to a nearby human were recorded in male Japanese quail of two lines selected for reduced (LS; low stress) or exaggerated (HS; high stress) plasma corticosterone (B) response to brief mechanical immobilization. Their adrenocortical responses to one of three treatments were then examined. These were: no human disturbance (undisturbed controls, CON), capture and return to the home cage before recapture and bleeding after 5 min (CR), or capture and manual restraint for 5 min before blood sampling (CREST). Quail of the HS line showed more fear-related behavior (crouching, escape) and avoidance of the experimenter than did their LS counterparts. Plasma B concentrations were markedly elevated following each capture treatment (CREST > CR) and the response appeared to be more pronounced in quail of the HS than the LS line. These findings indicate that HS quail perceived human contact to be more aversive than did those of the LS line. Avoidance scores and the adrenocortical responses to capture were positively correlated within individual birds. Therefore, simple behavioral tests of fear may have predictive value concerning physiological responsiveness to stressful stimulation.
Animals↗
Restraint, fear, and distress in Japanese quail genetically selected for long or short tonic immobility reactions.
Japanese quail genetically selected for long (LTI) rather than short (STI) tonic immobility reactions showed more pronounced overt fear-responses in a number of putatively frightening situations. Greater fear has also been found in Japanese quail selected, in an independent program, for exaggerated (HS, high stress) rather than reduced (LS, low stress) plasma corticosterone response to brief mechanical restraint. The present study examined tonic immobility (TI) and adrenocortical responses in male and female quail of the LTI, STI and CON (control) lines which had either remained undisturbed or had been briefly exposed to a mechanical restraint stressor similar to that used for selection of the HS and LS lines. Behavioral strategies during restraint differed across lines, i.e., struggling followed the pattern STI > CON > LTI. The LTI quail showed more pronounced TI reactions than did CON and STI birds. Mechanical restraint prolonged subsequent TI responses and markedly elevated plasma corticosterone concentrations in all lines, but there were no line x treatment interactions. The results are discussed in terms of the parallels between the four selected lines and of the likelihood that the independent selection programs may have affected the same intervening variable.
Animals↗
A prospective population based study of gender differential in mortality from cardiovascular disease and "all causes" in asymptomatic hyperglycaemics.
There have been few prospective epidemiological studies of asymptomatic hyperglycaemia as a risk factor for cardiovascular disease and all causes mortality in women. Gender-specific all causes, cardiovascular disease (CVD), ischaemic heart disease (IHD) and stroke mortality rates and relative risks for asymptomatic hyperglycaemics (top 5%) have been compared to normoglycaemics (bottom 95%) during a mean follow-up of 11.6 years (range 10-14) among 4696 men and 5714 women aged 45-64 at entry in the west of Scotland. Univariate analysis showed that asymptomatic hyperglycaemia was associated with increased risk of all causes, CVD, IHD and stroke mortality in both genders. The degree of this association was greater in women than in men. Using multiple logistic regression (MLR) analysis to take into account differences in age, systolic (SBP) and diastolic blood pressure (DBP), serum cholesterol, body mass index (BMI), and cigarette smoking, high causal blood glucose level was still a significant risk factor for CVD mortality in both genders. It was also a significant risk factor for all causes, IHD and stroke mortality in women but not in men. This study shows that to a lesser degree asymptomatic hyperglycaemia shows the same gender differentials in risk of mortality as have been demonstrated amongst known diabetics.
Cardiovascular Diseases↗
Transplantation of CD34+ hematopoietic progenitor cells.
Sixty-six stage IV breast cancer patients received high dose chemotherapy followed by autologous transplantation of CD34-positive(+) cells obtained from the bone marrow and/or granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood. Grafts were examined for the presence of tumor using conventional histology and immunocytochemical staining. Patients achieved a granulocyte count of 500 x 10(9)/liter 10-12 days posttransplant, with a platelet count of > 20 x 10(9)/liter in 14-15 days. Enrichment of CD34+ cells from the peripheral blood progenitor cell (PBPC) collections resulted in a 1.3 to 4.0 log depletion of breast cancer cells from the graft.
Antigens, CD↗
Clinical applications of filgrastim and stem cell factor in vivo and in vitro.
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Animals↗
Dissemination and commercialization of hematopoietic progenitor cell transplantation.
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Hematopoietic Stem Cell Transplantation↗
High-dose therapy with autologous bone marrow transplantation for the treatment of solid tumors.
Over the past decade, high-dose chemotherapy followed by autologous bone marrow support (ABMS) has been employed with increasing frequency to treat patients with a variety of solid tumors. This paper explores the rationale and relevant clinical data for the use of this approach to treat patients with breast and ovarian cancer for the solid tumors of which ABMS is most commonly employed.
Antineoplastic Combined Chemotherapy Protocols↗
Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: influence of CD34-positive peripheral-blood progenitors and growth factors on engraftment.
PURPOSE: To evaluate the capacity of enriched CD34-positive (CD34+) progenitor cells to reconstitute hematopoiesis in poor-prognosis breast cancer patients following administration of a high-dose alkylating agent chemotherapy regimen. PATIENTS AND METHODS: Forty-four breast cancer patients received high-dose chemotherapy followed by autologous bone marrow support (ABMS) with CD34+ hematopoietic progenitor cells in five sequentially treated cohorts. Following infusion of CD34+ marrow, cohort no. 1 received no growth factor, cohort no. 2 received granulocyte colony-stimulating factor (G-CSF), and cohort no. 3 received granulocyte-macrophage colony-stimulating factor (GM-CSF). Cohort no. 4 received the CD34+ fractions of both marrow and peripheral-blood progenitor cells (PBPCs) plus G-CSF. Cohort no. 5 received only the CD34+ PBPCs plus G-CSF. Immunohistochemical staining for breast cancer was performed on all hematopoietic cell products before and after the positive selection procedure, to assess quantitatively the level of tumor-cell contamination. RESULTS: Cohorts no. 1, 2, 3, 4, and 5 achieved a granulocyte count > or = 500 x 10(9)/L in a median of 23, 10, 16, 11, and 11 days, with a platelet count greater than 20,000 x 10(9)/L documented in a median of 22, 23, 32, 12, and 10 days, respectively. The time to granulocyte reconstitution was significantly shorter for patients who received CD34+ PBPCs alone (cohort no. 5), or in combination with CD34+ marrow (cohort no. 4), when compared with those who received only the CD34+ marrow fraction (P < .01). From 1 to greater than 4 logs of breast cancer cell depletion were documented after CD34-selection, for patients in whom tumor was initially detected. CONCLUSION: CD34+ marrow and/or PBPCs provide reliable and timely hematopoietic reconstitution in breast cancer patients receiving high-dose chemotherapy. Contamination of both marrow and PBPCs with breast cancer cells was reduced using this positive selection technique.
Adult↗
Effects of ascorbyl-2-polyphosphate on adrenocortical activation and fear-related behavior in broiler chickens.
The effects of supplemental ascorbyl-2-polyphosphate (APP) on adrenocortical function and underlying fearfulness in broiler chickens were assessed in a number of test situations. Chicks pretreated for a minimum of 24 h with APP (1,000 ppm equivalents of L-ascorbic acid) in their drinking water or with no APP (tap water controls; CON) had blood samples taken immediately following water treatment and again after exposure to a capture and cooping stressor for 10 min. First, although the cooping stressor markedly increased plasma corticosterone concentrations, pretreatment with APP failed to attenuate this adrenocortical response. Second, APP-treated chicks showed less freezing and vocalized sooner in an open field (novel environment) than did controls. They also showed nonsignificant tendencies toward accelerated and enhanced ambulation. Third, supplementation with APP reduced the duration of the birds' tonic immobility fear reactions. Collectively, these behavioral effects are indicative of dampened fear. The apparent reduction of nonspecific, underlying fearfulness by APP treatment may have important implications for poultry welfare and performance.
Animals↗
Effect of age and presence of perches during rearing on tonic immobility fear reactions of broiler breeder pullets.
Broiler breeders were housed in pens in an all-litter house with an 8-h photoperiod from hatching to 20 wk of age. They were reared either in the presence or absence of perches (7 cm per bird) and on either a 14% or a 17% CP diet. The duration of the tonic immobility (TI) fear response was measured in 15- and in 20-wk-old birds; each pullet was tested individually and once only. There was an apparent age-related increase in the duration of TI, which was attenuated by the provision of perches during rearing. The results are discussed in terms of maturational and environmental influences on the development and alleviation of fear.
Age Factors↗
White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support.
PURPOSE: To study MR changes in the white matter of the brain in patients with breast cancer treated with a widely used protocol of high-dose chemotherapy and autologous bone marrow support. METHODS: Thirteen patients with high-risk stage II or stage IV breast cancer treated with high-dose cyclophosphamide, cisplatin, carmustine, and bone marrow support underwent posttransplant MR examination of the brain. Serial posttransplant MR examinations were performed in 5 of the 13 patients and single MR examinations in 8. The severity of the white matter change was evaluated by two neuroradiologists and rated mild, moderate, or severe. RESULTS: In 9 of the 13 patients, central and peripheral cerebral white matter changes were observed. Four patients had severe changes, extending from the ependyma of the lateral ventricles to the gyri. An additional 4 patients had moderate white matter change at the last observation. One had mild change, and 4 had no white matter change. In all patients, there was sparing of inferior frontal, posterior inferior occipital, and anterior temporal lobes, and of the centrosylvian brain. CONCLUSIONS: White matter change occurred in patients treated with a high-dose chemotherapy and bone marrow support protocol. Most of the changes, and the more severe ones, occurred 5 or more months after the transplants. There was no apparent relationship between these changes and central nervous system function. Because of the increased longevity with this treatment, it is important to appreciate these white matter changes, recognizing however that their expression may be subclinical.
Adult↗
Diabetic care in general practice.
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Diabetes Mellitus↗
Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine.
BACKGROUND: Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. PURPOSE: The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. METHODS: We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. RESULTS: Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. CONCLUSIONS: These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. IMPLICATIONS: Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.
Acute Disease↗
Multicenter trial of fleroxacin versus ceftriaxone in the treatment of uncomplicated gonorrhea.
In a multicenter, randomized, open, comparative trial, patients with uncomplicated gonorrhea were treated with 400 mg of oral fleroxacin or 250 mg of intramuscular ceftriaxone. A total of 458 men and 447 women were enrolled. Of these, 312 men (68%) and 245 women (55%) were evaluable for efficacy. The treatment groups were demographically similar. Among evaluable men, fleroxacin eradicated 154 of 155 (99%; 95% confidence interval [CI]: 98.1-100%) urethral and 2 of 2 pharyngeal infections, while ceftriaxone eradicated 156 of 156 (95% CI: 99.4-100%) urethral and 5 of 5 pharyngeal infections. Among evaluable women, fleroxacin eradicated 127 of 128 (99%; 95% CI: 97.7-100%) cervical, 20 of 20 anorectal, 16 of 16 urethral, and 7 of 7 pharyngeal infections, while ceftriaxone eradicated 108 of 108 (95% CI: 99.1-100%) cervical, 24 of 24 anorectal, 25 of 25 urethral, and 9 of 9 pharyngeal infections. Adverse events were reported by 68 (16%) of 426 subjects in the fleroxacin group and 20 (5%) of 380 in the ceftriaxone group (p < 0.0001). The most common adverse events reported by the patients who received fleroxacin were nausea (5%), headache (3%), and vaginitis (3%). One patient had severe vomiting, 19 participants had adverse reactions classified as moderate, and 48 patients had mild adverse reactions. Fleroxacin was highly effective in the treatment of uncomplicated gonorrhea and represents an oral alternative to ceftriaxone. Adverse events were more common with fleroxacin than with ceftriaxone.
Administration, Oral↗
Laser mass spectrometry of oligonucleotides with isomer matrices.
Various isomer matrices were used for laser-desorption ionization of mixtures of oligomers. It was found that the efficiency of production of oligomer ions changed drastically when different isomers were used as matrices. For selected matrix materials, parent oligomer ions with sizes up to 64 bases were observed.
Base Sequence↗